Introduction: Despite the importance of pharmacokinetic (PK) information for patient management there are low numbers of paediatric PK studies and little guidance available on optimum study design and conduct. Method: Drawing on Implementation Science, a mixed-methods study was conducted, including a scoping review (SR) (PK literature: 1990-2015) and quantitative and qualitative inquiry (stakeholders: lay population, service users and health-care professionals). Aim: to explore the feasibility and acceptability of paediatric PK research. Results: The SR (203 papers) highlighted significant problems with participant recruitment, retention and sampling. Stakeholders (n=240) added insight into these phenomenon, with lack of research staff, additional blood-sampling and appointments highlighted as significant barriers to recruitment and conduct. Facilitators included sensitivity and timeliness of approach, communication, involvement of child/young person (CYP) in decision-making, engagement between research and clinical teams, reassurance of safety, pain minimisation, and avoidance/reduction of burden to the CYP and family. Dedicated research support was viewed as critical to success. Discussion: PK research was viewed as feasible and acceptable by service users and health professionals, even in the context of critical illness. Novel, evidence-based, patient-centred, recommendations for future PK study conduct and design have been generated which are applicable for those designing, approving and implementing PK research.

Infancy is a time of rapid physiological (e.g. anthropometric, immunological and neurological) development. Hence, during this period of life nutritional requirements are at their highest in relation to body mass. There is a paucity of data with respect to the nutritional quality of complementary foods manufactured in the UK for infants and young children. The primary objective of this study was to examine the nutritional value of ‘ready to feed‘ complementary infant foods on the UK market in order to ascertain their suitability, relative to dietary guidelines, for the target group. Quantitative analysis was conducted on eight different products representing four popular commercial brands (meat and vegetable based) currently on sale in the UK for infants aged between 6-12 months. The chemical analyses conducted included Kjeldhal for protein, acid hydrolysis and extraction for fat, phenol sulphuric acid for carbohydrate and AOAC 985.29 for fibre. The results of these studies were referenced to the Recommended Nutrient Intake (RNI) values for 6 to 9 months old children, and a listing of the entire daily intake of nutrients was composed taking into consideration the nutrient and energy intake from milk consumption in order to (1) accurately estimate the daily intake of these nutrients derived from commercial infant food consumption, and (2) ascertain their nutritional suitability relative to dietary guidelines for the 6-9 month age group. The only significant difference found between different product varieties (meat and vegetable-based) was with respect to the protein content (p = 0.04) per 100 g of food. The experimentally determined concentrations of macronutrients (g/100 kcal) were compared to the declared values provided by the manufacturers on the product labels and, despite some variations, the values obtained comply with regulatory requirements (Commission Directive 2006/125/EC). The total daily intake of fat (27.0 g/day), based on the menu composed from commercial complementary food, is suggested to exceed the Dietary Reference Values (DRVs) for fat (31%), if the intake of snacks and desserts are incorporated. The aforementioned results imply that the formulations of the recipes, based on a standard commercial menu, are of significant importance in relation to the nutritional quality of the diet of infants. In terms of elemental analysis, the concentrations of up to twenty (essential and non-essential) elements in a selected range of sixteen different products representing meat, poultry, fish and vegetable base varieties were established by ICP-OES and ICP-MS. Six major essential elements, namely: calcium, iron, magnesium, potassium, sodium and zinc were measured by ICP-OES. The concentrations of six essential trace elements (selenium, molybdenum, cobalt, copper, chromium, manganese) and eight non-essential, potentially toxic, elements (arsenic, barium, nickel, cadmium, antimony, lead, mercury, aluminium) in chicken and fish-based varieties were determined by ICP-MS due to the higher sensitivity required. Based on the results of elemental analysis, there was also some evidence of a lack of attention to micro-nutrient interactions in food. With reference to the guidelines, the RNI values for 6 to 9 month olds, all samples provided less than 20% of RNI values except for potassium (20%). In terms of the risk of exposure to toxicity, the concentration of non-essential elements in ready to feed products analysed were not considered to be of concern. With regard to the analyses of vitamins, a novel assay for the simultaneous quantitative determination of riboflavin (B2) and pyridoxine (B6) has been developed. The method involves a mild hydrolysis step, extraction of the supernatant by centrifugation followed by quantitative analysis using UHPLC. Separation of the two water soluble vitamins achieved is excellent and rapid - within one minute whilst the resultant sample is also LC-MS compatible. With respect to vitamin B analyses, despite wide individual differences between brands (p = 6.5e-12), no significant differences were observed in the levels of vitamin B6 between the meat and vegetable-based varieties (p = 0.7) per 100 g of commercial infant food. Vitamin B2 was not detected in any of the samples, where the detection limit was below 0.07μg/mL. In terms of the RNI of vitamin B6 for 6 - 9 month old infants, the complementary infant meal products analysed herein provided less than 15% of the RNI values with mean (SD) values of 12.87 (±4.46) % and 13.88 (±4.97) % for the meat- and vegetable-based recipes, respectively. The estimated total daily intake of vitamins B2 and B6 from the consumption of commercial complementary food was found to be satisfactory and in accordance with the DRVs. The intake of both vitamin B2 and B6 was estimated to be mainly derived from the consumption of formula milk which could be a cause of concern if the quality of an infant‘s milk diet is compromised by an inadequate or lack of supplemented milk intake. All the foregoing results suggest that commercial complementary infant foods on the UK market may not contain minimum levels of micronutrients required for labelling declaration of micronutrient content (Commission Directive 2006/125/EC). An attempt, therefore, was made to optimise the formulated version of the meat based infant food as a baseline and measure the post-process retention of its nutrient content after being subjected to different processing condition in terms of a combination of temperature and time. This was achieved by quantitative analysis of the post-process values of the nutrients in the optimised formula using the aforementioned analytical techniques. The results of this study indicates that careful formulation of the recipes, in the context of new product development, is important; the selection of high quality ingredients and the ratios in which they are used have a direct effect on the nutrient content of the final product. It also indicates that a carefully controlled temperature-time combination, pH, pressure and macroscopic conditions of processing (e.g. controlled leaching) are very important in reducing heat loss and improving the nutritional quality of the food product. This provides opportunities and scope for product optimisation, of ready to eat to eat infant foods, in order to improve their nutritional value.

Mestre -- Escola Nacional de Saude Publica, Rio de Janeiro, 2000.

Mestre -- Escola Nacional de Saude Publica, Rio de Janeiro, 2003.

Mestre -- Escola Nacional de Saude Publica, Rio de Janeiro, 2004.

Congenital heart disease (CHD) is the most common birth defect, causing an important rate of morbidity and mortality. Treatment of CHD requires surgical correction in a significant percentage of cases which exposes patients to cardiac and end organ injury. Cardiac surgical procedures often require the utilisation of cardiopulmonary bypass (CPB), a system that replaces heart and lungs function by diverting circulation into an external circuit. The use of CPB can initiate potent inflammatory responses, in addition a proportion of procedures require a period of aortic cross clamp during which the heart is rendered ischaemic and is exposed to injury. High O2 concentrations are used during cardiac procedures and when circulation is re-established to the heart which had adjusted metabolically to ischaemia, further injury is caused in a process known as ischaemic reperfusion injury (IRI). Several strategies are in place in order to protect the heart during surgery, however injury is still caused, having detrimental effects in patients at short and long term. Remote ischaemic preconditioning (RIPC) is a technique proposed as a potential cardioprotective measure. It consists of exposing a remote tissue bed to brief episodes of ischaemia prior to surgery in order to activate protective pathways that would act during CPB, ischaemia and reperfusion. This study aimed to assess RIPC in paediatric patients requiring CHD surgical correction with a translational approach, integrating clinical outcome, marker analysis, cardiac function parameters and molecular mechanisms within the cardiac tissue. A prospective, single blinded, randomized, controlled trial was conducted applying a RIPC protocol to randomised patients through episodes of limb ischaemia on the day before surgery which was repeated right before the surgery started, after anaesthesia induction. Blood samples were obtained before surgery and at three post-operative time points from venous lines, additional pre and post-bypass blood samples were obtained from the right atrium. Myocardial tissue was resected during the ischaemic period of surgery. Echocardiographic images were obtained before the surgery started after anaesthetic induction and the day after surgery, images were stored for later off line analysis. PICU surveillance data was collected including ventilation parameters, inotrope use, standard laboratory analysis and six hourly blood gas analysis. Pre and post-operative quantitation of markers in blood specimens included cardiac troponin I (cTnI) and B-type natriuretic peptide (BNP), inflammatory mediators including interleukins IL-6, IL-8, IL-10, tumour necrosis factor (TNF-α), and the adhesion molecules ICAM-1 and VCAM-1; the renal marker Cystatin C and the cardiovascular markers asymmetric dymethylarginine (ADMA) and symmetric dymethylarginine (SDMA). Nitric oxide (NO) metabolites and cyclic guanosine monophosphate (cGMP) were measured before and after bypass. Myocardial tissue was processed at baseline and after incubation at hyperoxic concentration during four hours in order to mimic surgical conditions. Expression of genes involved in IRI and RIPC pathways was analysed including heat shock proteins (HSPs), toll like receptors (TLRs), transcription factors nuclear factor κ-B (NF- κ-B) and hypoxia inducible factor 1 (HIF-1). The participation of hydrogen sulfide enzymatic genes, apelin and its receptor were explored. There was no significant difference according to group allocation in any of the echocardiographic parameters. There was a tendency for higher cTnI values and inotropic score in control patients post-operatively, however this was not statistically significant. BNP presented no significant difference according to group allocation. Inflammatory parameters tended to be higher in the control group, however only TNF- α was significantly higher. There was no difference in levels of Cystatin C, NO metabolites, cGMP, ADMA or SDMA. RIPC patients required shorter PICU stay, all other clinical and laboratory analysis presented no difference related to the intervention. Gene expression analysis revealed interesting patterns before and after incubation. HSP-60 presented a lower expression at baseline in tissue corresponding to RIPC patients, no other differences were found. This study provided with valuable descriptive information on previously known and newly explored parameters in the study population. Demographic characteristics and the presence of cyanosis before surgery influenced patterns of activity in several parameters, numerous indicators were linked to the degree of injury suffered by the myocardium. RIPC did not reduce markers of cardiac injury or improved echocardiographic parameters and it did not have an effect on end organ function; some effects were seen in inflammatory responses and gene expression analysis. Nevertheless, an important clinical outcome indicator, PICU length of stay was reduced suggesting benefit from the intervention. Larger studies with more statistical power could determine if the tendency of lower injury and inflammatory markers linked to RIPC is real. The present results mostly support findings of larger multicentre trials which have reported no cardiac benefit from RIPC in paediatric cardiac surgery.

No description available.

No description available.

Chest physiotherapy is integral to the management of mechanically ventilated children and previous research has confirmed that chest wall vibrations are the manual techniques used most frequently by physiotherapists in this population. Chest wall vibrations involve the application of a compressive force to the chest during expiration, with the aim of removing accumulated secretions and improving lung aeration. However, these techniques are largely unquantified and may vary greatly between practitioners and clinical units, with any significance of such variability remaining unknown. In order to evaluate the effectiveness of any therapy it is important to have a means of quantifying the treatment. It is challenging to measure techniques which involve manual contact between the therapist and patient, and at the inception of this project no means existed of directly measuring the force applied through the hand during treatments. The effectiveness of chest physiotherapy in mechanically ventilated patients is likely to be influenced by the interactions between different treatment components, such as the magnitude and pattern of the chest wall vibrations and the accompanying lung inflations. It is therefore essential to assess both the forces applied during the vibrations with the simultaneous changes in air flow, recording the ventilatory pattern throughout the treatment. The study hypotheses were: 1. It is possible to create a technique to measure chest wall vibration forces during clinical treatments, and to relate such forces to simultaneous changes in respiratory flows, volumes and pressures 2. Maximum and mean force applied during chest wall vibrations increase with the size and age of the child 3. Manual lung hyperinflations with chest wall vibrations result in an increase in peak expiratory flow above that observed during baseline mechanical ventilation 4. After adjusting for inflation volume, application of chest wall vibrations result in an increase in peak expiratory flow above that obtained during manual lung inflations alone The primary objectives of this research were to: 1. Develop a method of quantifying chest wall vibration forces and a means of evaluating simultaneous changes in force with those of respiratory flow and pressure in ventilated infants and children of all ages 2. Estimate the variability over time, within and between individual physiotherapists when treating the same and different subjects with chest wall vibrations 3. Conduct a study to: i) Assess the feasibility of measuring force and respiration in a population of critically ill, mechanically ventilated children ii) Characterise the magnitude and pattern of forces applied during chest wall vibrations and evaluate the direct effects of these manoeuvres on flow and pressure changes in the lungs iii) Determine the relative contribution of manual lung inflations and chest wall vibrations to any observed increase in expiratory airflow A secondary objective was to explore the short term effects of chest physiotherapy, by recording changes in ventilation, respiratory system mechanics and blood gases following treatment. The thesis comprises four chapters: Chapter 1 contains a comprehensive literature review of published studies demonstrating the current knowledge base of the respiratory problems of mechanical ventilation in children, chest physiotherapy in intensive care and the relationship of chest physiotherapy to normal mechanisms of airway clearance. Chapter 2 describes the process of creating a dynamic force-sensing technique to characterise manual chest physiotherapy, detailing protocol and analysis refinement during pilot force and respiratory data collection. Assessment of the variability within and between physiotherapists is also assessed. Chapter 3 details a clinical study undertaken in intensive care units at Great Ormond Street Hospital for Children NHS Trust, London. The results are presented and interpreted. Chapter 4 discusses the findings of the thesis in relation to earlier research, highlights the strengths and limitations of the current study, interprets the clinical implications of the research and suggests future work.

This thesis explores the appropriateness of suitably trained children's nurses undertaking the pre-operative assessment of children prior to day case and minor surgery. The central focus of the study is a 60 subject hypothesis refining randomised controlled trial (RCT), comparing the pre-operative assessment of children carried out by suitably trained nurses with the assessment carried out by senior house officers (SHO's). Findings demonstrate significantly greater accuracy by nurses in the detection of abnormalities in children's history, when compared with the SHO's. No significant difference is demonstrated between the performance of nurses and SHO's in detecting abnormalities within the physical examination, or in the correct identification of children who have no detectable abnormalities. However, these findings of 'no significant difference' must be substantiated within a larger equivalence trial before assurances can be given that paediatric pre-operative assessment might safely be transferred from SHO's to nurses. Supplementary data explores the perspectives of parents and practitioners with regard to children's nurses undertaking a pre-operative assessment role. The views of parents, gathered via questionnaires, are supportive of the initiative. The views of nurses and SHO's involved in the RCT are similarly supportive, although the conduct of in-depth interviews with the nurses also reveals insights into their perceived vulnerability when carrying out such expanded roles. The views of anaesthetists are less positive, and convey a reluctance to accept nurses carrying out the pre-operative assessment of children. Finally, a national survey explores the views of nurses and SHO's involved in paediatric pre-operative assessment, revealing that nurses attribute significantly greater importance and enjoyment to the pre-operative assessment role when compared with SHO's. This factor may in part explain the greater accuracy demonstrated by nurses in the RCT, but such speculation must be substantiated by further enquiry. This study contributes to the nursing literature in offering what is thought to be the first systematic UK exploration of the role of the paediatric nurse within pre-operative assessment. It is also the first study, as far as the author is aware, to demonstrate significantly greater accuracy in history taking by nurses when compared with doctors, in a paediatric specific UK study. It therefore makes a meaningful contribution to both the paediatric and expanded role evidence bases. It also offers systematically informed hypothesis generation to underpin the ongoing exploration of an expanded nursing role within paediatric pre-operative assessment.