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How do we organize smooth, effective transfer from paediatric to adult diabetes care?

Transition from paediatric to adult care is a major milestone in the life of a young person with diabetes, yet it is commonly poorly done. This finding is supported by the dearth of publications in the literature that particularly relate to transition in diabetes care. Other transitions occur at this time of life, for example: from parental supervision to growing independence and from secondary school to post-school options. Health professionals know, from anecdotal evidence, that this is the period when young people with diabetes 'drop out' of the system. They often have no specialist follow-up and attend only the primary care physician for insulin prescriptions. Then, inevitably, a problem occurs that cannot be managed by the family doctor, such as diabetic ketoacidosis or pregnancy, and the patient is finally referred to an adult unit. There are many contributing factors to poor transition but two major reasons are that members of this age group are classic non-attenders and, importantly, they have not been well prepared for the transition. Preparation is the key to success and this must include parents as well as the young person. Components of transition preparation include: self-advocacy, independent health care behaviours, sexual health, psychosocial support, education and vocational planning, and health and lifestyle (drugs, alcohol, etc.). Considerable differences exist between many of the paediatric and adult services, and this cultural shift has significant impact on the success or otherwise of transition. Paediatric care is often multidisciplinary, family focused, prescriptive and requires parental direction and consent. Adult care is often provided by a single doctor, is patient focused, more investigational and requires autonomous, independent skills on the part of the user. Young people and their families, unless well prepared, become confused and disillusioned with the adult system. To avoid this situation, there is a variety of solutions, including adolescent transition clinics attended by both paediatric and adult teams, a transition coordinator who is responsible for making the transfer as smooth as possible, etc. Unfortunately, the very nature of the group in question means that none of these solutions is perfect. In reality, transition is a process that takes place over a number of years and should not be considered an event. The transition process needs to begin in early adolescence, to foster independence and communication skills, and to incorporate health education.

Aging↗

Management of anticoagulation and its reversal during paediatric cardiopulmonary bypass: a review of current UK practice.

Protocols for management of heparin and protamine administration in patients undergoing open-heart surgery have been developed from experience gained mainly in adult practice. However, it has been demonstrated that there are marked differences between paediatric and adult patients in their response to systemic anticoagulation and its reversal. The aim of this study was to obtain an overview of current practice of management of anticoagulation and its reversal from paediatric cardiac surgical units of Great Britain and Ireland. All centres performing paediatric cardiac surgery agreed to participate in the survey (n = 16). Telephone interviews were carried out with the chief or a senior perfusionist from all participating institutions, which were based on a structured questionnaire compiled specifically for the purpose. The answers were anonymised. At present, in the UK and Ireland, unfractionated heparin is the anticoagulant of choice in all units, with a slight prevalence of porcine mucosal (9/16, 56.5%) versus bovine lung preparation (7/16, 44.0%). The policy for administration of heparin to the patient is uniform, with a dose of 300 IU/kg. However, there is great variability in the amount of heparin added to the prime and to the volume infused during cardiopulmonary bypass (CPB). Monitoring of anticoagulation is achieved by activated coagulation time alone in all but one centre, with lower limits varying between 400 and 750 s. Use of aprotinin is widely accepted, but clinical indications are highly variable. No centre adopts heparin-bonded or heparin-coated circuitry for CPB. Calculation of initial and additional protamine doses followed a variety of criteria, resulting in a very wide distribution of doses. The data obtained highlighted the lack of uniformity among paediatric cardiac surgical units of Great Britain and Ireland with regard to most of the issues related to the management of anticoagulation and its reversal. The striking heterogeneity of our cross-sectional observations clearly underlines the need for prospective, multicentre studies on a national basis to relate different clinical practices to outcome measures.

Adolescent↗

Neutrophil activation during cardiopulmonary bypass in paediatric and adult patients.

It has been reported that the 'systemic inflammatory' response occurring during cardiopulmonary bypass (CPB) may be responsible for postoperative complications. This inflammatory response is triggered by the platelet coagulation system, complement activation, resulting in neutrophil activation and degranulation. The aim of this study was to quantify the specific markers of neutrophil activation in the adult and paediatric patient during CPB. We report that neutrophil myeloperoxidase (MPO) and human neutrophil elastase (HNE) are significantly increased in both the paediatric and adult patients. This study utilized enzymatic assays that quantified the enzymatic activity in the blood circulation rather than measurement of the enzyme protein complex. Increased concentrations of MPO were, in part, related to the blood prime with the paediatric patients and the HNE concentrations were related to time on CPB in both the paediatric and adult patient. This study demonstrated that there are significantly elevated neutrophil enzyme activities in the CPB patient and underscores the pivotal role of the neutrophil in the pathophysiology of CPB.

Adult↗

Haemocompatibility of paediatric membrane oxygenators with heparin-coated surfaces.

Extracorporeal circulation (ECC) in paediatric patients with heparin-coated oxygenation systems is rarely investigated. The objective of this study was to evaluate, preclinically, the haemocompatibility of paediatric membrane oxygenators with heparin-coated surfaces. We compared 16 paediatric membrane oxygenators (Minimax, Medtronic) in an in vitro heart-lung machine model with fresh human blood. Eight of these oxygenation systems had a covalent heparin coating (Carmeda bioactive surface). After 90 min simulated ECC, the heparin-coated systems showed significantly higher platelet count, lower platelet-factor 4 release, reduced contact activation (factor XIIa and kallikrein), and lower neutrophil elastase levels (p < 0.05), compared to the noncoated oxygenator group. More biocompatible materials for paediatric operations may ameliorate the various postperfusion syndromes arising from ECC procedures, particularly unspecific inflammation, hyperfibrinolysis and blood loss.

Biocompatible Materials↗

How much paediatric HIV infection could be prevented by antenatal HIV testing?

OBJECTIVE: To estimate the reduction in the number of children infected with HIV that might be achieved by extending the provision of voluntary antenatal HIV testing. This effect would be mediated by increased numbers of women infected with HIV who receive an intervention to reduce the risk of vertical transmission (for example, zidovudine or caesarean section delivery), who use an alternative to breast feeding, or whose pregnancy is terminated. SETTING: London, United Kingdom. METHODS: Relevant data were derived from neonatal seroprevalence studies, obstetric and paediatric reporting schemes, and review of external information. Sensitivity analyses were performed for certain parameters. RESULTS: Of 106,000 births annually in London, an estimated 169 are to women infected with HIV whose infection is not currently recognised before pregnancy. An estimated 28-33 children born to these women will be infected. Precise prediction of the number of paediatric HIV infections that could be prevented is difficult because of uncertainty in certain factors, particularly the uptake of antenatal testing and the efficacy and acceptability of interventions to reduce prenatal or perinatal transmission. If a testing programme detected 70% of infected women, none of whom opted for a termination but all of whom exclusively bottle fed and received an intervention which halved the risk of transmission, about 12-16 (42-46%) paediatric HIV infections would be prevented annually. CONCLUSIONS: The estimated cost of preventing each paediatric infection is high, but this should be seen in the context of the lifetime health and social care costs for a child infected with HIV. The feasibility of selective testing should be considered when formulating policies on antenatal HIV testing. Programmes that are introduced should be audited to obtain better estimates of costs and benefits.

Bottle Feeding↗

Can generic paediatric mortality scores calculated 4 hours after admission be used as inclusion criteria for clinical trials?

INTRODUCTION: Two generic paediatric mortality scoring systems have been validated in the paediatric intensive care unit (PICU). Paediatric RISk of Mortality (PRISM) requires an observation period of 24 hours, and PRISM III measures severity at two time points (at 12 hours and 24 hours) after admission, which represents a limitation for clinical trials that require earlier inclusion. The Paediatric Index of Mortality (PIM) is calculated 1 hour after admission but does not take into account the stabilization period following admission. To avoid these limitations, we chose to conduct assessments 4 hours after PICU admission. The aim of the present study was to validate PRISM, PRISM III and PIM at the time points for which they were developed, and to compare their accuracy in predicting mortality at those times with their accuracy at 4 hours. METHODS: All children admitted from June 1998 to May 2000 in one tertiary PICU were prospectively included. Data were collected to generate scores and predictions using PRISM, PRISM III and PIM. RESULTS: There were 802 consecutive admissions with 80 deaths. For the time points for which the scores were developed, observed and predicted mortality rates were significantly different for the three scores (P < 0.01) whereas all exhibited good discrimination (area under the receiver operating characteristic curve >or=0.83). At 4 hours after admission only the PIM had good calibration (P = 0.44), but all three scores exhibited good discrimination (area under the receiver operating characteristic curve >or=0.82). CONCLUSIONS: Among the three scores calculated at 4 hours after admission, all had good discriminatory capacity but only the PIM score was well calibrated. Further studies are required before the PIM score at 4 hours can be used as an inclusion criterion in clinical trials.

Adolescent↗

Thromboembolism in paediatric lupus patients.

Paediatric patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL), specifically lupus anticoagulants (LAC) are at high risk of developing thromboembolic events (TE). Our objectives were to determine the prevalence of TE in paediatric SLE patients with LAC and to determine if anticoagulation was effective to decrease morbidity, and prevent recurrent TE. We reviewed data on 149 paediatric SLE patients treated over 10 years. In all, 24 patients (16%) were LAC positive, and 21 TE occurred in 13 of these LAC positive patients (54% incidence of TE in LAC positive patients). The events were cerebral venous thrombosis (9), arterial stroke (3), deep venous thrombosis (4), pulmonary embolism (2), other venous event (1) and other arterial events (2). The median duration between SLE diagnosis and first TE was 15.2 months (range 0-62), and the median age at first TE was 15.1 years (range 11.4-18.4). Long-term anticoagulation was prescribed, and eight patients (62%) were transferred to adult care on lifelong oral warfarin; four (31%) remain under our care on lifelong warfarin, and one patient died of causes unrelated to her TE. No patient has been identified with deficiencies of protein C, protein S or antithrombin III. One patient is heterozygous for Factor V Leiden, and one is heterozygous for both the Prothrombin 20210A mutation and the MTHFR (methylene tetrahydrofolate reductase) mutation. Four patients had recurrent TE (31%), and three were not anticoagulated at the time of their second event. One patient had two recurrences on therapeutic anticoagulation. Thromboembolic events are prevalent in the LAC positive paediatric SLE population, and consideration for lifelong anticoagulation must occur after an initial TE.

Adolescent↗

Pressure area care in infants and children: Nimbus Paediatric System.

Survival rates in both critically and chronically ill infants and children have improved dramatically in recent years and new challenges exist in the nursing care given to these patients. Among these is the increased risk of pressure ulcer development. Children in intensive care environments are especially at risk. Prevention and management of pressure ulceration in the paediatric population requires clinical judgement and skill. The use of pressure ulcer risk assessment tools can assist in this process; however, to date, there is a lack of research evidence and further studies are needed. The pressure relief requirements of the paediatric patient are significantly different to those of the adult patient. In children under the age of 36 months, the ears and occiput are the areas most at risk of pressure injury as a result of the fact that this area is proportionately the largest and heaviest bony prominence. Despite the abundance of specialist pressure redistributing devices for adults, there is little available specifically for the paediatric patient. This article describes a review of the literature on these subject areas and follows with a short report of the evaluation of the new Paediatric Nimbus System undertaken at the Royal Hospital for Sick Children in Edinburgh.

Age Distribution↗

Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations.

In children, the therapeutic benefits and potential risks associated with drug treatment may be different from those in adults and will depend on the exposure, receptor sensitivity and relationship between effect and exposure. In this paper, key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the paediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, secretion and activity of bile and pancreatic fluid, bacterial colonisation and transporters, such as P-glycoprotein (P-gp), are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the paediatric population and adults are organ size, membrane permeability, plasma protein concentration and characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and transporters such as P-gp, which is present not only in the gut, but also in liver, kidney, brain and other tissues. As far as drug metabolism is concerned, important differences have been found in the paediatric population compared with adults both for phase I enzymes (oxidative [e.g., cytochrome P450 (CYP)1A2, and CYP3A7 versus -3A4], reductive and hydrolytic enzymes) and phase II enzymes (e.g., N-methyltransferases and glucuronosyltransferases). Generally, the major enzyme differences observed in comparison with the adult age are in newborn infants, although for some enzymes (e.g., glucuronosyltransferases and other phase II enzymes) important differences still exist between infants and toddlers and adults. Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the paediatric population compared with adults are glomerular filtration and tubular secretion. The ranking of the key factors varies according to the chemical structure and physicochemical properties of the drug examined, as well as to the characteristics of its formulation. It would be important to generate additional information on the developmental aspects of renal P-gp and of other renal transporters, as has been done and is still being done with the different -isozymes involved in drug metabolism.

Adult↗

Factors influencing cure by transsphenoidal selective adenomectomy in paediatric Cushing's disease.

OBJECTIVE: Early diagnosis and effective treatment of paediatric Cushing's disease (CD) is necessary to minimise associated morbidity. Accepted first-line treatment is selective transsphenoidal microadenomectomy (TSS), which can be technically difficult, and cure rates vary considerably between centres. In our paediatric CD patient group we have assessed the possible factors which may influence cure by TSS. SUBJECTS AND METHODS: From 1983-2004, 27 paediatric patients (16 males, 11 females; mean age+/-s.d., 13.1+/-3.2 yr; range, 6.4-17.8 yr) with CD were managed in our centre and underwent TSS. Sixteen patients (59%), seven males and nine females (mean age+/-s.d., 14.2+/-2.5 yr; range, 8.2-17.8 yr), were cured (post-operative serum cortisol < 50 nM). Eleven patients, nine males and two females (mean age+/-s.d., 11.5+/-3.6 yr; range, 6.4-17.8 yr) had post-operative cortisol levels above 50 nM (2-20 days), with mean serum cortisol levels at 09:00 h of 537 nM (range 269-900 nM) indicating a lack of cure. These 11 patients received external beam pituitary radiotherapy (RT). One patient with a pituitary macroadenoma had a post-operative cortisol level of < 50 nM but 0.8 yr later showed an elevated cortisol and residual disease. RESULTS: The patients cured by TSS alone were significantly older than those not cured (P = 0.038; Student's t test). All patients had CT/MRI pituitary imaging: 14 were reported to have microadenomas and one macroadenoma, while 12 were reported as normal. Bilateral simultaneous inferior petrosal sinus sampling (BSIPSS) with i.v. corticotropin-releasing hormone (CRH) administration was introduced as a pre-operative investigation in 1986 and was performed in 21 patients (78%), on BSIPSS, 16 (76%) had evidence suggesting pituitary adrenocorticotropic hormone (ACTH) secretion (central to peripheral (IPS:P) ACTH ratio after CRH of > or = 3.0) and 16 (76%) showed lateralisation of ACTH secretion (IPSG of > or = 1.4). There was concordance between the BSIPSS finding and the position of the microadenoma at surgery in 17/21 (81%) patients. Of the 16 patients showing lateralisation of ACTH secretion, 12 (75%) were cured by TSS. Of the four without lateralisation of ACTH, suggesting a midline lesion, 3 (75%) were cured by TSS. Post-operative pituitary hormone deficiencies in the patients cured by TSS were: pan-hypopituitarism 1/16, isolated growth hormone deficiency (GHD) (peak GH on glucagon/ITT < 1-17.9 mU/l) 9/16 and diabetes insipidus 3/16. CONCLUSION: Over a 21-year period selective adenomectomy by TSS cured 59% of all paediatric CD patients, with higher age favouring cure. Introduction of BSIPSS resulted in the demonstration of a high rate of lateralisation of ACTH secretion consistent with the surgical identification of the adenoma, and therefore appears likely to have contributed to the higher surgical cure rate.

Adenoma↗

Comparative tolerability of erythromycin and newer macrolide antibacterials in paediatric patients.

The macrolides are a well established group of antibacterials frequently used in general practice. The most frequently used macrolides in paediatric patients are erythromycin, a naturally occurring compound, and clarithromycin and azithromycin, recently developed macrolides. Overall adverse effect rates of 7 to 26% for erythromycin, 14 to 26% for clarithromycin, and 6 to 27% for azithromycin have been described in children. Adverse gastrointestinal effects, including nausea, vomiting, diarrhoea and abdominal cramps, are the most common problems in children. Allergic reactions, hepatotoxicity, ototoxicity and adverse effects involving the central and peripheral nervous systems have also been observed in children. Stevens-Johnson, Schonlein-Henoch and Churg-Strauss syndromes have been rarely described in children. Treatment-related laboratory abnormalities have been recorded in 2 to 4% of erythromycin- and in 0 to 1% of both clarithromycin- and azithromycin-treated children. Elevation in liver function tests was the most common abnormality cited. Increased macrolide use in children in recent years has resulted in a growing potential for drug interactions between them and other pharmacologically active agents via the inhibition of cytochrome P450 (CYP) microsomal enzymes. Drug interactions with theophylline, cyclosporin, carbamazepine, terfenadine and warfarin limit erythromycin use. Clarithromycin is a weak inducer of CYP and exhibits fewer drug-drug interactions than erythromycin. However, its use with theophylline, carbamazepine and terfenadine is contraindicated. In contrast, no significant interactions have been reported with azithromycin to date. Macrolides have been proven to be well tolerated in the treatment of upper and lower respiratory tract infections, skin and soft tissue infections, and also in less frequent infections occurring in paediatric patients. In addition, clarithromycin and azithromycin have shown good tolerability profiles in immunocompromised paediatric patients. In conclusion, macrolides antibacterials have proven to be well tolerated in paediatric patients. Although the incidence of adverse effects is similar with the use of erythromycin and the newer macrolides, drug interactions occur significantly less when clarithromycin or azithromycin are administered.

Anti-Bacterial Agents↗

The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients.

BACKGROUND AND OBJECTIVE: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients. PATIENTS AND METHODS: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nuremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information. RESULTS: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs. CONCLUSION: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.

Adolescent↗

Detecting adverse drug reactions on paediatric wards: intensified surveillance versus computerised screening of laboratory values.

BACKGROUND: Adverse drug reactions (ADRs) contribute significantly to patient morbidity and mortality, as well as to costs for healthcare systems. Our aim was to evaluate the type and incidence of ADRs in a paediatric hospital population, comparatively ascertained by two different methodological approaches. METHODS: Our prospective study enrolled all patients admitted to two of the general children wards (46 beds) and the paediatric intensive care unit (6 beds) at the HELIOS Klinikum Wuppertal teaching hospital in Germany, over the study period of 3 months. We used two methods to detect ADRs. The intensified surveillance system relied on a trained physician conducting ward rounds and assessing patient charts. The computer-assisted screening of pathological laboratory parameters used values slightly below or above the age-specific normal range as a trigger signal for a potential ADR, which was subsequently assessed by trained personnel. RESULTS: By applying both methods simultaneously we observed that 14.1% of children experienced an ADR while they were hospitalised and 2.7% of children were admitted to hospital because of the ADR. Intensified surveillance resulted in the detection of 101 ADRs in 11.9% of patients, predominantly presenting with gastrointestinal symptoms, skin and CNS disorders; computer-assisted screening identified 45 ADRs in 5.7% of patients, mainly with drug-induced blood dyscrasia and liver damage. Furthermore, the ADRs detected by the intensified method were more severe, affected younger children and showed a closer causal attributability to the reaction than the ADRs observed by the computerised method. The spectra of drugs involved were similar, with the anti-infectives being suspected most frequently. The sensitivities of the intensified surveillance system and the computerised surveillance screening came to 67.2% and 44.8%, respectively, with computer-assisted screening having a specificity of 72.8%. The mean positive predictive value of the pathological laboratory values under surveillance by computer-assisted screening was 18.6%. Approximately 25% of ADR-related drugs administered were used for off-label indications. CONCLUSION: Using the published literature for comparison, we found that ADRs occur as frequently in paediatric patients as in adult patients. Intensified surveillance and computerised surveillance applied in the paediatric setting show substantial differences in their detection specificities. A higher number of and more severe ADRs can be detected by intensified surveillance than by computerised surveillance, but require higher personnel resources.

Child↗

Pharmacokinetics and pharmacodynamics of famotidine in paediatric patients.

Famotidine, an H2 receptor antagonist, has several potential advantages over cimetidine and ranitidine. These advantages include its potency, relatively longer elimination half-life, and lack of interaction with the cytochrome P450 isoforms. Eight studies addressing the use of famotidine in paediatric patients have been published. Data from these studies demonstrate that the pharmacokinetics and pharmacodynamics of intravenous famotidine appear to be similar in both children over the age of 1 year and adults. These data support a starting paediatric dosage for intravenous famotidine of 0.5 mg/kg every 8 to 12 hours. In addition, the safety and efficacy of famotidine in the treatment of peptic ulcer disease and esophagitis in paediatric patients is supported by these studies involving over 150 children. Future studies with famotidine in paediatrics should address its disposition in children under the age of 1 year and in children with compromised renal function, as well as the bioavailability of the oral formulation.

Adolescent↗

The future potential of eicosanoids and their inhibitors in paediatric practice.

Eicosanoids may have many potential uses in paediatric practice. Since E-type prostaglandins were first applied to treat ductus-dependent congenital heart diseases in paediatric practice, many eicosanoid-related drugs have been examined for the treatment of pathophysiological conditions in children. Prostaglandins (PG), thromboxane (TX) and leukotrienes (LT), produced from arachidonic acid in the phospholipids of cell membranes, are considered to be biologically active eicosanoids. Corticosteroids reduce eicosanoid production by impairing phospholipase A2 activation, while cyclo-oxygenase inhibiting drugs such as the nonsteroidal anti-inflammatory drugs (NSAID) suppress PG and TX production. PGE1 (alprostadil) and PGE2 (dinoprostone) therapy has been shown to improve oxygenation in neonates whose pulmonary and systemic blood flow are dependent on a patent ductus arteriosus, while epoprostenol (prostacyclin, PGI2) and beraprost (beraprost sodium), another PGI2 analogue, are often effective as acute vasodilators in paediatric pulmonary hypertension. Synthetic PGE analogues such as misoprostol have gastric antisecretory and cytoprotective effects, and are effective in both prophylaxis and treatment of NSAID-induced gastroduodenal mucosal lesions. Both alprostadil and epoprostenol have been shown to be effective in treating peripheral vascular and skin diseases. Since TX, a platelet aggregator and vasoconstrictor, has been implicated as a potential mediator of asthma, its inhibition by agents such as seratrodast (AA-2414) and ozagrel (OKY-046) has proven effective in the treatment of adult patients with asthma; studies of these agents in paediatric patients is awaited with interest. Developing the clinical use of eicosanoid-related drugs and assessing the potential use of these drugs requires a 3-phase approach: reducing the complications in the treatment of neonates with ductus-dependent congenital heart diseases and primary pulmonary hypertension requiring PGE1, PGE2 and PGI2 therapy; conducting clinical trials of the synthesis inhibitors and receptor antagonists of TXA2 and LT that have already been used in the treatment of adult patients with bronchial asthma; and evaluating the efficacy of new modulators of eicosanoid biosynthesis, such as eicosapentaenoic acid and antiallergy drugs, in the treatment of eicosanoid-related diseases in children.

Child↗

Amoxicillin/clavulanic acid: a review of its use in the management of paediatric patients with acute otitis media.

UNLABELLED: Amoxicillin/clavulanic acid (Augmentin), Augmentin ES-600 is a well established, orally administered combination of amoxicillin (a semisynthetic antibacterial agent) and clavulanic acid (a beta-lactamase inhibitor). Amoxicillin/clavulanic acid shows good activity against the main pathogens associated with acute otitis media (AOM), including penicillin-susceptible and -intermediate strains of Streptococcus pneumoniae, and beta-lactamase producing strains of Haemophilus influenzae and Moraxella catarrhalis. It has moderate activity against penicillin-resistant S. pneumoniae; a high-dose formulation has been developed with the aim of providing better coverage for penicillin-resistant strains. Amoxicillin/clavulanic acid (conventional formulations, mostly 40/10 mg/kg/day in three divided doses) produced clinical response rates similar to those of oral cephalosporin comparators and similar to or significantly greater than those for intramuscular ceftriaxone in randomised trials in paediatric patients with AOM (mean age approximately 2 to 5 years). Clinical response rates were generally similar for amoxicillin/clavulanic acid and macrolide comparators (mean patient age approximately 1 to 6 years), although significantly better clinical and bacteriological responses were seen versus azithromycin in one randomised trial (mean patient age approximately 1 year). The high-dose formulation of amoxicillin/clavulanic acid (90/6.4 mg/kg/day in two divided doses) eradicated a high proportion of penicillin-resistant S. pneumoniae (penicillin MICs 2 or 4 mg/L) in a large noncomparative trial in children with AOM (upper limit of the US indication for S. pneumoniae is 2 mg/L). Amoxicillin/clavulanic acid is generally well tolerated. A low total incidence of adverse events (3.6%) and no serious events were reported from a large paediatric postmarketing study. The most frequently reported adverse events in children are mild gastrointestinal disturbances. Diarrhoea is generally less frequent with twice-daily than with three-times-daily treatment. The new high-dose formulation showed similar tolerability to a conventional twice-daily formulation (45/6.4 mg/kg/day) in a well controlled trial. CONCLUSIONS: Amoxicillin/clavulanic acid is a well established broad-spectrum antibacterial treatment which is effective and well tolerated in the treatment of AOM in paediatric patients. The high-dose combination should prove valuable in treating AOM caused by penicillin-intermediate and -resistant S. pneumoniae (approved in the US for penicillin MIC < or =2 mg/L). Based on recent recommendations and the available data, high-dose amoxicillin/clavulanic acid can be considered a treatment of choice for recurrent or persistent paediatric AOM (after failure of amoxicillin alone) where involvement of resistant pathogens is suspected.

Acute Disease↗

Evaluating health-related quality-of-life studies in paediatric populations: some conceptual, methodological and developmental considerations and recent applications.

Although numerous paediatric-based health-related quality-of-life (HR-QOL) instruments are currently in use, there still remain conceptual, methodological and developmental issues to address. This paper provides an up-to-date critical review of the HR-QOL literature in paediatric medicine. Our analysis indicates that there is no consensus on how HR-QOL and overall QOL should be defined and measured in children. It is recommended that future studies focus on operationalising and distinguishing these constructs from each other and from traditional health-status measures. A clear empirical basis for generating instrument items and for prioritising specific domains must be described. Researchers should consider using the data gathered during their first interviews as a springboard from which to test their ideas of HR-QOL and QOL, reformulate concepts and subsequently retest their notions before developing instruments. Related to methodological challenges, consistency and agreement are still used interchangeably when comparing child and parent reports of children's HR-QOL. The Pearson correlation is a measure of co-variation in scores, and not a measure of agreement. We recommend that researchers focus on determining agreement as opposed to consistency. Few, if any, attempts have been made to account for the possibility that a response shift may have occurred in the evaluation of HR-QOL. Most studies have compared HR-QOL scores of children with illness with their healthy peers. As such, there is a dearth of knowledge regarding the normative process of adaptation within the context of illness. It is recommended that researchers focus on gathering data using a relative standard of comparison. We further recommend that researchers interpret HR-QOL data in line with their intended purpose. Regarding developmental consideration, particular attention ought to be paid to developing instruments that consider children's emerging sense of self, cognitive capacity and emotional awareness. Instruments that include items that are age appropriate are more likely to maximise reliability and validity of reports. The results of many HR-QOL instruments are applied in pharmacotherapeutic and pharmacoeconomic assessments. However, there has been relative infrequent application of economically valid HR-QOL tools (utility scales) and the use of HR-QOL scales as outcome measures in paediatric drug trials. As such, few cost-utility analyses have been performed to inform paediatric decision making. In addition, many of the concerns in the development of HR-QOL instruments should also be applied to the utility scales such that they reflect adequately children's preferences for health states.

Adolescent↗

Haemopoietic growth factors in paediatric oncology: a review of the literature.

Recombinant haemopoietic growth factors (HGFs) are an attractive adjunct to reduce morbidity from chemotherapy regimens and their use has become widespread in paediatric oncology. Although patients receiving HGFs often have faster haematological recovery after intensive chemotherapy, this does not always translate into meaningful clinical benefits. This article reviews the clinical effectiveness of HGFs in a variety of different contexts. Most published studies have used granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) as prophylaxis to ameliorate the subsequent neutropenia following intensive chemotherapy. These 2 agents have also been used to mobilise peripheral blood stem cells for autologous transplantation. HGFs specific for anaemia and thrombocytopenia are currently in paediatric clinical trials and it is hoped that the proper context and administration strategy can be found to make their use clinically effective. This article also reviews data on toxicity, specifically focusing on differences between various formulations of growth factors. HGFs are expensive, and cost-benefit analyses reviewed in this article give an important perspective on the financial aspects of paediatric cancer care. Because HGFs do not benefit every child receiving chemotherapy and overuse increases costs and may result in unnecessary adverse effects, evidence-based guidelines for their rational use in paediatric oncology are proposed.

Anemia↗