Quality of Active versus Spontaneous Reporting of Adverse Drug Reactions in Pediatric Patients: Relevance for Pharmacovigilance and Knowledge in Pediatric Medical Care.

For drug safety in pediatric patients, knowledge about adverse drug reactions (ADRs) is essential to balance benefits and risks, especially because of the high incidence of off-label drug use. However, underreporting of ADRs is a serious problem, leading to a deficit in knowledge affecting clinical practice. The aim of this study is to find a method by which we can improve the quantity of ADR reporting while maintaining or improving the quality of the ADR reports. This was done in several steps. First, health care providers were educated to increase awareness of ADRs. Thereafter, a novel active supporting system was introduced, where reporting ADRs was simplified; if clinical physicians suspected an ADR, they only had to send the name or hospital number of the patient, the observed ADR, and the suspected drug to a supportive team. This team collects all information needed about the possible ADR from the patient's medical records and hospital charts. With this information, the supportive team fills in the forms necessary for reporting ADRs to the nationwide pharmacovigilance centre Lareb. With this system, the quantity of ADR reports from both inpatients and outpatients rose dramatically. Subsequently, the quality of the obtained ADR reports was measured using the ClinDoc and vigiGrade systems. This study shows there is no loss of quality of the ADR reports in the active reporting system compared to spontaneous reporting systems. Based on the data of the present study, we suggest that an active reporting system has the potential to increase our knowledge about ADRs in pediatric patients.

Patient engagement in the design of clinical research in Noonan syndrome spectrum disorders: a scoping review.

BACKGROUND: Noonan syndrome spectrum disorders are a group of disorders caused by mutations in several genes of the RAS/MAPK pathway. Because of a highly heterogeneity and variable phenotypical manifestations of the disorders, these children and adults have a variable number of symptoms. Inclusion of their perceived experience of their health and developmental problems in research (design) could contribute to increased relevance of the research process and outcomes. The aim of this study is to get insight in what way patients with a Noonan syndrome spectrum disorder have been involved in the research process in order to learn for future engagement practices. METHODS AND RESULTS: To that end, the degree of engagement was measured by the eight levels of the participation ladder of Arnstein. Using a scoping review approach, 18 articles were selected in which patient engagement in the design of studies in patients with Noonan syndrome spectrum disorders was described over the past twenty years. Six of these articles reported engagement on the level of informing (level 3), 8 on the level of consultation (level 4), 2 on the level of placation (level 5)and 2 on the level of partnership (level 6). CONCLUSIONS: The current results do show a positive albeit still modest development of patient engagement over the last few years. A promising way to stimulate engagement is aiming to yield insights in the most important patients' needs by developing a patient guided research agenda. However, this is not automatically followed by patient engagement at higher levels of participation in subsequent research steps. For this reason, in the Netherlands for example, a Dutch Noonan syndrome spectrum disorders research agenda is being developed, in a collaboration between the Dutch Noonan Syndrome Foundation and national scientific and clinical professionals.

Validation of an Assessment Instrument for Pediatric Basic Life Support.

OBJECTIVES: To develop a valid and reliable instrument for the assessment of pediatric basic life support (PBLS). METHODS: An assessment instrument for PBLS was developed, based on 3 existing scoring systems and the European Resuscitation Council PBLS guideline. We tested if experienced PBLS instructors performed better than medical students on a standard PBLS examination on a low-fidelity pediatric manikin (construct validity). To pass the examination, 15 penalty points or less were required. The examinations were videotaped. One researcher assessed all videos once, and approximately half of them twice (intrarater reliability). A second researcher independently assessed part of the videos (interrater reliability). The time needed to assess 1 examination was determined. RESULTS: Face and content validity were established, because PBLS experts reached consensus on the instrument and because the instrument incorporated all items of the European Resuscitation Council algorithm. Of the 157 medical students that were scored, 98 (62.4%) passed the examination. Fourteen PBLS instructors were scored; all passed (100%). Pass rate (62.4% vs 100%) and median penalty points (15 [interquartile range, 10-22.5] vs 7.5 [interquartile range, 1.25-10]) were significantly different between students and instructors (P = 0.005 and <0.001, respectively). Reassessment demonstrated a κ for intrarater reliability of 0.62 (95% confidence interval, 0.45-0.81) (substantial agreement); κ for interrater reliability was 0.51 (95% confidence interval, 0.09-0.93) (moderate agreement). It took approximately 3 minutes to assess 1 videotaped examination. CONCLUSIONS: Our instrument for the (video-based) assessment of PBLS is valid and sufficiently reliable. It is also designed to be practical, time-efficient, and applicable in various settings, including resource limited.

Physical activity and asthma development in childhood: Prospective birth cohort study.

BACKGROUND: Sedentary behavior and decreased physical activity are possible risk factors for developing asthma. This longitudinal study investigates the association between physical activity and subsequent asthma. We hypothesize that children with decreased physical activity at early school age, have higher risk of developing asthma. METHODS: One thousand eight hundred thirty-eight children from the KOALA Birth Cohort Study were analyzed. Children who were born prematurely or with congenital defects/diseases with possible influence on either physical activity or respiratory symptoms were excluded. Physical activity, sedentary behavior, and screen time were measured at age 4 to 5 years by questionnaire and accelerometry in a subgroup (n = 301). Primary outcome was asthma, assessed by repeated ISAAC questionnaires between age 6 and 10. Secondary outcome was lung function measured by spirometry in a subgroup (n = 485, accelerometry subgroup n = 62) (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC] and FEV1/FVC ratio) at age 6 to 7 years. RESULTS: Reported physical activity was not associated with reported asthma nor lung function. Accelerometry data showed that daily being 1 hour less physically active was associated with a lower FEV1/FVC (z score ß, -0.65; 95% confidence interval, -1.06 to -0.24). CONCLUSIONS: Physical activity at early school age was not associated with reported asthma development later in life. However, lung function results showed that sedentary activity time was associated with lower FEV1/FVC later in childhood. As this is the first longitudinal study with objectively measured physical activity and lung function, and because the subgroup sample size was small, this result needs replication.

Ocular Manifestations of Noonan Syndrome: A Prospective Clinical and Genetic Study of 25 Patients.

PURPOSE: To determine the full spectrum of ocular manifestations in patients with Noonan syndrome (NS). DESIGN: Prospective cross-sectional clinical and genetic study in a tertiary referral center. PARTICIPANTS: Twenty-five patients with NS (mean age, 14 years; range, 8 months-25 years) clinically diagnosed by validated criteria. METHODS: All patients were examined by the same team following a detailed study protocol. Genetic analyses were performed in 23 patients. MAIN OUTCOME MEASURES: Ocular abnormalities of vision and refraction, external ocular features, ocular position and motility, anterior segment, posterior segment, and intraocular pressure. RESULTS: Ocular features of vision and refraction were amblyopia (32%), myopia (40%), and astigmatism (52%). External ocular features were epicanthic folds (84%), hypertelorism (68%), ptosis (56%), high upper eyelid crease (64%), lower eyelid retraction (60%), abnormal upward slanting palpebral fissures (36%), downward slanting palpebral fissures (32%), and lagophthalmos (28%). Orthoptic abnormalities included strabismus (40%), abnormal stereopsis (44%), and limited ocular motility (40%). Anterior segment abnormalities included prominent corneal nerves (72%) and posterior embryotoxon (32%). Additional ocular features were found, including nonglaucomatous optic disc excavation (20%), relatively low (<10 mmHg) intraocular pressure (22%), and optic nerve hypoplasia (4%). Mutations were established in 22 patients: 19 PTPN11 mutations (76%), 1 SOS1 mutation, 1 BRAF mutation, and 1 KRAS mutation. The patient with the highest number of prominent corneal nerves had an SOS1 mutation. The patient with the lowest visual acuity, associated with bilateral optic nerve hypoplasia, had a BRAF mutation. Patients with severe ptosis and nearly total absence of levator muscle function had PTPN11 mutations. All patients showed at least 3 ocular features (range, 3-13; mean, 7), including at least 1 external ocular feature in more than 95% of the patients. CONCLUSIONS: Noonan syndrome is a clinical diagnosis with multiple genetic bases associated with an extensive variety of congenital ocular abnormalities. Ocular features of NS are characterized by 1 or more developmental anomalies of the eyelids (involving the position, opening, and closure) associated with various other ocular abnormalities in childhood, including amblyopia, myopia, astigmatism, strabismus, limited ocular motility, prominent corneal nerves, and posterior embryotoxon.

External ear anomalies and hearing impairment in Noonan Syndrome.

OBJECTIVE: This is the first cohort in which hearing impairment and external ear anomalies in Noonan Syndrome are described extensively. METHODS: Retrospective analysis of the otorhinolaryngological and clinical genetic data from 97 Noonan Syndrome (NS) patients. Forty-four NS patients were seen by an otorhinolaryngologist for the analysis of hearing impairment. In our cohort 80 of the 97 patients were genetically tested. In 71 of these mutations were found: in 48 patients a mutation in PTPN11, in 10 patients in SOS1, in 5 patients in SHOC2, in 5 patients in RAF1, in 1 patient in MAP2K2, in 1 patient in KRAS and in 1 patient in A2ML1. RESULTS: External ear anomalies were reported in 75 NS patients (77%). In 69 patients the ears were low-set, 28 patients had posteriorly rotated ears, 14 patients showed protruding ears and 18 had thickened helices. Hearing impairment was detected in 34 NS patients. Nine patients had sensorineural hearing impairment, two a permanent conductive hearing impairment, two other patients had mixed hearing impairment and 20 patients had conductive hearing impairment in the past, caused by otitis media with effusion. Their temporary conductive hearing impairment resolved between the ages of 2 and 18 years. Sensorineural hearing impairment varied between mild high-frequency hearing impairment and profound (uni- and bilateral) hearing impairment and was progressive in three patients. Four NS patients received cochlear implants for their severe sensorineural hearing impairment. The cohort is small for genotype-phenotype correlations, but sensorineural hearing impairment, especially the bilateral severe hearing impairment, was only seen in patients with a PTPN11 mutation. CONCLUSION: NS is characterized by dysmorphic external ear anomalies and both sensorineural and conductive hearing impairment. Audiological examinations are recommended in all patients with Noonan Syndrome.

Diagnostic value of FDG-PET/(CT) in children with fever of unknown origin and unexplained fever during immune suppression.

PURPOSE: Fever of unknown origin (FUO) and unexplained fever during immune suppression in children are challenging medical problems. The aim of this study is to investigate the diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and FDG-PET combined with computed tomography (FDG-PET/CT) in children with FUO and in children with unexplained fever during immune suppression. METHODS: All FDG-PET/(CT) scans performed in the Radboud university medical center for the evaluation of FUO or unexplained fever during immune suppression in the last 10 years were reviewed. Results were compared with the final clinical diagnosis. RESULTS: FDG-PET/(CT) scans were performed in 31 children with FUO. A final diagnosis was established in 16 cases (52 %). Of the total number of scans, 32 % were clinically helpful. The sensitivity and specificity of FDG-PET/CT in these patients was 80 % and 78 %, respectively. FDG-PET/(CT) scans were performed in 12 children with unexplained fever during immune suppression. A final diagnosis was established in nine patients (75 %). Of the total number of these scans, 58 % were clinically helpful. The sensitivity and specificity of FDG-PET/CT in children with unexplained fever during immune suppression was 78 % and 67 %, respectively. CONCLUSIONS: FDG-PET/CT appears a valuable imaging technique in the evaluation of children with FUO and in the diagnostic process of children with unexplained fever during immune suppression. Prospective studies of FDG-PET/CT as part of a structured diagnostic protocol are warranted to assess the additional diagnostic value.

Cardiac anomalies in individuals with the 18q deletion syndrome; report of a child with Ebstein anomaly and review of the literature.

Individuals with the 18q deletion syndrome are presented with various clinical characteristics, including cardiac anomalies in 24-36% of the reported cases. Nonetheless, genotype-phenotype correlations for cardiac anomalies in the 18q deletion syndrome have rarely been reported. We report on two girls with a terminal 18q deletion, one in whom an Ebstein anomaly and Wolff-Parkinson-White syndrome were detected and the other with multiple valve stenosis and a ventricular septal defect. The genotype and cardiac abnormalities of these girls and 17 other individuals with a de novo 18qter deletion reported in the literature are reviewed. All 19 individuals shared a small overlapping deletion region between 18q22.3q23. The most common cardiac defects detected were pulmonary valve anomalies and atrial septal defects. Ebstein anomaly, a rare cardiac malformation, was diagnosed in two individuals. Additional molecularly based genotype-phenotype studies are needed in order to pinpoint candidate genes within this region that contribute to normal cardiac development. A careful cardiac evaluation consisting of physical examination, ECG and ultrasound examination should be performed in all individuals diagnosed with the 18q deletion syndrome.

Physical activity and asthma: a systematic review and meta-analysis.

INTRODUCTION: This review aims to give an overview of available published evidence concerning the association between physical activity and asthma in children, adolescents and adults. METHODS: We included all original articles in which both physical activity and asthma were assessed in case-control, cross-sectional or longitudinal (cohort) studies. Excluded were studies concerning physical fitness, studies in athletes, therapeutic or rehabilitation intervention studies such as physical training or exercise in asthma patients. Methodological quality of the included articles was assessed according to the Newcastle-Ottawa Scale (NOS). RESULTS: A literature search was performed until June 2011 and resulted in 6,951 publications derived from PubMed and 1,978 publications from EMBASE. In total, 39 studies met the inclusion criteria: 5 longitudinal studies (total number of subjects n = 85,117) with physical activity at baseline as exposure, and asthma incidence as outcome. Thirty-four cross-sectional studies (n = 661,222) were included. Pooling of the longitudinal studies showed that subjects with higher physical activity levels had lower incidence of asthma (odds ratio 0.88 (95% CI: 0.77-1.01)). When restricting pooling to the 4 prospective studies with moderate to good study quality (defined as NOS≥5) the pooled odds ratio only changed slightly (0.87 (95% CI: 0.77-0.99)). In the cross-sectional studies, due to large clinical variability and heterogeneity, further statistical analysis was not possible. CONCLUSIONS: The available evidence indicates that physical activity is a possible protective factor against asthma development. The heterogeneity suggests that possible relevant effects remain hidden in critical age periods, sex differences, or extremes of levels of physical activity (e.g. sedentary). Future longitudinal studies should address these issues.

Prehospital intraosseus access with the bone injection gun by a helicopter-transported emergency medical team.

BACKGROUND: To evaluate the use of the bone injection gun to obtain vascular access in the prehospital setting by an Helicopter-Transported Emergency Medical Team. METHODS: Prospective descriptive study to assess the frequency and success rate of the use of the bone injection gun in prehospital care by a Helicopter-Transported Emergency Medical Team. RESULTS: In 40 of 780 (5.1%) patients, an attempt was made to obtain intraosseous access with the bone injection gun. Intraosseous access was attempted more often in children than in adults (p < 0.01). The success rate was 71% (10 out of 14) in children <16 years and 73% (19 out of 26) in adults (p = 1.0). There were no complications to the health care providers involved and no unwanted sequels to the patients involved. CONCLUSIONS: The bone injection gun is an effective and safe device for the resuscitation of patients in a prehospital setting. It seems to be equivalent in success rate as intraosseous needles in children, but it seems to be more successful in adults.

Decreased mortality but increased morbidity in neonates with jejunoileal atresia; a study of 114 cases over a 34-year period.

PURPOSE: The aim of the study was to evaluate patient demographics, classification and location of the atresia, operative management, postoperative care, and outcome in 114 infants with jejunoileal atresia (JIA) over a period of more than 3 decades. METHODS: This was a retrospective case series in a tertiary care teaching hospital. Records of all patients with JIA treated at the authors' institution between 1971 and 2004 were examined. RESULTS: Sixty-two percent of atresia and stenosis was noted in the jejunum, 30% in the ileum, and 8% in both the jejunum and the ileum. Atresias and stenosis were classified as follows: 7% type 0, 16% type I, 21% type II, 24% type IIIa, 10% type IIIb, 22% type IV. Gastrointestinal anomalies were encountered in 24% of patients, genitourinary malformations in 9%, cystic fibrosis in 9%, neurologic anomalies in 6%, and congenital heart disease in 4%. Operative management included resection with primary anastomosis in 69% of all patients and temporary enterostomies in 26%. After operative management, 15% of children had resultant short bowel syndrome. Oral feeding was allowed on median day 7, and full energy expenditure via the enteric route was reached on median day 20. Forty-seven percent of infants required central venous line placement for total parenteral nutrition. Early postoperative complications occurred in 28% of patients with JIA and late postoperative complications in 17%. We observed a mortality rate of 11%. CONCLUSIONS: This is one of the largest series of neonates with JIA described. Short bowel syndrome seems to be the biggest problem resulting in longer hospital stay, more feeding problems, and higher morbidity and mortality rates. Management of children with short bowel syndrome has improved because of the use of total parenteral nutrition, new operative techniques, and better intensive care. In the last 15 years, survival has increased at the cost of the surviving children as we noted a higher percentage of late complications.

Should EMS-paramedics perform paediatric tracheal intubation in the field?

OBJECTIVE: To determine the incidence and success rate of out-of-hospital tracheal intubation (TI) and ventilation of children, taking account of the type of healthcare provider involved. METHODS: A prospective observational study to analyse a consecutive group of children for which a helicopter-transported medical team (HMT) was called. In all cases, the emergency medical service (EMS)-paramedics arrived at the scene first. Data regarding type of incident, physiological parameters, treatment, and survival until hospital discharge were collected and subsequently analysed. RESULTS: Of the 300 children examined and treated by the HMT on scene, 155 (52%) children required out-of-hospital tracheal intubation. Ninety-five children had an initial Glasgow Coma Scale (GCS) rating of 3-4: the EMS-paramedics performed bag-valve-mask-ventilation (BVMV) until arrival with subsequent TI carried out by the HMT (54 children, survival 63%) or the EMS-paramedics performed TI themselves (41 children, subsequent correction of tube/ventilation by HMT in 37% and survival rate 5%). Two hundred and five children had an initial GCS of 5-15, from which 60 children required TI (survival rate 67%) and 145 children required no TI (survival rate 100%). CONCLUSION: We do not recommend early TI by EMS-paramedics in children with a GCS of 3-4. The rate of complications of this procedure is unacceptably high. BVMV is the preferred choice for ventilation by paramedics, whenever possible. Out-of-hospital TI performed by HMT is safe and effective. The HMT has skills in advanced airway management not provided by the EMS.

Electrocardiography in Noonan syndrome PTPN11 gene mutation--phenotype characterization.

Noonan syndrome is a developmental disorder with distinctive facial features, short stature and cardiac abnormalities. In this cross-sectional study, we evaluated characteristic electrocardiographic (ECG) findings and cardiac abnormalities in 84 patients with Noonan syndrome, 56 (67%) of who were positive for a PTPN11 mutation. As reported previously, pulmonary stenosis was the most common cardiac abnormality, followed by atrial septal defect and hypertrophic cardiomyopathy. The ECG showed at least one characteristic finding in 50% of cases including left axis deviation in 38 (45%), small R waves in the left precordial leads in 20 (24%) and an abnormal Q wave in 5 (6%) patients with Noonan syndrome. A wide QRS complex was not detected in any of these patients. The characteristic ECG findings of Noonan syndrome patients were not associated with a PTPN11 gene mutation, or with a (specific) cardiac anomaly. We conclude that there are characteristic ECG findings in Noonan syndrome, but the ECG pattern is neither a useful tool for the phenotype characterization of a PTPN11 mutation, nor for the presence or type of cardiac abnormality.

The effect of the Advanced Paediatric Life Support course on perceived self-efficacy and use of resuscitation skills.

BACKGROUND: Perceived self-efficacy is a predictor of behaviour and therefore an important dimension of resuscitation training which may have consequences for patient care. The Advanced Paediatric Life Support (APLS) course makes use of techniques which would be expected to increase self-efficacy. We examined the effect of this course on perceived self-efficacy in respect of resuscitation skills and on the use of these skills. DESIGN: A prospective descriptive study using a questionnaire. METHODS: Questionnaires were sent to all doctor candidates following the course in the Netherlands over a period of 15 months and to a matched control group. Perceived self-efficacy in respect of paediatric resuscitation as a whole and six of its component skills was measured on a visual analogue scale. Questionnaires were sent out before the course and 3 and 6 months afterwards. FINDINGS: The candidate and control groups were not significantly different in terms of sex, specialty, grade or experience with children. Perceived self-efficacy increased significantly (p<0.01) in candidates following the course for all skills and remained increased for at least 6 months. There was no significant change in perceived self-efficacy in the control group. There was no change in the use of skills or in the number of critically ill children seen, in either group. CONCLUSIONS: The APLS course does have an important effect on perceived self-efficacy but this is not related to an increase in the frequency of use of the skills learned on the course, partly because the opportunity for increased use is lacking. Further work is needed to determine whether the quality of those skills is improved by the course.

Allergic colitis presenting within the first hours of premature life.

UNLABELLED: A prematurely born infant developed rectal blood loss several hours after birth, after his first formula feeding. Discontinuing the feeding resolved symptoms, but after resuming feeding rectal blood loss reappeared. There were no signs of necrotizing enterocolitis. Suspecting cow's milk allergy, the feeding was changed to a casein-based protein hydrolysate, without effect. Meanwhile, laboratory tests indicated cow's milk allergy. Symptoms only resolved after introducing an amino acid-based formula supporting a definite diagnosis of cow's milk-induced allergic colitis. This is the first description of a premature infant with symptoms of allergic colitis, appearing within hours after birth, suggestive of intrauterine sensitization. The exact mechanisms of sensitization remain obscure. CONCLUSION: Cow's milk-induced allergic colitis can occur after the first feed, even in a prematurely born neonate. This is most probably due to intrauterine sensitization, and should be included in the differential diagnosis of rectal blood loss.