Pediatric Surgery

Neonatal Extra Corporeal Membrane Oxygenation: Impaired health at five years of age (Article)

Madderom, M.J. — 2012-06-27T00:00:00Z

Objective: Children treated with neonatal Extra Corporeal Membrane Oxygenation (ECMO) may show physical and mental morbidity at later age. We compared the health-related quality of life (HRQOL) of these children with normative data. Design: Prospective longitudinal follow-up study. Setting: Outpatient clinic of a III level university hospital. Patients: 95 five-year-olds who had received neonatal ECMO support between January 1999 and December 2005. Interventions: None. Measurements: The Pediatric Quality of Life Inventory (PedsQL) was administered at 5 years of age. Main results: The mothers (n=74) as proxy-reporters assigned significantly lower HRQOL scores for their children than did the parents in the healthy reference group for the total functioning scale of the PedsQL (mean difference:8.1, p<0.001). Mothers’ scores for 31 children (42%) were indicative of impaired HRQOL (≥-1 SD below the reference norm). The children (n=78) themselves scored significantly lower than did their healthy peers on total functioning (mean difference:11.0, p<0.001). Thirty-two children (41%) indicated an impaired HRQOL themselves. For the mother proxy-reports, duration of ECMO support (R2=0.009, p=0.010) and the presence of chronic lung disease (R2=0.133, p=0.002) were negatively related to total functioning. Children with a disabled health status for neuromotor functioning, maximum exercise capacity, behavior and cognitive functioning at five years of age had a higher odds ratio of also having a lower HRQOL. Health status had no influence on reported emotional functioning. Conclusions: Overall, children treated with ECMO in the neonatal period reported low HRQOL at 5 years of age. Because only emotional HRQOL was not associated with health status, the PedsQL might be a measure of health status rather than of HRQOL. In contrast with conclusions from others we found that 5-year-old children might be too young to rate their own HRQOL.

Sensorineural hearing loss and language development following neonatal extracorporeal membrane oxygenation (Article)

Hondel, D. van den — 2012-06-27T00:00:00Z

OBJECTIVE: To determine the prevalence of hearing loss in school-age children who have undergone neonatal extracorporeal membrane oxygenation (ECMO) treatment and to identify any effects of hearing loss on speech- and language development. DESIGN: Prospective longitudinal follow-up study within the framework of a structured post-ECMO follow-up program. SETTING: Outpatient clinic of a level III university hospital. RESULTS: Tone audiometry was performed by standardized protocol in 136 children aged 5 to 12 years. Hearing loss was considered clinically significant when >20dB. Hearing was normal in 75.7% of children. Five children (3.7%) had bilateral sensorineural or combined hearing loss; 3 of them received special audiological care (2.2% of total sample). Of the 24 children with congenital diaphragmatic hernia, 19 (79.2%) had normal hearing; and only 2 (8.3%) had mild SNHL, unilateral in one of them. Follow-up at 24 months of age had shown normal verbal and non-verbal developmental scores. Language development and intelligence median (range) scores at 5 years of age were also normal: receptive language development 104 (55-133); syntactical development 104 (68-132); and lexical development 101 (50-141) for 89 children; intelligence quotient was 104 (68-132) in 106 children. Scores did not differ between those with normal hearing, and those with mild hearing loss, or those with moderate to severe hearing loss (p=0.800, p=0.639, p=0.876, and p=0.886, for the respective developmental tests). CONCLUSIONS: We found normal language development and intelligence in a cohort of neonatal ECMO survivors. The prevalence of bilateral sensorineural hearing loss was in accordance with that of larger series in the United States – which exceeds the prevalence in the normal population.

Biomarkers and clinical tools in critically ill children: are we heading toward tailored drug therapy? (Article)

Buijs, E.A.B. — 2012-06-01T00:00:00Z

In pediatric critical care, validated biomarkers are essential for guiding drug therapy. The aim of this article is to present examples of current biomarker developments in its full breadth, including biochemical substances, physiological measurements and clinical scoring tools, with a focus on the field of circulatory, renal and neurophysiologic failure. Within each field we consecutively discuss the rationale for the selected biomarkers, studies in critically ill children, biomarker validation stage and biomarker use or potential use in drug studies and clinical drug dosing. This article demonstrates that there is paucity of properly validated biomarkers. Nevertheless, recent developments in, for instance, the field of sepsis, point us toward a future wherein, for critically ill children, drug therapy may be personalized using proteomic profiling instead of a small number of biomarkers, in order to establish a personal and dynamic disease profile.

The COMFORT behavior scale: Is a shorter observation period feasible? (Article)

Boerlage, A.A. — 2012-03-01T00:00:00Z

Objective: The COMFORT behavior scale has been validated for postoperative pain in 0- to 3-yr-old children. Scoring is preceded by a 2-min observation period, which nurses may consider too long. The objective of this study was to test the reliability of a 30-sec observation period. Design: Observational study. Setting: One Level III intensive care unit at a university children’s hospital. Participants: Designated pain specialist and all nursing staff. Interventions: None. Measurements: The pain specialist and caregiver nurse each conducted a bedside COMFORT behavior scale assessment and assigned an additional pain rating on the 11-point Numerical Rating Scale. Main Results: Total COMFORT behavior Scale score for the 2-min observation was 17 or higher in 19% of the patients and 11% for the 30-sec observation. The mean COMFORT behavior scale score for the 2-min observation was 13.5 (SD 3.8) and 12.7 (SD 3.7) for the 30-sec observation. The mean difference therefore was 0.8 (confidence interval 0.6–1.1, paired t test, p < .001). Sensitivity and positive predictive value for the 30-sec observa- tion were 0.44 and 0.80, respectively. Conclusions: A 30-sec COMFORT behavior scale observation increases the risk of underscoring pain. Therefore, the 2-min observation period should be adhered to in the interest of the patients.

The Microcirculation Is Unchanged in Neonates with Severe Respiratory Failure after the Initiation of ECMO Treatment (Article)

Top, A.P.C. — 2012-01-01T00:00:00Z

Purpose. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is known to improve cardiorespiratory function and outcome in neonates with severe respiratory failure. We tested the hypothesis that VA-ECMO therapy improves the microcircu- lation in neonates with severe respiratory failure. Methods. This single-center prospective observational pilot study took place in an intensive care unit of a level III university children’s hospital. Twenty-one-term neonates, who received VA-ECMO treatment, were included. The microcirculation was assessed in the buccal mucosa, using Orthogonal Polarization Spectral imaging, within 24 hours before (T1) and within the first 24 hours after initiation of ECMO treatment (T2). Data were compared to data of a ventilated control group (N = 7). Results. At baseline (T1), median functional capillary density (FCD), microvascular flow index (MFI), and heterogeneity index (HI) did not differ between the ECMO group and the control group. At T2 the median FCD was lower in the control group (median [range]: 2.4 [1.4–4.2] versus 4.3 [2.8–7.4] cm/cm2 ; P value <0.001). For MFI and HI there were no differences at T2 between the two groups. Conclusion. The perfusion of the microcirculation does not change after initiation of VA-ECMO treatment in neonates with severe respiratory failure.

Having a Feel for Others’ Pain (Doctoral Thesis)

Boerlage, A.A. — 2011-12-16T00:00:00Z

Pain is a phenomenon so common that almost all individuals become familiar with this sensation at some point in life. Some consider it as unavoidable and others as a challenge that has to be defeated. During the second part of the last century researchers became interested in the neurobiological source and regulation of pain, the use of assessment instruments to “objectify” pain, and treatment options for distinct patient groups and types of pain. Meanwhile we have become aware of the negative impact of pain on quality of life, recovery from surgery and survival, as well as the risk of acute pain turning into chronic pain. Babies and intellectually disabled individuals of all ages have often been excluded from pain studies; for long it was believed that they were unable to experience pain. For infants and young children this belief was not specifically based on a scientific rationale but more on a lack of knowledge about the status of the myelinisation process of the nerves in neonates, the individual variability in drug disposition and fear of harmful side effects of analgesics and narcotics. Intellectually disabled individuals have always been considered to be unable to experience or suffer from pain. This misconception was partly based on absence of visible emotion during potentially painful situations, like continuing to walk with a broken hip or leg. Such observations seemed more important than the knowledge that a condition is known to be (extremely) painful in individuals that are not intellectually disabled. Fortunately enough we have done away with these misconceptions. A landmark publication of Anand and Hickey in 1987 reported huge circulatory and metabolic complications in (prematurely born) neonates after ligation of a patent ductus arteriosus without fentanyl compared to children that received fentanyl. Since then it was acknowledged that babies are capable to feel pain and require treatment just like in older patients.

Screening pediatric delirium with an adapted version of the Sophia Observation withdrawal Symptoms scale (SOS) (Letter To Editor)

Dijk, M. van — 2011-12-08T00:00:00Z

Protocolized post-operative pain management in infants; do we stick to it? (Article)

Ceelie, I. — 2011-10-28T00:00:00Z

Background: The American Academy of Pediatrics states that ongoing assessment of pain is essential for adequate pain treatment. Pain assessment by means of the COMFORT behaviour scale and the Numeric Rating Scale is therefore an important component of the post-operative pain treatment protocol for neonates and infants in our intensive care unit (ICU). Aim: The study aims to determine degrees of staff compliance with this protocol. Patients and methods: This retrospective chart review concerned post-surgical patients under the age of 3 years admitted to our level III ICU over a 1-year period. The degree of compliance to the post-operative pain protocol was measured by the frequency of deviations from protocol-dictated drug treatment and pain assessments. Results: Records of 200 children with a median age at surgery of 98 days (interquartile range 6–320) were analysed. A mean of 11 assessments in the first 72 h post-operatively per patient had been recorded. A total of 2103 pain assessments were retrieved, of which 1675 (79.7%) suggested comfort. Compliance to the protocol (reassessment and correct medication) was provided in 66 (15.4%) of the 428 assessments suggesting pain or distress. Conclusion: The post-operative pain protocol applied in our ICU appears to be effective; however, full compliance to the protocol was marginal, possibly leading to under-treatment of pain.

Correlates of lower respiratory tract infections and nutritional state in children with severe generalized cerebral palsy and intellectual disability (Doctoral Thesis)

Calis, E.A. — 2011-10-05T00:00:00Z

Children with severe generalized cerebral palsy and intellectual disability represent a small part of the general Dutch population. Their share in healthcare, however, is disproportionally large. Due to their disabilities they are particularly susceptible to various medical problems, which cause much distress, and may even shorten their life expectancy. Many children do not reach adulthood, the main cause of death in this population being lower respiratory tract infections. The present study was initiated in 2001 in reaction to the need to gain insight into causes of pulmonary infections in these children, as expressed by paediatricians and intellectual disability physicians in the Netherlands. Although children were treated with antibiotics (as a prophylaxis and/or as treatment in case of acute pulmonary infection), recurrent lower respiratory tract infections continued to cause much morbidity and mortality. Preventive measures were needed. This study was set up to evaluate the incidence and correlates of pulmonary infections in this population, and should be considered as a first step that may lead towards the development of a guideline for the prevention of lower respiratory tract infections. The present dissertation is the second of two, resulting from this study. The first dissertation was written by Rebekka Veugelers, and dealt primarily with feasibility of diagnostic methods in this population.

Creating or preventing opioid addiction, finding the right dose (Article)

Ista, E. — 2011-09-01T00:00:00Z

Application to Add Midazolam to the Model List of Essential Medicines (Research Paper)

Wildschut, E.D. — 2011-08-01T00:00:00Z

Summary statement of the proposal for inclusion The benzodiazepine midazolam has proven sedative, anxiolytic and amnesic properties. It is extensively used for premedication and procedural sedation in both adults and children. In comparison to other benzodiazepine and non-benzodiazepine drugs, midazolam is equally or more effective for premedication/preoperative sedation. No evidence exists that premedication with midazolam prolongs discharge time from hospital. Its efficacy and safety have been extensively studied in both adults and children. This contrasts its comparator drug, diazepam for which data in children and elderly are scarce or lacking. Midazolam is also effective for procedural sedation as a single drug or in combination with an opioid. As a single drug, adequate sedation for procedures in the emergency room, is achieved in over 90% of all procedures. Comparative efficacy was shown for propofol. Data are insufficient to determine comparative efficacy for procedural sedation for other drugs. When administered with the appropriate precautions, e.g. titration to effect, adequate monitoring and personnel to support ventilation, midazolam is very safe. No major adverse events were seen in 847 adults who received midazolam for procedural sedation. Also, adverse effects can be antagonized with an effective antagonist, flumazenil. As midazolam is off-patent, drug costs are relatively low. Drug costs per procedure range from approximately 0.15 US$ to 2.6 US$ in an adult, depending on dose and country, with significantly lower costs in developing countries.

Scoring the proliferative activity of haemangioma of infancy: The Haemangioma Activity Score (HAS) (Article)

Janmohamed, S.R. — 2011-06-14T00:00:00Z

Background. Haemangioma of infancy (HOI) is the most frequently occurring benign tumour of infancy. A good, reliable and objective scoring system for haemangioma activity is not yet available. Aim. We have developed a simple system called the Haemangioma Activity Score (HAS) for scoring the (disease) proliferative activity of haemangiomas. The current study was undertaken to validate this system. Methods. We validated the HAS in a comparative study of photographs taken during consultations from 2000 until 2008 (n=78). Agreement between three observers was assessed at two different time points (t0and t1) with a minimum interval of 6months between them, using interclass correlation coefficients (ICC). Results. Agreement between observers was good. The average ICC of the HAS at t0and t1was 0.72 and 0.76, respectively. The average ICC of the HAS for the changes from baseline (HAS at t0minus HAS at t1) was 0.69. Conclusions. We conclude that the HAS is a good system for scoring the proliferative activity of haemangiomas, and believe it to be useful in future investigations. The number of studies comparing different therapies for treating haemangiomas is steadily increasing, and the HAS (before and after treatment) may provide a valuable scoring system for evaluating such therapies. © The Author(s). CED

The COMFORT-Behavior scale is useful to assess pain and distress in 0- to 3-year-old children with Down syndrome (Article)

Valkenburg, A.J. — 2011-06-02T00:00:00Z

Many pediatric intensive care units use the COMFORT-Behavior scale (COMFORT-B) to assess pain in 0- to 3-year-old children. The objective of this study was to determine whether this scale is also valid for the assessment of pain in 0- to 3-year-old children with Down syndrome. These children often undergo cardiac or intestinal surgery early in life and therefore admission to a pediatric intensive care unit. Seventy-six patients with Down syndrome were included and 466 without Down syndrome. Pain was regularly assessed with the COMFORT-B scale and the pain Numeric Rating Scale (NRS). For either group, confirmatory factor analyses revealed a 1-factor model. Internal consistency between COMFORT-B items was good (Cronbach's α = 0.84-0.87). Cutoff values for the COMFORT-B set at 17 or higher discriminated between pain (NRS pain of 4 or higher) and no pain (NRS pain below 4) in both groups. We concluded that the COMFORT-B scale is also valid for 0- to 3-year-old children with Down syndrome. This makes it even more useful in the pediatric intensive care unit setting, doing away with the need to apply another instrument for those children younger than 3.

Is the temporal artery thermometer a reliable instrument for detecting fever in children? (Article)

Penning, C. — 2011-06-01T00:00:00Z

Aims and objective. We aimed to study the diagnostic accuracy of the temporal artery thermometer vs. rectal temperature in a large group of children with and without fever, aged 0-18years. Background. Many have studied the diagnostic accuracy of the temporal artery thermometer in children compared with a reference method, with contradictory outcomes. No studies have been carried out in a large group of children of all ages. Design. Diagnostic accuracy/validation study. Method. Children (0-18years) with fever (T>38·0°C) were recruited through the emergency department and children with normal temperatures through the day-care department of the Children's Hospital. All children routinely had rectal temperature recordings. Temporal artery temperature was recorded shortly after the rectal recording. The mean absolute difference in temperature, the level of agreement (intraclass correlation coefficient) and the sensitivity and specificity of detecting fever were calculated. Results. A total number of 198 children (121 boys) participated, with a mean age of 5·1 (SD 4·7)years. Of those children, 81 had fever according to the rectal recording. Mean difference between temporal artery temperature and rectal temperature was -0·11 (SD 0·63)°C, with an agreement of 0·812. The sensitivity and specificity of the temporal artery thermometer for detecting fever were 67·9 and 98·3%, respectively. Conclusions. The diagnostic accuracy of the temporal artery thermometer in detecting fever in children of all ages is low. Relevance to clinical practice. We do not recommend replacement of standard clinical thermometers with temporal artery thermometers.

Placental vascularization in early onset small for gestational age and preeclampsia (Article)

Oppenraaij, R.H.F. van — 2011-06-01T00:00:00Z

The objective was to determine whether chorionic villous vascularization is diminished in cases of early onset (<34 weeks) small for gestational age (SGA) and/or preeclampsia (PE). Placental morphometrical measurements were performed in 4 gestational-age-matched groups complicated by SGA, SGA with PE, PE, and spontaneous preterm delivery without SGA or PE as the reference group. Using a video image analysis system, in randomly selected intermediate and terminal villi, the stromal area and the following villous vascular parameters were manually traced and analyzed: number of total, centrally and peripherally localized vessels, vascular area, and vascular area density. No differences were observed in intermediate and terminal villous vascular area. Preeclampsia was associated with smaller terminal villous stromal area (reference 2299 μm2, SGA 2412 μm2, SGA + PE 2073 μm2, and PE 2164 μm2, P =.011), whereas SGA was associated with an increased terminal villous vascular area density (reference 26.1%, SGA 35.7%, SGA + PE 33.4%, and PE 32.0%, P =.029). Compared with preserved flow, lower terminal villous vascular area density was found in cases with absent or reversed end-diastolic (ARED) umbilical artery flow (39.3% vs 30.3%, P =.013). These data demonstrate that villous vascularization was not influenced by PE, whereas in terminal villi an increased vascular area density was associated with SGA. Lower terminal villous vascular area density was associated with ARED flow in SGA pregnancies, indicating an increased risk of fetal compromise.

Overexpression of the natural antisense hypoxia-inducible factor-1α transcript is associated with malignant pheochromocytoma/paraganglioma (Article)

Span, P.N. — 2011-06-01T00:00:00Z

Paragangliomas (PGLs) have widely different metastastic potentials. Two different types of PGLs can be defined by expression profiling. Cluster 1 PGLs exhibit VHL and/or succinate dehydrogenase (SDH) mutations and a pseudohypoxic phenotype. RET and neurofibromatosis type 1 (NF1) mutations occur in cluster 2 tumors characterized by deregulation of the RAS/RAF/MAP kinase signaling cascade. Sporadic PGLs can exhibit either profile. During sustained hypoxia, a natural antisense transcript of hypoxia-inducible factor 1 (aHIF) is expressed. The role of aHIF in the metastatic potential of PGL has not yet been investigated. The aim was to test the hypothesis that genotype-specific overexpression of aHIF is associated with an increased metastatic potential. Tumor samples were collected from87 patients with PGL. Quantitative PCR was performed for aHIF, vascular endothelial growth factor (VEGF), aquaporin 3, cytochrome b561, p57Kip2, slit homolog 3, and SDHC. Expression was related to mutation status, benign versus malignant tumors, and metastasis-free survival. We found that both aHIF and VEGF were overexpressed in cluster 1 PGLs and inmetastatic tumors. In contrast, slit homolog 3, p57Kip2, cytochrome b561, and SDHC showed overexpression in non-metastatic tumors, whereas no such difference was observed for aquaporin 3. Patients with higher expression levels of aHIF and VEGF had a significantly decreased metastasis free survival. Higher expression levels of SDHC are correlated with an increased metastasis-free survival. In conclusion, we not only demonstrate a higher expression of VEGF in cluster 1 PGL, fitting a profile of pseudohypoxia and angiogenesis, but also of aHIF. Moreover, overexpression of aHIF and VEGF marks a higher metastatic potential in PGL.

The role of population PK-PD modelling in paediatric clinical research (Article)

Cock, R.F.W. De — 2011-05-01T00:00:00Z

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.

Chlamydia trachomatis and placental inflammation in early preterm delivery (Article)

Rours, G.I.J.G. — 2011-05-01T00:00:00Z

Chlamydia trachomatis may infect the placenta and subsequently lead to preterm delivery. Our aim was to evaluate the relationship between the presence of Chlamydia trachomatis and signs of placental inflammation in women who delivered at 32 weeks gestation or less. Setting: placental histology and clinical data were prospectively obtained from 304 women and newborns at the Erasmus MC-Sophia, Rotterdam, the Netherlands. C. trachomatis testing of placentas was done retrospectively using PCR. C. trachomatis was detected in 76 (25%) placentas. Histological evidence of placental inflammation was present in 123 (40%) placentas: in 41/76 (54%) placentas with C. trachomatis versus 82/228 (36%) placentas without C. trachomatis infection (OR 2.1, 95% CI 1.2-3.5). C. trachomatis infection correlated with the progression (P = 0.009) and intensity (P = 0.007) of materno-fetal placental inflammation. C. trachomatis DNA was frequently detected in the placenta of women with early preterm delivery, and was associated with histopathological signs of placental inflammation.

Rhabdoid tumor mimicking hemangioma (Article)

Assen, Y.J. — 2011-05-01T00:00:00Z

We report a young boy with a malignant tumor, which remained unrecognized for 8 months because it was assumed to be a hemangioma. The presentation of a rhabdoid tumor mimicking hemangioma is very rare. It was reported only on two earlier occasions. Rhabdoid tumors are one of the most aggressive types of malignancies encountered in pediatric oncology. It is important to recognize that a fast growing vascular lesion in a child will often be a hemangioma, but could also be an aggressive tumor.

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2 (Article)

Osorio, A. — 2011-05-01T00:00:00Z

Background: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. Methods: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. Results: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.Conclusions and inteNo evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.