Trends in community response and long-term outcomes from pediatric cardiac arrest: A retrospective observational study.

AIM: This study aimed to investigate trends over time in pre-hospital factors for pediatric out-of-hospital cardiac arrest (pOHCA) and long-term neurological and neuropsychological outcomes. These have not been described before in large populations. METHODS: Non-traumatic arrest patients, 1 day-17 years old, presented to the Sophia Children's Hospital from January 2002 to December 2020, were eligible for inclusion. Favorable neurological outcome was defined as Pediatric Cerebral Performance Categories (PCPC) 1-2 or no difference with pre-arrest baseline. The trend over time was tested with multivariable logistic and linear regression models with year of event as independent variable. FINDINGS: Over a nineteen-year study period, the annual rate of long-term favorable neurological outcome, assessed at a median 2.5 years follow-up, increased significantly (OR 1.10, 95%-CI 1.03-1.19), adjusted for confounders. Concurrently, annual automated external defibrillator (AED) use and, among adolescents, initial shockable rhythm increased significantly (OR 1.21, 95% CI 1.10-1.33 and OR 1.15, 95% CI 1.02-1.29, respectively), adjusted for confounders. For generalizability purposes, only the total intelligence quotient (IQ) was considered for trend analysis of all tested domains. Total IQ scores and bystander basic life support (BLS) rate did not change significantly over time. INTERPRETATION: Long-term favorable neurological outcome, assessed at a median 2.5 years follow-up, improved significantly over the study period. Total IQ scores did not significantly change over time. Furthermore, AED use (OR 1.21, 95%CI 1.10-1.33) and shockable rhythms among adolescents (OR1.15, 95%CI 1.02-1.29) increased over time.

SARS-CoV-2 incidence in secondary schools; the role of national and school-initiated COVID-19 measures.

INTRODUCTION: Our aim was to gain insight into the effect of COVID-19 measures on SARS-CoV-2 incidence in secondary schools and the association with classroom CO2 concentration and airborne contamination. METHODS: Between October 2020-June 2021, 18 schools weekly reported SARS-CoV-2 incidence and completed surveys on school-initiated COVID-19 measures (e.g. improving hygiene or minimizing contacts). CO2 was measured in occupied classrooms twice, and SARS-CoV-2 air contamination longitudinally using electrostatic dust collectors (EDC) and analyzed using RT-qPCR. National COVID-19 policy measures varied during pre-lockdown, lockdown and post-lockdown periods. During the entire study, schools were recommended to improve ventilation. SARS-CoV-2 incidence rate ratios (IRR) were estimated by Generalized Estimating Equation (GEE) models. RESULTS: During 18 weeks follow-up (range: 10-22) SARS-CoV-2 school-incidence decreased during national lockdown (adjusted IRR: 0.41, 95%CI: 0.21-0.80) and post-lockdown (IRR: 0.60, 0.39-0.93) compared to pre-lockdown. School-initiated COVID-19 measures had no additional effect. Pre-lockdown, IRRs per 10% increase in time CO2 exceeded 400, 550 and 800 ppm above outdoor level respectively, were 1.08 (1.00-1.16), 1.10 (1.02-1.19), and 1.08 (0.95-1.22). Post-lockdown, CO2-concentrations were considerably lower and not associated with SARS-CoV-2 incidence. No SARS-CoV-2 RNA was detected in any of the EDC samples. CONCLUSION: During a period with low SARS-CoV-2 population immunity and increased attention to ventilation, with CO2 levels most of the time below acceptable thresholds, only the national policy during and post-lockdown of reduced class-occupancy, stringent quarantine, and contact testing reduced SARS-CoV-2 incidence in Dutch secondary schools. Widespread SARS-CoV-2 air contamination could not be demonstrated in schools under the prevailing conditions during the study.

The Pharmacokinetics of Beta-Lactam Antibiotics Using Scavenged Samples in Pediatric Intensive Care Patients: The EXPAT Kids Study Protocol.

Background: Emerging evidence supports the importance of optimized antibiotic exposure in pediatric intensive care unit (PICU) patients. Traditional antibiotic dosing is not designed for PICU patients, as the extreme pharmacokinetic (PK) behavior of drugs threatens the achievement of optimal antibiotic treatment outcomes. Scavenged sampling is a sampling strategy which may have positive implications for routine TDM and PK research, as well as monitoring other biomarkers. EXPAT Kids study was designed to analyze whether current empiric dosing regimens of frequently used beta-lactam antibiotics achieve defined therapeutic target concentrations in PICU patients. Methods: A mono-centre, exploratory pharmacokinetic and pharmacodynamic study was designed to assess target attainment of beta-lactam antibiotics. One hundred forty patients will be included within 24 months after start of inclusion. At various time points serum concentration of the study antibiotic (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, flucloxacillin, and meropenem) are determined. In parallel with these sampling moments, residual material is collected to validate the use of blood of scavenged heparinized astrup syringes for the quantification of antibiotic exposure. The primary outcome is the time that the free (unbound) concentration of the study antibiotic remains above one to four the minimal inhibitory concentration during a dosing interval (100%ƒT > MIC and 100%ƒT>4xMIC). Other included outcomes are disease severity, safety, length of stay, and inflammatory biomarkers. Discussion: Potentially, scavenged sampling may enrich the EXPAT Kids dataset, and reduce additional blood sampling and workload for clinical personnel. The findings from the EXPAT Kids study will lead to new insights in the PK parameters of beta-lactams and consecutive effects on target attainment and clinical outcomes. Is there a need for more precision in dosing? Netherlands Trial Register Number: Trial NL9326.

Association between shockable rhythms and long-term outcome after pediatric out-of-hospital cardiac arrest in Rotterdam, the Netherlands: An 18-year observational study.

INTRODUCTION: Shockable rhythm following pediatric out-of-hospital cardiac arrest (pOHCA) is consistently associated with hospital and short-term survival. Little is known about the relationship between shockable rhythm and long-term outcomes (>1 year) after pOHCA. The aim was to investigate the association between first documented rhythm and long-term outcomes in a pOHCA cohort over 18 years. METHODS: All children aged 1 day-18 years who experienced non-traumatic pOHCA between 2002-2019 and were subsequently admitted to the emergency department (ED) or pediatric intensive care unit (PICU) of Erasmus MC-Sophia Children's Hospital were included. Data was abstracted retrospectively from patient files, (ground) ambulance and Helicopter Emergency Medical Service (HEMS) records, and follow-up clinics. Long-term outcome was determined using a Pediatric Cerebral Performance Category (PCPC) score at the longest available follow-up interval through august 2020. The primary outcome measure was survival with favorable neurologic outcome, defined as PCPC 1-2 or no difference between pre- and post-arrest PCPC. The association between first documented rhythm and the primary outcome was calculated in a multivariable regression model. RESULTS: 369 children were admitted, nine children were lost to follow-up. Median age at arrest was age 3.4 (IQR 0.8-9.9) years, 63% were male and 14% had a shockable rhythm (66% non-shockable, 20% unknown or return of spontaneous circulation (ROSC) before emergency medical service (EMS) arrival). In adolescents (aged 12-18 years), 39% had shockable rhythm. 142 (39%) of children survived to hospital discharge. On median follow-up interval of 25 months (IQR 5.1-49.6), 115/142 (81%) of hospital survivors had favorable neurologic outcome. In multivariable analysis, shockable rhythm was associated with survival with favorable long-term neurologic outcome (OR 8.9 [95%CI 3.1-25.9]). CONCLUSION: In children with pOHCA admitted to ED or PICU shockable rhythm had significantly higher odds of survival with long-term favorable neurologic outcome compared to non-shockable rhythm. Survival to hospital discharge after pOHCA was 39% over the 18-year study period. Of survivors to discharge, 81% had favorable long-term (median 25 months, IQR 5.1-49.6) neurologic outcome. Efforts for improving outcome of pOHCA should focus on early recognition and treatment of shockable pOHCA at scene.

Lactose after Roux-en-Y gastric bypass for morbid obesity, is it a problem?

BACKGROUND: Roux-en-Y gastric bypass (RYGB) can cause multiple food intolerances and gastrointestinal complaints are frequently reported after dairy consumption. We aimed to determine the prevalence of lactose malabsorption and intolerance, and complaints associated with dairy consumption in daily life, before and after RYGB. METHOD: The lactose breath test (LBT) and lactose tolerance test (LTT) was performed in 84 patients awaiting RYGB surgery and 84 patients after surgery. Gastrointestinal symptoms at baseline and after testing were recorded. Lactose malabsorption was defined as a positive LBT and/or LTT. Lactose intolerance as a positive test combined with an increase of gastrointestinal complains. Dairy consumption in daily life and successive gastrointestinal complaints were registered via a questionnaire. Results of preoperative and postoperative patients were compared. RESULTS: Lactose malabsorption was present in 15 (17.9%) of the preoperative patients and in 25 (29.8%) of the postoperative patients (OR 2.46; 95%CI: 1.08-5.59; p = .03). Of the preoperative patients 6 (7.1%) patients met the criteria for lactose intolerance, compared to 8 (9.5%) patients in the postoperative group (OR 1.48; 95%CI 0.48-4.57; p = .50). Twelve (14.3%) preoperative patients indicated to have gastrointestinal complaints after dairy consumption in daily life versus 45 (53.6%) postoperative patients (p < .01). CONCLUSION: This study shows no increase in patients with proven lactose intolerance after RYGB compared to preoperative patients. Gastrointestinal complaints after dairy consumption in daily life were far more frequently reported by RYGB patients. It is unlikely that all reported gastrointestinal complaints are actually caused by lactose. Other ingredients in dairy, like fat, are possibly contributory.

Human bocavirus infection as a cause of severe acute respiratory tract infection in children.

In 2005 human bocavirus (HBoV) was discovered in respiratory tract samples of children. The role of HBoV as the single causative agent for respiratory tract infections remains unclear. Detection of HBoV in children with respiratory disease is frequently in combination with other viruses or bacteria. We set up an algorithm to study whether HBoV alone can cause severe acute respiratory tract infection (SARI) in children. The algorithm was developed to exclude cases with no other likely cause than HBoV for the need for admission to the paediatric intensive care unit (PICU) with SARI. We searched for other viruses by next-generation sequencing (NGS) in these cases and studied their HBoV viral loads. To benchmark our algorithm, the same was applied to respiratory syncytial virus (RSV)-positive patients. From our total group of 990 patients who tested positive for a respiratory virus by means of RT-PCR, HBoV and RSV were detected in 178 and 366 children admitted to our hospital. Forty-nine HBoV-positive patients and 72 RSV-positive patients were admitted to the PICU. We found seven single HBoV-infected cases with SARI admitted to PICU (7/49, 14%). They had no other detectable virus by NGS. They had much higher HBoV loads than other patients positive for HBoV. We identified 14 RSV-infected SARI patients with a single RSV infection (14/72, 19%). We conclude that our study provides strong support that HBoV can cause SARI in children in the absence of viral and bacterial co-infections.

Mechanical circulatory support in the Dutch National Paediatric Heart Transplantation Programme.

OBJECTIVES: Mechanical circulatory support (MCS) with a ventricular assist device (VAD) as a bridge to heart transplantation (HTx) or recovery may improve outcome in children with terminal heart failure. We report our experience with MCS in children eligible for HTx and its effect on waiting list mortality. METHODS: Retrospective single-centre cohort study, National Paediatric HTx Programme including all children eligible for HTx, since the introduction of MCS-VAD in 2006. RESULTS: A total of 43 patients were eligible for HTx, median age 11.7 years [Inter Quartile Range (IQR) 3.0-14.7]. In 18 patients, (42%) a VAD was implanted, 11 (61%) survived to HTx (n = 9) or recovery (n = 2). Techniques and devices used were left ventricular assist device (n = 16, 89%), in 4 cases preceded by extracorporeal membrane oxygenation (ECMO), and biventricular assist device (n = 2, 11%), both preceded by ECMO. In the VAD group, median time to death (n = 7) was 18 days (IQR 7-75), median time to HTx (n = 9) 66 days (IQR 33-223) and 2 patients recovered after 30 and 308 days. The main cause of death on MCS was neurological injury in 4 patients (22%) and systemic thrombo-embolic events in 2 (11%). The most common serious adverse events included confirmed thrombus requiring pump replacement (in 11 patients, 61%) and pericardial effusion leading to rethoracotomy (in 5 patients, 28%). Compared with the era before MCS (1998-2006), waiting list mortality decreased from 44 to 21%, and is now mainly related to complications of VAD support. CONCLUSIONS: Since the introduction of MCS-VAD, waiting list mortality halved and more children with end-stage heart failure survived to heart transplantation, thus improving outcome. Although there is substantial mortality and morbidity, overall mortality decreases, making MCS-VAD an essential therapeutic tool. The need for donor organs remains critically urgent.

Sevoflurane therapy for life-threatening asthma in children.

BACKGROUND: Asthma is a common disease in children and often develops early in life. This multicentre retrospective case series describe the use and effectiveness of sevoflurane inhalation therapy in a series of children with severe asthma in the paediatric intensive care unit (PICU). METHODS: Seven children ranging from 4 to 13 yr of age admitted to the PICU of two tertiary care hospitals in the Netherlands were included. They all were admitted with the diagnosis of severe asthma requiring invasive mechanical ventilation and were treated with sevoflurane inhalation therapy. RESULTS: The median (range) Pco2 level at the start, after 2 h, and at the end of sevoflurane treatment were 14 (5.1-24.8), 9.8 (5.4-17.0), and 6.2 (4.5-11.4) kPa (P=0.05) while the median (range) pH was 7.02 (6.97-7.36), 7.18 (7.04-7.35), and 7.43 (7.15-7.47) kPa (P=0.01), respectively. The median (range) peak pressure values declined from 30 (23-56) to 20.4 (14-33) cm H2O (P=0.03). No severe adverse effects besides hypotension, with sufficient response to norepinephrine treatment, were seen. CONCLUSIONS: Sevoflurane inhalation corrects high levels of Pco2 and provides clinical improvement in mechanically ventilated children with life-threatening asthma who fail to respond to conventional treatment.

Hypereosinophilic syndrome in children.

Recently, according to the Hypereosinophilic Diseases Working Group of the International Eosinophil Society, six variants of hypereosinophilic syndrome have been proposed, i.e. (1) myeloproliferative, (2) lymphoproliferative, (3) idiopathic/undefined, (4) overlapping, (5) associated and (6) familial variant. Hypereosinophilic syndrome is a rare disorder in children and can occur at any age during childhood. Corticosteroids are the treatment of choice, whereas other treatment options are hydroxyurea, IFNα, imatinib, vincristine, mepolizumab. We present a fulminant fatal case of hypereosinophilic syndrome in a teenager with an initial presentation of an idiopathic thrombocytopenia (ITP) and present a narrative review of literature.

Ethnic differences in maternal underestimation of offspring's weight: the ABCD study.

OBJECTIVE: To determine the ethnic variation in maternal underestimation of their child's weight status and the explanatory role of socio-economic status (SES), acculturation and parental body mass index (BMI). METHOD: A multi-ethnic sample of 2769 normal or overweight/obese children (underweight children excluded) aged 5-7 years was examined (The Amsterdam Born Child and their Development study), comprising five ethnic subgroups: Dutch (n=1744), African descent (n=184), Turkish (n=86), Moroccan (n=161) and other non-Dutch (n=592). Data on mothers' perception of their child's weight status (5-point scale from 'too low' to 'too high'), SES, acculturation, parental BMI and the children's height and weight were collected. Underestimation was defined by comparing maternal perception with the actual weight status of her child (International Obesity Task Force guidelines). Ethnic differences in underestimation were calculated in the normal weight and overweight/obese categories. RESULTS: Underestimation ranged from 3.6 (Dutch) to 15.7% (Moroccan) in normal-weight children, and from 73.0 (Dutch) to 92.3% (Turkish) in overweight/obese children. After correction for ethnic differences in child's BMI, higher odds ratios (ORs) for underestimation were found in the Turkish (normal weight: OR 6.83; 95% confidence interval (CI) 2.33-20.05 and overweight: OR 2.80; 95% CI 1.12-6.98) and Moroccan (normal weight: OR 11.55; 95% CI 5.28-25.26) groups (reference is the Dutch group). Maternal educational level and immigrant generation largely explained the ethnic differences, with a minor contribution of maternal age. After correction, ORs remained higher in the Moroccan group (OR 4.37; 95% CI 1.79-10.62) among the normal-weight children. CONCLUSION: Mothers frequently underestimate the actual weight status of their child, especially mothers from Turkish or Moroccan origin. Having a lower SES, being first-generation immigrant and a young mother are important determinants in explaining these differences. As weight perceptions may affect weight gain and almost all mothers of overweight/obese children underestimate their child's weight, health professionals should help mothers (particularly those from ethnic minority groups) to acquire a realistic perception of their children's weight status.

Recognizing Guillain-Barre syndrome in preschool children.

OBJECTIVE: To determine whether recognition of Guillain-Barré syndrome (GBS) is delayed in preschool children, what causes this delay, and if the clinical presentation differs from older children. METHODS: In a retrospective cohort study, standardized data from all children with GBS seen at the Erasmus MC Sophia Children's University Hospital in Rotterdam from 1987 to 2009 were collected regarding clinical presentation, patient's delay, initial diagnosis, and doctor's delay to the diagnosis. We compared preschool children (<6 years old) with older children (6-18 years old). RESULTS: GBS was diagnosed in 23 preschool children and in 32 older children. Fifteen (68%) of the preschool children were initially misdiagnosed compared to 6 (21%) of the older children (p = 0.001). Median patient delay to consult a pediatrician in both age groups was the same (5.0 days). The median doctor's delay to diagnose possible GBS in preschool children was significantly longer than in older children (3 days vs 0 days). In one-quarter of preschool children, this doctor's delay was more than 1 week, up to 22 days. In preschool children, refusal to walk and pain in the legs were the most frequent presenting symptoms (65%), while older children presented with more classic symptoms of weakness and paresthesias. The preschool children were initially misdiagnosed with myopathy, tonsillitis, meningitis, rheumatoid disorders, coxitis, or discitis. CONCLUSION: The diagnosis of GBS in preschool children is delayed compared to older children. This delay is partly explained by the nonspecific clinical presentation, challenging neurologic examination, and alternative diagnoses in preschool children.

Local vasoconstriction in spinal cord-injured and able-bodied individuals.

Local vasoconstriction plays an important role in maintaining blood pressure in spinal cord-injured individuals (SCI). We aimed to unravel the mechanisms of local vasoconstriction [venoarteriolar reflex (VAR) and myogenic response] using both limb dependency and cuff inflation in SCI and compare these with control subjects. Limb blood flow was measured in 11 male SCI (age: 24-55 yr old) and 9 male controls (age: 23-56 yr old) using venous occlusion plethysmography in forearm and calf during three levels of 1) limb dependency, and 2) cuff inflation. During limb dependency, vasoconstriction relies on both the VAR and the myogenic response. During cuff inflation, the decrease in blood flow is caused by the VAR and by a decrease in arteriovenous pressure difference, whereas the myogenic response does not play a role. At the highest level of leg dependency, the percent increase in calf vascular resistance (mean arterial pressure/calf blood flow) was more pronounced in SCI than in controls (SCI 186 +/- 53%; controls 51 +/- 17%; P = 0.032). In contrast, during cuff inflation, no differences were found between SCI and controls (SCI 17 +/- 17%; controls 14 +/- 10%). Percent changes in forearm vascular resistance in response to either forearm dependency or forearm cuff inflation were equal in both groups. Thus local vasoconstriction during dependency of the paralyzed leg in SCI is enhanced. The contribution of the VAR to local vasoconstriction does not differ between the groups, since no differences between groups existed for cuff inflation. Therefore, the augmented local vasoconstriction in SCI during leg dependency relies, most likely, on the myogenic response.

Life threatening central nervous system manifestations and hypothermia due to maneb intoxication in a child: a case report.

Maneb, manganese ethylene-bis-dithiocarbamate, is a fungicide pesticide used in the agriculture and bulb flower culture sector. Toxicological effects for humans have been reported in literature and are diverse. They vary from allergic reactions (dermatitis, conjunctivitis, and bronchitis), central nervous system effects (muscarinic, nicotinic, central and extrapyramidal) and renal toxicity (acute renal failure).A 7-year old girl was admitted to the pediatric intensive care unit because of status epilepticus. Physical examination showed respiratory insufficiency, convulsions, and severe hypothermia (32.5 degrees C). The patient was intubated and her convulsions were successfully treated with benzodiazepines. Except for a combined metabolic and respiratory acidosis and hyperglycemia, diagnostic investigations on admission (full blood count, electrolytes, liver and renal functions, cerebrospinal fluid investigation, toxicology screening of blood and urine for barbiturates and benzodiazepines, blood culture, herpes PCR, and a CT scan of the brain) were normal. Within 24 hours, there was a complete recovery of all neurological signs. Within 72 hours, the patient was discharged from the hospital. Liquid chromatography-mass spectrometric investigation of her blood showed amounts of maneb, which can explain all symptoms and signs. However, effects of this magnitude on the central nervous system have not previously been reported in humans.

[Fatal asthma in childhod preventable by recognizing risk factors and presenting features]. / Fataal astma op de kinderleeftijd te voorkomen door herkenning van risicofactoren en presentatiewijze.

A 6-year-old child known with asthma died from an asthma attack after having had severe dyspnoea which lasted for 1 day. She had been having an average of 40 salbutamol 'puffs' each day for 1 month. For the preceding 8 months she had been having just over half this number as well as fluticasone. A 13-year-old girl died of an asthma attack. Three weeks previously she had been dyspnoeic and had taken salbutamol and prednisone as well as amoxicillin at a later stage. Each year between 8 and 10 children die of an acute exacerbation of asthma in the Netherlands. There are 2 different types of acute fatal asthma: a slow type (I) and a rapidly progressing type (II). In type I there is progressive obstruction of the airways due to oedema, mucous and spasm. Type II predominantly consists of bronchoconstriction. The main risk factors are previous hospital admission with asthma and inadequate maintenance medication. Effective maintenance therapywith the correct dosage ofinhalational corticosteroids administered correctly can probably stop the potentially fatal asthma type II from developing.

Short use of muscle relaxants following single stage laryngotracheoplasty in children.

OBJECTIVE: The postoperative management of children undergoing single stage laryngotracheoplasty (SSLTP) includes intubation and muscle paralysis to secure the airway and protect the wound. We reduced the period of postoperative muscle paralysis in an attempt to decrease the incidence of pulmonary complications. The objective of this study was to evaluate the influence of the duration of muscle paralysis on pulmonary complications and outcome. METHODS: Medical records of all children admitted, between 1994 and 2002, to the pediatric intensive care unit following SSLTP were analysed. Children were grouped according to the number of days muscle paralysis was used. RESULTS: Thirty-six children (15 male, 21 female, mean age 32 months (9-162 months)) underwent SSLTP for laryngeal stenosis. Prior to surgery 29 needed a tracheotomy (mean duration 11.1 months). Shorter muscle paralysis leads to shorter intubation and mechanical ventilation and therefore PICU and hospital length of stay were 12.4 and 9.9days shorter in the group with short use of muscle paralysis (p<0.001 and p=0.002, respectively). There was no significant difference in postoperative complications, but a trend towards fewer atelectases in children with short muscle paralysis could be recognised. Postoperatively we observed no auto-extubations in either group and success rate of SSLTP was comparable in both groups (94 and 95%). CONCLUSION: Children undergoing SSLTP can safely benefit from a postoperative strategy using a short duration of muscle relaxants. They have fewer days on mechanical ventilation with a concomitant decrease in duration of hospital stay.

Population pharmacokinetics and metabolism of midazolam in pediatric intensive care patients.

OBJECTIVE: To determine the pharmacokinetics and metabolism of midazolam in pediatric intensive care patients. DESIGN: Prospective population pharmacokinetic study. SETTING: Pediatric intensive care unit. PATIENTS: Twenty-one pediatric intensive care patients aged between 2 days and 17 yrs. INTERVENTIONS: The pharmacokinetics of midazolam and metabolites were determined during and after a continuous infusion of midazolam (0.05-0.4 mg/kg/hr) for 3.8 hrs to 25 days administered for conscious sedation. MEASUREMENTS AND MAIN RESULTS: Blood samples were taken at different times during and after midazolam infusion for determination of midazolam, 1-OH-midazolam, and 1-OH-midazolam-glucuronide concentrations via high-performance liquid chromatography-ultraviolet detection. A population analysis was conducted via a two-compartment pharmacokinetic model by the NPEM program. The final population model was used to generate individual Bayesian posterior pharmacokinetic parameter estimates. Total body clearance, apparent volume distribution in terminal phase, and plasma elimination half-life were (mean +/- sd, n = 18): 5.0 +/- 3.9 mL/kg/min, 1.7 +/- 1.1 L/kg, and 5.5 +/- 3.5 hrs, respectively. The mean 1-OH-midazolam/midazolam ratio and (1-OH-midazolam + 1-OH-midazolam-glucuronide)/midazolam ratio were 0.14 +/- 0.21 and 1.4 +/- 1.1, respectively. Data from three patients with renal failure, hepatic failure, and concomitant erythromycin-fentanyl therapy were excluded from the final pharmacokinetic analysis. CONCLUSIONS: We describe population and individual midazolam pharmacokinetic parameter estimates in pediatric intensive care patients by using a population modeling approach. Lower midazolam elimination was observed in comparison to other studies in pediatric intensive care patients, probably as a result of differences in study design and patient differences such as age and disease state. Covariates such as renal failure, hepatic failure, and concomitant administration of CYP3A inhibitors are important predictors of altered midazolam and metabolite pharmacokinetics in pediatric intensive care patients. The derived population model can be useful for future dose optimization and Bayesian individualization.

A survey of the use of off-label and unlicensed drugs in a Dutch children's hospital.

BACKGROUND: The treatment of pediatric patients with drugs in hospitals is being impeded by a shortage in the availability of licensed drugs in an appropriate formulation. We have studied the extent of use of drugs that are not licensed for use in children (unlicensed) and drugs that are used outside the terms of the product license (off-label). We conducted this study in a Dutch academic children's hospital. METHODS: In a prospective study of 5 weeks' duration, we reviewed drug prescriptions in a pediatric ward and 3 intensive care units. We classified the prescribed drugs in 3 main categories-licensed, unlicensed, and off-label-and determined the nature of their unlicensed and off-label use. RESULTS: Two thousand one hundred thirty-nine courses of drugs were administered to 237 patients in 442 patient-days. Of 2139 prescriptions, 725 (34%) were licensed, 1024 (48%) were unlicensed, and 390 (18%) were off-label. In 392 (90%) of 435 patient-days, children received 1 or more courses of an unlicensed or off-label drug prescription in hospital. CONCLUSION: With regard to the availability of drugs of proven quality and adequate license for pediatric patients in hospital, dramatic shortcomings exist. As a result, drug legislation originally designed to protect patients and prescribing physicians against unsafe drug use and unjustified claims has turned into an insurmountable threshold to make proper drugs available for a vulnerable minority of patients.

DNase treatment for atelectasis in infants with severe respiratory syncytial virus bronchiolitis.

Respiratory insufficiency due to respiratory syncytial virus (RSV) bronchiolitis is partly due to the abundance of thickened mucus and the inability to clear it from the airways. Mucus in RSV bronchiolitis contains necrotic inflammatory and epithelial cells. The viscoelastic properties of purulent airway secretions are largely due to the presence of highly polymerized deoxyribonucleic acid (DNA). Recombinant human deoxyribonuclease (rhDNase) is known to liquefy such mucus in patients with cystic fibrosis, whereas case reports described a beneficial effect in other respiratory disorders. The authors hypothesized that rhDNase would diminish atelectasis and mucus plugging in infants with severe RSV bronchiolitis. Two infants with RSV bronchiolitis with massive unilateral atelectasis in whom mechanical ventilation was imminent due to exhaustion, and three mechanically ventilated infants (two neonates, one with bronchopulmonary dysplasia) with RSV bronchiolitis with pneumonia received treatment with 2.5 mg nebulized rhDNase twice daily. Following administration of nebulized recombinant human deoxyribonuclease, clinical and radiological parameters improved quickly. Mechanical ventilation could be avoided in two infants while in three infants on artificial ventilation, clinical recovery started following the first dose of the drug. A therapeutic trial of recombinant human deoxyribonuclease may be an option in the treatment for atelectasis in severe or complicated respiratory syncytial virus bronchiolitis in infancy.

Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors.

To get insight in the endocrine and metabolic responses in children with meningococcal sepsis 26 children were studied the first 48 h after admission. On admission there was a significant difference in cortisol/ACTH levels between nonsurvivors (n = 8) and survivors (n = 18). Nonsurvivors showed an inadequate cortisol stress response in combination to very high ACTH levels, whereas survivors showed a normal stress response with significantly higher cortisol levels (0.62 vs. 0.89 micromol/L) in combination with moderately increased ACTH levels (1234 vs. 231 ng/L). Furthermore, there was a significant difference between nonsurvivors and survivors regarding pediatric risk of mortality score (31 vs. 17), TSH (0.97 vs. 0.29 mE/L), T3 (0.53 vs. 0.38 nmol/L), reverse T3 (rT3) (0.75 vs. 1.44 nmol/L), C-reactive protein (34 vs. 78 mg/L), nonesterified fatty acids (0.32 vs. 0.95 mmol/L), and lactate (7.3 vs. 3.2 mmol/L). In those who survived, the most important changes within 48 h were seen in a normalization of cortisol and ACTH levels, but without a circadian rhythm; a decrease of rT3 and an increase in the T3/rT3 ratio; and a decrease in the levels of the nonesterified free fatty acids and an unaltered high urinary nitrogen excretion. At this moment, it is yet unknown whether the hormonal abnormalities are determining factors in the outcome of acute meningococcal sepsis or merely represent secondary effects. Understanding the metabolic and endocrine alterations is required to design possible therapeutic approaches. The striking difference between nonsurvivors and survivors calls for reconsideration of corticosteroid treatment in children with meningococcal sepsis.