Nasopharyngeal microbiota in children is associated with severe asthma exacerbations.

BACKGROUND: The respiratory microbiome has been associated with the etiology and disease course of asthma. OBJECTIVE: We sought to assess the nasopharyngeal microbiota in children with a severe asthma exacerbation and their associations with medication, air quality, and viral infection. METHODS: A cross-sectional study was performed among children aged 2 to 18 years admitted to the medium care unit (MCU; n = 84) or intensive care unit (ICU; n = 78) with an asthma exacerbation. For case-control analyses, we matched all cases aged 2 to 6 years (n = 87) to controls in a 1:2 ratio. Controls were participants of either a prospective case-control study or a longitudinal birth cohort (n = 182). The nasopharyngeal microbiota was characterized by 16S-rRNA-gene sequencing. RESULTS: Cases showed higher Shannon diversity index (ICU and MCU combined; P = .002) and a distinct microbial community composition when compared with controls (permutational multivariate ANOVA R2 = 1.9%; P < .001). We observed significantly higher abundance of Staphylococcus and "oral" taxa, including Neisseria, Veillonella, and Streptococcus spp. and a lower abundance of Dolosigranulum pigrum, Corynebacterium, and Moraxella spp. (MaAsLin2; q < 0.25) in cases versus controls. Furthermore, Neisseria abundance was associated with more severe disease (ICU vs MCU MaAslin2, P = .03; q = 0.30). Neisseria spp. abundance was also related with fine particulate matter exposure, whereas Haemophilus and Streptococcus abundances were related with recent inhaled corticosteroid use. We observed no correlations with viral infection. CONCLUSIONS: Our results demonstrate that children admitted with asthma exacerbations harbor a microbiome characterized by overgrowth of Staphylococcus and "oral" microbes and an underrepresentation of beneficial niche-appropriate commensals. Several of these associations may be explained by (environmental or medical) exposures, although cause-consequence relationships remain unclear and require further investigations.

When will the Glomerular Filtration Rate in Former Preterm Neonates Catch up with Their Term Peers?

AIMS: Whether and when glomerular filtration rate (GFR) in preterms catches up with term peers is unknown. This study aims to develop a GFR maturation model for (pre)term-born individuals from birth to 18 years of age. Secondarily, the function is applied to data of different renally excreted drugs. METHODS: We combined published inulin clearance values and serum creatinine (Scr) concentrations in (pre)term born individuals throughout childhood. Inulin clearance was assumed to be equal to GFR, and Scr to reflect creatinine synthesis rate/GFR. We developed a GFR function consisting of GFRbirth (GFR at birth), and an Emax model dependent on PNA (with GFRmax, PNA50 (PNA at which half of GFR max is reached) and Hill coefficient). The final GFR model was applied to predict gentamicin, tobramycin and vancomycin concentrations. RESULT: In the GFR model, GFRbirth varied with birthweight linearly while in the PNA-based Emax equation, GA was the best covariate for PNA50, and current weight for GFRmax. The final model showed that for a child born at 26 weeks GA, absolute GFR is 18%, 63%, 80%, 92% and 96% of the GFR of a child born at 40 weeks GA at 1 month, 6 months, 1 year, 3 years and 12 years, respectively. PopPK models with the GFR maturation equations predicted concentrations of renally cleared antibiotics across (pre)term-born neonates until 18 years well. CONCLUSIONS: GFR of preterm individuals catches up with term peers at around three years of age, implying reduced dosages of renally cleared drugs should be considered below this age.

Evaluation of an aPTT guided versus a multimodal heparin monitoring approach in patients on extra corporeal membrane oxygenation: A retrospective cohort study.

INTRODUCTION: Bleeding and thrombotic complications are common in extracorporeal membrane oxygenation (ECMO) patients and are associated with increased mortality and morbidity. The optimal anticoagulation monitoring protocol in these patients is unknown. This study aims to compare the incidence of thrombotic and hemorrhagic complications before and after a protocol change. In addition, the association between hemostatic complications, coagulation tests and risk factors is evaluated. METHODS: This is a retrospective single center cohort study of adult ECMO patients. We collected demographics, ECMO parameters and coagulation test results. Outcomes of the aPTT guided and multimodal protocol, including aPTT, anti-Xa assay and rotational thromboelastometry were compared and the association between coagulation tests, risk factors and hemostatic complications was determined using a logistic regression analysis for repeated measurements. RESULTS: In total, 250 patients were included, 138 in the aPTT protocol and 112 in the multimodal protocol. The incidence of thrombosis (aPTT: 14%; multimodal: 12%) and bleeding (aPTT: 36%; multimodal: 40%), did not significantly differ between protocols. In the aPTT guided protocol, the aPTT was associated with thrombosis (Odds Ratio [OR] 1.015; 95% confidence interval [CI] 1.004-1.027). In both protocols, surgical interventions were risk factors for bleeding and thrombotic complications (aPTT: OR 93.2, CI 39.9-217.6; multimodal OR 17.5, CI 6.5-46.9). DISCUSSION: The incidence of hemostatic complications was similar between both protocols and surgical interventions were a risk factor for hemostatic complications. Results from this study help to elucidate the role of coagulation tests and risk factors in predicting hemostatic complications in patients undergoing ECMO support.

Hospital-to-home transitions for children with medical complexity: part 2-a core outcome set.

Appropriate outcome measures as part of high-quality intervention trials are critical to advancing hospital-to-home transitions for Children with Medical Complexity (CMC). Our aim was to conduct a Delphi study and focus groups to identify a Core Outcome Set (COS) that healthcare professionals and parents consider essential outcomes for future intervention research. The development process consisted of two phases: (1) a three-round Delphi study in which different professionals rated outcomes, previously described in a systematic review, for inclusion in the COS and (2) focus groups with parents of CMC to validate the results of the Delphi study. Forty-five professionals participated in the Delphi study. The response rates were 55%, 57%, and 58% in the three rounds, respectively. In addition to the 24 outcomes from the literature, the participants suggested 12 additional outcomes. The Delphi rounds resulted in the following core outcomes: (1) disease management, (2) child's quality of life, and (3) impact on the life of families. Two focus groups with seven parents highlighted another core outcome: (4) self-efficacy of parents.   Conclusion: An evidence-informed COS has been developed based on consensus among healthcare professionals and parents. These core outcomes could facilitate standard reporting in future CMC hospital to home transition research. This study facilitated the next step of COS development: selecting the appropriate measurement instruments for every outcome. What is Known: • Hospital-to-home transition for Children with Medical Complexity is a challenging process. • The use of core outcome sets could improve the quality and consistency of research reporting, ultimately leading to better outcomes for children and families. What is New: • The Core Outcome Set for transitional care for Children with Medical Complexity includes four outcomes: disease management, children's quality of life, impact on the life of families, and self-efficacy of parents.

Neurocognitive, Psychosocial, and Quality of Life Outcomes After Multisystem Inflammatory Syndrome in Children Admitted to the PICU.

OBJECTIVES: To investigate neurocognitive, psychosocial, and quality of life (QoL) outcomes in children with Multisystem Inflammatory Syndrome in Children (MIS-C) seen 3-6 months after PICU admission. DESIGN: National prospective cohort study March 2020 to November 2021. SETTING: Seven PICUs in the Netherlands. PATIENTS: Children with MIS-C (0-17 yr) admitted to a PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children and/or parents were seen median (interquartile range [IQR] 4 mo [3-5 mo]) after PICU admission. Testing included assessment of neurocognitive, psychosocial, and QoL outcomes with reference to Dutch pre-COVID-19 general population norms. Effect sizes (Hedges' g ) were used to indicate the strengths and clinical relevance of differences: 0.2 small, 0.5 medium, and 0.8 and above large. Of 69 children with MIS-C, 49 (median age 11.6 yr [IQR 9.3-15.6 yr]) attended follow-up. General intelligence and verbal memory scores were normal compared with population norms. Twenty-nine of the 49 followed-up (59%) underwent extensive testing with worse function in domains such as visual memory, g = 1.0 (95% CI, 0.6-1.4), sustained attention, g = 2.0 (95% CI 1.4-2.4), and planning, g = 0.5 (95% CI, 0.1-0.9). The children also had more emotional and behavioral problems, g = 0.4 (95% CI 0.1-0.7), and had lower QoL scores in domains such as physical functioning g = 1.3 (95% CI 0.9-1.6), school functioning g = 1.1 (95% CI 0.7-1.4), and increased fatigue g = 0.5 (95% CI 0.1-0.9) compared with population norms. Elevated risk for posttraumatic stress disorder (PTSD) was seen in 10 of 30 children (33%) with MIS-C. Last, in the 32 parents, no elevated risk for PTSD was found. CONCLUSIONS: Children with MIS-C requiring PICU admission had normal overall intelligence 4 months after PICU discharge. Nevertheless, these children reported more emotional and behavioral problems, more PTSD, and worse QoL compared with general population norms. In a subset undergoing more extensive testing, we also identified irregularities in neurocognitive functions. Whether these impairments are caused by the viral or inflammatory response, the PICU admission, or COVID-19 restrictions remains to be investigated.

Career coach preferences of medical students: coaching specialist or specialistic coach?

BACKGROUND: Medical students' demand for career coaching is growing. However, little is known about what type of career coach they prefer. Using the Warmth-Competence Framework, we investigated if and why medical students prefer physician coaches compared to career psychologist coaches. We also examined whether students' coach choice related to coaches' amount of experience with medical students. METHODS: In a two-by-two between participants vignette study (n = 147), we manipulated coach occupational background (physician vs. psychologist) and experience with coaching medical students (limited vs. considerable). Participants read one coach description, rated the likelihood that they would choose the coach, and rated the coach on dimensions of warmth and competence. RESULTS: Students who evaluated a physician career coach were more likely to choose the coach than students who evaluated a psychologist career coach. Students expected that a physician career coach would better understand their situation and be better able to provide career information, while they expected a psychologist career coach to have better conversation skills, all of which were relevant to choosing a coach. Coaches' experience with coaching medical students was unrelated to students' coach choice and their assessment of the coach's warmth and competence. CONCLUSIONS: Our findings highlight the relevance of coaches' occupational background and have implications for the implementation of career coach interventions. Medical schools could help students choose a career coach by providing information about the coach qualities that students value. Future studies could investigate whether career coaches with different occupational backgrounds differ in coach behaviors and coaching effectiveness.

The Dutch national paediatric heart transplantation programme: outcomes during a 23-year period.

BACKGROUND: Since 1998, there has been a national programme for paediatric heart transplantations (HT) in the Netherlands. In this study, we investigated waiting list mortality, survival post-HT, the incidence of common complications, and the patients' functional status during follow-up. METHODS: All children listed for HT from 1998 until October 2020 were included. Follow-up lasted until 1 January 2021. Data were collected from the patient charts. Survival, post-operative complications as well as the functional status (Karnofsky/Lansky scale) at the end of follow-up were measured. RESULTS: In total, 87 patients were listed for HT, of whom 19 (22%) died while on the waiting list. Four patients were removed from the waiting list and 64 (74%) underwent transplantation. Median recipient age at HT was 12.0 (IQR 7.2-14.4) years old; 55% were female. One-, 5­, and 10-year survival post-HT was 97%, 95%, and 88%, respectively. Common transplant-related complications were rejections (50%), Epstein-Barr virus infections (31%), cytomegalovirus infections (25%), post-transplant lymphoproliferative disease (13%), and cardiac allograft vasculopathy (13%). The median functional score (Karnofsky/Lansky scale) was 100 (IQR 90-100). CONCLUSION: Children who undergo HT have an excellent survival rate up to 10 years post-HT. Even though complications post-HT are common, the functional status of most patients is excellent. Waiting list mortality is high, demonstrating that donor availability for this vulnerable patient group remains a major limitation for further improvement of outcome.

Review of Scavenged Sampling for Sustainable Therapeutic Drug Monitoring: Do More With Less.

PURPOSE: Innovative and sustainable sampling strategies for bioanalytical quantification of drugs and metabolites have gained considerable interest. Scavenging can be stratified as a sustainable sampling strategy using residual material because it aligns with the green principles of waste reduction and sampling optimization. Scavenged sampling includes all biological fluids' (eg, blood, liquor, and urine) leftover from standard clinical care. This review elaborates on the past and current landscape of sustainable sampling within therapeutic drug monitoring, with a focus on scavenged sampling. METHODS: In February 2021, 4 databases were searched to assess the literature on the clinical use of innovative and sustainable sampling techniques without applying publication date restrictions. Studies reporting the clinical use of scavenged blood sampling and bridging studies of scavenged sampling and normal blood sampling were eligible for inclusion. RESULTS: Overall, 19 eligible studies concerning scavenged sampling were identified from 1441 records. Scavenged sampling is mainly applied in the pediatric population, although other patient groups may benefit from this strategy. The infrastructure required for scavenged sampling encounters several challenges, including logistic hurdles, storage and handling conditions, and documentation errors. A workflow is proposed with identified opportunities that guide the implementation of scavenged sampling. CONCLUSIONS: This review presents current evidence on the clinical use of scavenged sampling strategies. Scavenged sampling can be a suitable approach for drug quantification to improve dosage regimens, perform pharmacokinetic studies, and explore the value of therapeutic drug monitoring without additional sample collection.

Efficacy of a loading dose of IV salbutamol in children with severe acute asthma admitted to a PICU: a randomized controlled trial.

The optimal dose regimen for intravenous (IV) treatment in children with severe acute asthma (SAA) is still a matter of debate. We assessed the efficacy of adding a salbutamol loading dose to continuous infusion with salbutamol in children admitted to a pediatric intensive care unit (PICU) with SAA. This multicentre, placebo-controlled randomized trial in the PICUs of four tertiary care children's hospitals included children (2-18 years) with SAA admitted between 2017 and 2019. Children were randomized to receive either a loading dose IV salbutamol (15 mcg/kg, max. 750 mcg) or normal saline while on continuous salbutamol infusion. The primary outcome was the asthma score (Qureshi) 1 h after the intervention. Analysis of covariance models was used to evaluate sensitivity to change in asthma scores. Serum concentrations of salbutamol were obtained. Fifty-eight children were included (29 in the intervention group). Median baseline asthma score was 12 (IQR 10-13) in the intervention group and 11 (9-12) in the control group (p = 0.032). The asthma score 1 h after the intervention did not differ significantly between the groups (p = 0.508, ß-coefficient = 0.283). The median increase in salbutamol plasma levels 10 min after the intervention was 13 µg/L (IQR 5-24) in the intervention group and 4 µg/L (IQR 0-7) in the control group (p = 0.001). Side effects were comparable between both groups. CONCLUSION: We found no clinical benefit of adding a loading dose IV salbutamol to continuous infusion of salbutamol, in children admitted to the PICU with SAA. Clinically significant side effects from the loading dose were not encountered. WHAT IS KNOWN: • Pediatric asthma guidelines struggle with an evidence-based approach for the treatment of SAA beyond the initial steps of oxygen suppletion, repetitive administration of inhaled ß2-agonists, and systemic steroids. • During an SAA episode, effective delivery of inhaled drugs is unpredictable due to severe airway obstruction. WHAT IS NEW: • This study found no beneficial effect of an additional loading dose IV salbutamol in children admitted to the PICU. • This study found no clinically significant side effects from the loading dose.

Timing and Cause of Death in Children Following Return of Circulation After Out-of-Hospital Cardiac Arrest: A Single-Center Retrospective Cohort Study.

OBJECTIVES: To determine timing and cause of death in children admitted to the PICU following return of circulation after out-of-hospital cardiac arrest. DESIGN: Retrospective observational study. SETTING: Single-center observational cohort study at the PICU of a tertiary-care hospital (Erasmus MC-Sophia, Rotterdam, The Netherlands) between 2012 and 2017. PATIENTS: Children younger than 18 years old with out-of-hospital cardiac arrest and return of circulation admitted to the PICU. MEASUREMENTS AND RESULTS: Data included general, cardiopulmonary resuscitation and postreturn of circulation characteristics. The primary outcome was defined as survival to hospital discharge. Modes of death were classified as brain death, withdrawal of life-sustaining therapies due to poor neurologic prognosis, withdrawal of life-sustaining therapies due to refractory circulatory and/or respiratory failure, and recurrent cardiac arrest without return of circulation. One hundred thirteen children with out-of-hospital cardiac arrest were admitted to the PICU following return of circulation (median age 53 months, 64% male, most common cause of out-of-hospital cardiac arrest drowning [21%]). In these 113 children, there was 44% survival to hospital discharge and 56% nonsurvival to hospital discharge (brain death 29%, withdrawal of life-sustaining therapies due to poor neurologic prognosis 67%, withdrawal of life-sustaining therapies due to refractory circulatory and/or respiratory failure 2%, and recurrent cardiac arrest 2%). Compared with nonsurvivors, more survivors had witnessed arrest (p = 0.007), initial shockable rhythm (p < 0.001), shorter cardiopulmonary resuscitation duration (p < 0.001), and more favorable clinical neurologic examination within 24 hours after admission. Basic cardiopulmonary resuscitation event and postreturn of circulation (except for the number of extracorporeal membrane oxygenation) characteristics did not significantly differ between the withdrawal of life-sustaining therapies due to poor neurologic prognosis and brain death patients. Timing of decision-making to withdrawal of life-sustaining therapies due to poor neurologic prognosis ranged from 0 to 18 days (median: 0 d; interquartile range, 0-3) after cardiopulmonary resuscitation. The decision to withdrawal of life-sustaining therapies was based on neurologic examination (100%), electroencephalography (44%), and/or brain imaging (35%). CONCLUSIONS: More than half of children who achieve return of circulation after out-of-hospital cardiac arrest died after PICU admission. Of these deaths, two thirds (67%) underwent withdrawal of life-sustaining therapies based on an expected poor neurologic prognosis and did so early after return of circulation. There is a need for international guidelines for accurate neuroprognostication in children after cardiac arrest.

Unraveling the medical residency selection game.

The diversity of modern society is often not represented in the medical workforce. This might be partly due to selection practices. We need to better understand decision-making processes by selection committees in order to improve selection procedures with regard to diversity. This paper reports on a qualitative study with a socio-constructivist perspective conducted in 2015 that explored how residency selection decision-making occurred within four specialties in two regions in the Netherlands. Data included transcripts of the decision-making meetings and of one-on-one interviews with committee members before and after the group decision-making meetings. Candidates struggled to portray themselves favorably as they had to balance playing by the rules and being authentic; between fitting in and standing out. Although admissions committees had a welcoming stance to diversity, their practices were unintentionally preventing them from hiring underrepresented minority (URM) candidates. While negotiating admissions is difficult for all candidates, it is presumably even more complicated for URM candidates. This seems to be having a negative influence on attaining workforce diversity. Current beliefs, which make committees mistakenly feel they are acting fairly, might actually justify biased practices. Awareness of the role of committee members in these processes is an essential first step.

Current practices in children with severe acute asthma across European PICUs: an ESPNIC survey.

Most pediatric asthma guidelines offer evidence-based or best practice approaches to the management of asthma exacerbations but struggle with evidence-based approaches for severe acute asthma (SAA). We aimed to investigate current practices in children with SAA admitted to European pediatric intensive care units (PICUs), in particular, adjunct therapies, use of an asthma severity score, and availability of a SAA guideline. We designed a cross-sectional electronic survey across European PICUs. Thirty-seven PICUs from 11 European countries responded. In 8 PICUs (22%), a guideline for SAA management was unavailable. Inhaled beta-agonists and anticholinergics, combined with systemic steroids and IV MgSO4 was central in SAA treatment. Seven PICUs (30%) used a loading dose of a short-acting beta-agonist. Eighteen PICUs (49%) used an asthma severity score, with 8 different scores applied. Seventeen PICUs (46%) observed an increasing trend in SAA admissions.Conclusion: Variations in the treatment of children with SAA mainly existed in the use of adjunct therapies and asthma severity scores. Importantly, in 22% of the PICUs, a SAA guideline was unavailable. Standardizing SAA guidelines across PICUs in Europe may improve quality of care. However, the limited number of PICUs represented and the data compilation method are constraining our findings.What is Known:• Recent reports demonstrate increasing numbers of children with SAA requiring PICU admission in several countries across the world.• Most pediatric guidelines offer evidence-based approaches to the management of asthma exacerbations, but struggle with evidence-based approaches for SAA beyond these initial steps.What is New:• A large arsenal of adjunct therapies and 8 different asthma scores were used.• In a large number of PICUs, a written guideline for SAA management is lacking.

Predicting CYP3A-mediated midazolam metabolism in critically ill neonates, infants, children and adults with inflammation and organ failure.

AIMS: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. METHODS: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. RESULTS: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). CONCLUSION: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.

Validation of the SOS-PD scale for assessment of pediatric delirium: a multicenter study.

BACKGROUNDS: Reports of increasing incidence rates of delirium in critically ill children are reason for concern. We evaluated the measurement properties of the pediatric delirium component (PD-scale) of the Sophia Observation Withdrawal Symptoms scale Pediatric Delirium scale (SOS-PD scale). METHODS: In a multicenter prospective observational study in four Dutch pediatric ICUs (PICUs), patients aged ≥ 3 months and admitted for ≥ 48 h were assessed with the PD-scale thrice daily. Criterion validity was assessed: if the PD-scale score was ≥ 4, a child psychiatrist clinically assessed the presence or absence of PD according to the Diagnostic and statistical manual of mental disorders (DSM)-IV. In addition, the child psychiatrist assessed a randomly selected group to establish the false-negative rate. The construct validity was assessed by calculating the Pearson coefficient (rp) for correlation between the PD-scale and Cornell Assessment Pediatric Delirium (CAP-D) scores. Interrater reliability was determined by comparing paired nurse-researcher PD-scale assessments and calculating the intraclass correlation coefficient (ICC). RESULTS: Four hundred eighty-five patients with a median age of 27.0 months (IQR 8-102) were included, of whom 48 patients were diagnosed with delirium by the child psychiatrist. The PD-scale had overall sensitivity of 92.3% and specificity of 96.5% compared to the psychiatrist diagnosis for a cutoff score ≥4 points. The rp between the PD-scale and the CAP-D was 0.89 (CI 95%, 0.82-0.93; p < 0.001). The ICC of 75 paired nurse-researcher observations was 0.99 (95% CI, 0.98-0.99). CONCLUSIONS: The PD-scale has good reliability and validity for early screening of PD in critically ill children. It can be validly and reliably used by nurses to this aim.

Sophia Observation withdrawal Symptoms-Paediatric Delirium scale: A tool for early screening of delirium in the PICU.

BACKGROUND: Delirium in critically ill children is a severe neuropsychiatric disorder which has gained increased attention from clinicians. Early identification of delirium is essential for successful management. The Sophia Observation withdrawal Symptoms-Paediatric Delirium (SOS-PD) scale was developed to detect Paediatric Delirium (PD) at an early stage. OBJECTIVE: The aim of this study was to determine the measurement properties of the PD component of the SOS-PD scale in critically ill children. METHODS: A prospective, observational study was performed in patients aged 3 months or older and admitted for more than 48h. These patients were assessed with the SOS-PD scale three times a day. If the SOS-PD total score was 4 or higher in two consecutive observations, the child psychiatrist was consulted to assess the diagnosis of PD using the Diagnostic and Statistical Manual-IV criteria as the "gold standard". The child psychiatrist was blinded to outcomes of the SOS-PD. The interrater reliability of the SOS-PD between the care-giving nurse and a researcher was calculated with the intraclass correlation coefficient (ICC). RESULTS: A total of 2088 assessments were performed in 146 children (median age 49 months; IQR 13-140). The ICC of 16 paired nurse-researcher observations was 0.90 (95% CI 0.70-0.96). We compared 63 diagnoses of the child psychiatrist versus SOS-PD assessments in 14 patients, in 13 of whom the diagnosis of PD was confirmed. The sensitivity was 96.8% (95% CI 80.4-99.5%) and the specificity was 92.0% (95% CI 59.7-98.9%). CONCLUSIONS: The SOS-PD scale shows promising validity for early screening of PD. Further evidence should be obtained from an international multicentre study.

Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children.

RATIONALE: Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity. OBJECTIVES: To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children. METHODS: From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3. MEASUREMENTS AND MAIN RESULTS: In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ. CONCLUSIONS: Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.

Safety of the Manchester Triage System to Detect Critically Ill Children at the Emergency Department.

OBJECTIVE: To assess the safety of the Manchester Triage System in pediatric emergency care for children who require admission to the intensive care unit (ICU). STUDY DESIGN: Between 2006 and 2013, 50 062 consecutive emergency department visits of children younger than the age of 16 years were included. We determined the percentage of undertriage, defined as the proportion of children admitted to ICU triaged as low urgent according to the Manchester Triage System, and diagnostic performance measures, including sensitivity, specificity, and diagnostic OR. Characteristics of undertriaged patients were compared with correctly triaged patients. In a logistic regression model, risk factors for undertriage were determined. RESULTS: In total, 238 (28.7%) of the 830 children admitted to ICU during the study period were undertriaged. Sensitivity of high Manchester Triage System urgency levels to detect ICU admission was 71% (95% CI 68%-74%) and specificity 85% (95% CI 85%-85%). Severity of illness was lower in undertriaged children than correctly triaged children admitted to ICU. Risk factors for undertriage were age <3 months, medical presenting problem, comorbidity, referral by a medical specialist or emergency medical services, and presentation during the evening or night shift. CONCLUSION: The Manchester Triage System misclassifies a substantial number of children who require ICU admission. Modifications targeted at young children and children with a comorbid condition could possibly improve safety of the Manchester Triage System in pediatric emergency care.

Short-Term Health-Related Quality of Life of Critically Ill Children Following Daily Sedation Interruption.

OBJECTIVE: Our earlier pediatric daily sedation interruption trial showed that daily sedation interruption in addition to protocolized sedation in critically ill children does not reduce duration of mechanical ventilation, length of stay, or amounts of sedative drugs administered when compared with protocolized sedation only, but undersedation was more frequent in the daily sedation interruption + protocolized sedation group. We now report the preplanned analysis comparing short-term health-related quality of life and posttraumatic stress symptoms between the two groups. DESIGN: Preplanned prospective part of a randomized controlled trial. SETTING: Two tertiary medical-surgical PICUs in the Netherlands. PATIENTS: Critically ill children requiring mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eight weeks after a child's discharge from the PICU, health-related quality of life was assessed with the validated Child Health Questionnaire and, only for children above 4 years old, posttraumatic stress was assessed with the Dutch Children's Responses to Trauma Inventory. Additionally, health-related quality of life of all study patients was compared with Dutch normative data. Of the 113 patients from two participating centers in the original study, 96 patients were eligible for follow-up and 64 patients were included (response rate, 67%). No difference was found with respect to health-related quality of life between the two study groups. None of the eight children more than 4 years old showed posttraumatic stress symptoms. CONCLUSIONS: Daily sedation interruption in addition to protocolized sedation for critically ill children did not seem to have an effect on short-term health-related quality of life. Also in view of the earlier found absence of effect on clinical outcome, we cannot recommend the use of daily sedation interruption + protocolized sedation.

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates.

OBJECTIVES: In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. METHODS: Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. RESULTS: Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. CONCLUSIONS: The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatment.