Breath Markers of Oxidative Stress in Children with Severe Viral Lower Respiratory Tract Infection.

Severe viral lower respiratory tract infection (LRTI), resulting in both acute and long-term pulmonary disease, constitutes a substantial burden among young children. Viral LRTI triggers local oxidative stress pathways by infection and inflammation, and supportive care in the pediatric intensive care unit may further aggravate oxidative injury. The main goal of this exploratory study was to identify and monitor breath markers linked to oxidative stress in children over the disease course of severe viral LRTI. Exhaled breath was sampled during invasive ventilation, and volatile organic compounds (VOCs) were analyzed using gas chromatography and mass spectrometry. VOCs were selected in an untargeted principal component analysis and assessed for change over time. In addition, identified VOCs were correlated with clinical parameters. Seventy breath samples from 21 patients were analyzed. A total of 15 VOCs were identified that contributed the most to the explained variance of breath markers. Of these 15 VOCs, 10 were previously linked to pathways of oxidative stress. Eight VOCs, including seven alkanes and methyl alkanes, significantly decreased from the initial phase of ventilation to the day of extubation. No correlation was observed with the administered oxygen dose, whereas six VOCs showed a poor to strong positive correlation with driving pressure. In this prospective study of children with severe viral LRTI, the majority of VOCs that were most important for the explained variance mirrored clinical improvement. These breath markers could potentially help monitor the pulmonary oxidative status in these patients, but further research with other objective measures of pulmonary injury is required.

Predicting long-term neurocognitive outcome after pediatric intensive care unit admission for bronchiolitis-preliminary exploration of the potential of machine learning.

PURPOSE: For successful prevention and intervention, it is important to unravel the complex constellation of factors that affect neurocognitive functioning after pediatric intensive care unit (PICU) admission. This study aims (1) to elucidate the potential relevance of patient and PICU-related characteristics for long-term adverse neurocognitive outcome after PICU admission for bronchiolitis, and (2) to perform a preliminary exploration of the potential of machine learning as compared to linear regression to improve neurocognitive outcome prediction in a relatively small sample of children after PICU admission. METHODS: This cross-sectional observational study investigated 65 children aged 6-12 years with previous PICU admission for bronchiolitis (age ≤ 1 year). They were compared to demographically comparable healthy peers (n = 76) on neurocognitive functioning. Patient and PICU-related characteristics used for the prediction models were as follows: demographic characteristics, perinatal and disease parameters, laboratory results, and intervention characteristics, including hourly validated mechanical ventilation parameters. Neurocognitive outcome was measured by intelligence and computerized neurocognitive testing. Prediction models were developed for each of the neurocognitive outcomes using Regression Trees, k-Nearest Neighbors, and conventional linear regression analysis. RESULTS: The patient group had lower intelligence than the control group (p < .001, d = -0.59) and poorer performance in neurocognitive functions, i.e., speed and attention (p = .03, d = -0.41) and verbal memory (p < .001, d = -0.60). Lower intelligence was predicted by lower birth weight and lower socioeconomic status (R2 = 25.9%). Poorer performance on the speed and attention domain was predicted by younger age at follow-up (R2 = 53.5%). Poorer verbal memory was predicted by lower birth weight, younger age at follow-up, and greater exposure to acidotic events (R2 = 50.6%). The machine learning models did not reveal added value in terms of model performance as compared to linear regression. CONCLUSION: The findings of this study suggest that in children with previous PICU admission for bronchiolitis, (1) lower birth weight, younger age at follow-up, and lower socioeconomic status are associated with poorer neurocognitive outcome; and (2) greater exposure to acidotic events during PICU admission is associated with poorer verbal memory outcome. The findings of this study provide no evidence for the added value of machine learning models as compared to linear regression analysis in the prediction of long-term neurocognitive outcome in a relatively small sample of children. WHAT IS KNOWN: • Adverse neurocognitive outcomes are described in PICU survivors, which are known to interfere with development in other major domains of functioning, such as mental health, academic achievement, and socioeconomic success, highlighting neurocognition as an important outcome after PICU admission. • Machine learning is a rapidly growing field of artificial intelligence that is increasingly applied in health care settings, with great potential to capture the complexity of outcome prediction. WHAT IS NEW: • This study shows that lower birth weight, lower socioeconomic status, and greater exposure to acidotic events during PICU admission for bronchiolitis are associated with poorer long-term neurocognitive outcome after PICU admission. Results provide no evidence for the added value of machine learning models in a relatively small sample of children. • As bronchiolitis seldom manifests neurologically, the relation between acidotic events and neurocognitive outcome may reflect either potentially harmful effects of acidosis itself or related processes such as hypercapnia or hypoxic and/or ischemic events during PICU admission. This study further highlights the importance of structured follow-up to monitor long-term outcome of children after PICU admission.

Long-Term Follow-Up of Daily Life Functioning After Pediatric Intensive Care Unit Admission.

OBJECTIVE: To investigate the long-term impact of pediatric intensive care unit (PICU) admission on daily life functioning while exploring the potential mediating role of neurocognitive outcome. STUDY DESIGN: This cross-sectional observational study compared children aged 6-12 years with previous PICU admission (age ≤1 year) for bronchiolitis requiring mechanical ventilation ("patient group," n = 65) to demographically comparable healthy peers ("control group," n = 76). The patient group was selected because bronchiolitis is not expected to affect neurocognitive functioning in itself. Assessed daily life outcome domains were behavioral and emotional functioning, academic performance, and health-related quality of life (QoL). The role of neurocognitive outcomes in the relationship between PICU admission and daily life functioning was assessed by mediation analysis. RESULTS: The patient group did not differ from the control group regarding behavioral and emotional functioning but performed poorer on academic performance and school-related QoL (Ps ≤ .04, d = -0.48 to -0.26). Within the patient group, lower full-scale IQ (FSIQ) was associated with poorer academic performance and school-related QoL (Ps ≤ .02). Poorer verbal memory was associated with poorer spelling performance (P = .002). FSIQ mediated the observed effects of PICU admission on reading comprehension and arithmetic performance. CONCLUSIONS: Children admitted to the PICU are at risk for long-term adverse daily life outcomes in terms of academic performance and school-related QoL. Findings suggest that lower intelligence may contribute to academic difficulties after PICU admission. Findings underline the importance of monitoring daily life and neurocognitive functioning after PICU admission.

Viral, Bacterial, Metabolic, and Autoimmune Causes of Severe Acute Encephalopathy in Sub-Saharan Africa: A Multicenter Cohort Study.

OBJECTIVES: To assess whether viral, bacterial, metabolic, and autoimmune diseases are missed by conventional diagnostics among children with severe acute encephalopathy in sub-Saharan Africa. STUDY DESIGN: One hundred thirty-four children (6 months to 18 years) presenting with nontraumatic coma or convulsive status epilepticus to 1 of 4 medical referral centers in Uganda, Malawi, and Rwanda were enrolled between 2015 and 2016. Locally available diagnostic tests could be supplemented in 117 patients by viral, bacterial, and 16s quantitative polymerase chain reaction testing, metagenomics, untargeted metabolomics, and autoimmune immunohistochemistry screening. RESULTS: Fourteen (12%) cases of viral encephalopathies, 8 (7%) cases of bacterial central nervous system (CNS) infections, and 4 (4%) cases of inherited metabolic disorders (IMDs) were newly identified by additional diagnostic testing as the most likely cause of encephalopathy. No confirmed cases of autoimmune encephalitis were found. Patients for whom additional diagnostic testing aided causal evaluation (aOR 3.59, 90% CI 1.57-8.36), patients with a viral CNS infection (aOR 7.91, 90% CI 2.49-30.07), and patients with an IMD (aOR 9.10, 90% CI 1.37-110.45) were at increased risk for poor outcome of disease. CONCLUSIONS: Viral and bacterial CNS infections and IMDs are prevalent causes of severe acute encephalopathy in children in Uganda, Malawi, and Rwanda that are missed by conventional diagnostics and are associated with poor outcome of disease. Improved diagnostic capacity may increase diagnostic yield and might improve outcome of disease.

Long-term neurocognitive outcomes after pediatric intensive care: exploring the role of drug exposure.

BACKGROUND: Concerns exist regarding the impact of widely used clinical drugs on brain development. This study investigates long-term neurocognitive functioning in relation to frequently used drug exposure at the Pediatric Intensive Care Unit (PICU). METHODS: This study compared children aged 6-12 years with previous PICU admission (age ≤1 year) for bronchiolitis requiring mechanical ventilation (patient group, n = 65) to a demographically comparable control group (n = 76) on a broad range of neurocognitive outcomes. The patient group was selected because bronchiolitis seldom manifests neurologically and is therefore not expected to affect neurocognitive functioning in itself. The relation between exposure to sedatives, analgesics and anesthetics and neurocognitive outcomes was assessed by regression analyses. RESULTS: The patient group had lower intelligence than the control group (p < 0.001, d = -0.59) and poorer performance in neurocognitive functions; i.e., speed and attention (p = 0.03, d = -0.41) and verbal memory (p < 0.001, d = -0.60). Exposure to sedatives, analgesics and anesthetics was not related to neurocognitive outcomes. CONCLUSIONS: Children with PICU admission for bronchiolitis requiring mechanical ventilation are at risk of adverse neurocognitive outcomes. This study found no evidence for a role of exposure to sedatives, analgesics or anesthetics. Findings underline the importance of long-term follow-up after PICU admission, even in the absence of disease with neurological manifestation. IMPACT: Animal studies have indicated that exposing the maturing brain to clinical drugs may cause neurodegeneration. Clinical studies show mixed evidence regarding the association between clinical drugs and neurocognitive outcomes. This study provides evidence for considerably lower neurocognitive functioning among children with a history of PICU admission for bronchiolitis compared to healthy peers. Bronchiolitis seldom manifests neurologically and is therefore not expected to affect neurocognitive functioning in itself. We found no evidence supporting a relation between drug exposure (i.e., sedatives, analgesics and anesthetics) and long-term neurocognitive outcomes. Findings underline the importance of structured follow-up after PICU admission.

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.

Hospital-to-home transitions for children with medical complexity: part 1, a systematic review of reported outcomes.

Outcome selection to evaluate interventions to support a successful transition from hospital to home of children with medical complexity (CMC) may be difficult due to the variety in available outcomes. To support researchers in outcome selection, this systematic review aimed to summarize and categorize outcomes currently reported in publications evaluating the effectiveness of hospital-to-home transitional care interventions for CMC. We searched the following databases: Medline, Embase, Cochrane library, CINAHL, PsychInfo, and Web of Science for studies published between 1 January 2010 and 15 March 2023. Two reviewers independently screened the articles and extracted the data with a focus on the outcomes. Our research group extensively discussed the outcome list to identify those with similar definitions, wording or meaning. Consensus meetings were organized to discuss disagreements, and to summarize and categorize the data. We identified 50 studies that reported in total 172 outcomes. Consensus was reached on 25 unique outcomes that were assigned to six outcome domains: mortality and survival, physical health, life impact (the impact on functioning, quality of life, delivery of care and personal circumstances), resource use, adverse events, and others. Most frequently studied outcomes reflected life impact and resource use. Apart from the heterogeneity in outcomes, we also found heterogeneity in designs, data sources, and measurement tools used to evaluate the outcomes.     Conclusion: This systematic review provides a categorized overview of outcomes that may be used to evaluate interventions to improve hospital-to-home transition for CMC. The results can be used in the development of a core outcome set transitional care for CMC.

The Local and Systemic Exposure to Oxygen in Children With Severe Bronchiolitis on Invasive Mechanical Ventilation: A Retrospective Cohort Study.

OBJECTIVES: Oxygen supplementation is a cornerstone treatment in critically ill children with bronchiolitis in the PICU. However, potential deleterious effects of high-dose oxygen are well-known. In this study, we aim to describe the pulmonary (local) and arterial (systemic) oxygen exposure over the duration of invasive mechanical ventilation (IMV) in children with severe bronchiolitis. Our secondary aim was to estimate potentially avoidable exposure to high-dose oxygen in these patients. DESIGN: Retrospective cohort study. SETTING: Single-center, tertiary-care PICU. PATIENTS: Children younger than 2 years old admitted to the PICU for severe bronchiolitis receiving IMV. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hourly measurements of Fio2 and peripheral oxygen saturation (Spo2), and arterial blood gas data were collected up to day 10 of IMV. A total of 24,451 hours of IMV were observed in 176 patients (median age of 1.0 mo [interquartile range (IQR), 1.0-2.3 mo]). The pulmonary exposure to oxygen was highest during the first day of IMV (median time-weighted average [TWA]-Fio2 0.46 [IQR, 0.39-0.53]), which significantly decreased over subsequent days. The systemic exposure to oxygen was relatively low, as severe hyperoxemia (TWA-Pao2 > 248 Torr [> 33 kPa]) was not observed. However, overuse of oxygen was common with 52.3% of patients (n = 92) having at least 1 day of possible excessive oxygen exposure and 14.8% (n = 26) with severe exposure. Furthermore, higher oxygen dosages correlated with increasing overuse of oxygen (rrepeated measures, 0.59; 95% CI, 0.54-0.63). Additionally, caregivers were likely to keep Fio2 greater than or equal to 0.50 when Spo2 greater than or equal to 97%. CONCLUSIONS: Moderate to high-dose pulmonary oxygen exposure and potential overuse of oxygen were common in this cohort of severe bronchiolitis patients requiring IMV; however, this was not accompanied by a high systemic oxygen burden. Further studies are needed to determine optimal oxygenation targets to prevent overzealous use of oxygen in this vulnerable population.

Outcome in Children Admitted to the First PICU in Malawi.

OBJECTIVES: Dedicated PICUs are slowly starting to emerge in sub-Saharan Africa. Establishing these units can be challenging as there is little data from this region to inform which populations and approaches should be prioritized. This study describes the characteristics and outcome of patients admitted to the first PICU in Malawi, with the aim to identify factors associated with increased mortality. DESIGN: Review of a prospectively constructed PICU database. Univariate analysis was used to assess associations between demographic, clinical and laboratory factors, and mortality. Univariate associations ( p < 0.1) for mortality were entered in two multivariable models. SETTING: A recently opened PICU in a public tertiary government hospital in Blantyre, Malawi. PATIENTS: Children admitted to PICU between August 1, 2017, and July 31, 2019. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Of 531 included PICU admissions, 149 children died (28.1%). Mortality was higher in neonates (88/167; 52.7%) than older children (61/364; 16.8%; p ≤ 0.001). On univariate analysis, gastroschisis, trachea-esophageal fistula, and sepsis had higher PICU mortality, while Wilms tumor, other neoplasms, vocal cord papilloma, and foreign body aspiration had higher survival rates compared with other conditions. On multivariable analysis, neonatal age (adjusted odds ratio [AOR], 4.0; 95% CI, 2.0-8.3), decreased mental state (AOR, 5.8; 95 CI, 2.4-13.8), post-cardiac arrest (AOR, 2.0; 95% CI, 1.0-8.0), severe hypotension (AOR, 6.3; 95% CI, 2.0-19.1), lactate greater than 5 mmol/L (AOR, 4.2; 95% CI, 1.5-11.2), pH less than 7.2 (AOR, 3.1; 95% CI, 1.2-8.0), and platelets less than 150 × 10 9 /L (AOR, 2.4; 95% CI, 1.1-5.2) were associated with increased mortality. CONCLUSIONS: In the first PICU in Malawi, mortality was relatively high, especially in neonates. Surgical neonates and septic patients were identified as highly vulnerable, which stresses the importance of improvement of PICU care bundles for these groups. Several clinical and laboratory variables were associated with mortality in older children. In neonates, severe hypotension was the only clinical variable associated with increased mortality besides blood gas parameters. This stresses the importance of basic laboratory tests, especially in neonates. These data contribute to evidence-based approaches establishing and improving future PICUs in sub-Saharan Africa.

Structured Multidisciplinary Follow-Up After Pediatric Intensive Care: A Model for Continuous Data-Driven Health Care Innovation.

OBJECTIVES: Morbidity after PICU admission for critical illness is a growing concern. Sequelae may occur in various domains of functioning and can only appropriately be determined through structured follow-up. Here, we describe the process of designing and implementing a structured multidisciplinary follow-up program for patients and their parents after PICU admission and show the first results illustrating the significance of our program. DESIGN: Prospective observational cohort study. SETTING: Outpatient PICU follow-up clinic. PATIENTS: Patients 0-18 years old admitted to our PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In our structured multidisciplinary follow-up program, follow-up care is provided by a pediatric intensivist and psychologist and in addition, depending on patient's critical illness and received PICU treatment(s), by a pediatric pulmonologist, cardiologist, neurologist, and/or neuropsychologist. All consultations are scheduled consecutively. Collected data are stored in a hospital-wide data warehouse and used for yearly health care evaluation sessions as well as scientific research. Challenges in organizing this follow-up program include technological challenges, providing time-efficient care, participation rate, and completeness of questionnaires. In our experience, a dedicated team is essential to tackle these challenges. Our first results, obtained in 307 of 388 referred patients (79.1%), showed the diversity of problems arising after PICU discharge, including physical, neurocognitive, and psychosocial sequelae. In addition, our data also reflected the risk of psychosocial problems among parents. Within the limited operation time of our follow-up program, the program has evolved based on our experiences and the data collected. CONCLUSIONS: We successfully developed and implemented a structured multidisciplinary follow-up program for patients and their parents after PICU admission. This program may help to timely initiate appropriate interventions, improve the standard of care during and after PICU admission, and facilitate scientific research on outcome and prognosis after PICU admission.

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.

Barriers and perceived benefits of early mobilisation programmes in Dutch paediatric intensive care units.

BACKGROUND: Early mobilisation of critically ill adults has been proven effective and is safe and feasible for critically ill children. However, barriers and perceived benefits of paediatric intensive care unit (PICU) staff involvement in mobilising critically ill children are largely unknown. AIM: To explore the barriers and perceived benefits regarding early mobilisation of critically ill children as perceived by PICU staff. STUDY DESIGN: A cross-sectional survey study among staff from seven PICUs in the Netherlands has been carried out. RESULTS: Two hundred and fifteen of the 641 health care professionals (33.5%) who were invited to complete a questionnaire responded, of whom 159 (75%) were nurses, 40 (19%) physicians, and 14 (6%) physical therapists. Respondents considered early mobilisation potentially beneficial to shorten the duration of mechanical ventilation (86%), improve wake/sleep rhythm (86%) and shorten the length of stay in the PICU (85%). However, staff were reluctant to mobilise patients on extracorporeal membrane oxygenation (ECMO) (63%), and patients with traumatic brain injury (49%). Perceived barriers to early mobilisation were hemodynamic instability (78%), risk of dislocation of lines/tubes (74%), and level of sedation (62%). In total, 40.3% of PICU nurses stated that physical therapists provided enough support in their PICU, but 84.6% of the physical therapists believed support was sufficient. CONCLUSION: Participating PICU staff considered early mobilisation as potentially beneficial in improving patient outcomes, although barriers were noted in certain patient groups. RELEVANCE TO CLINICAL PRACTICE: We identified barriers to early mobilisation which should be addressed in implementation research projects in order to make early mobilisation in critically ill children work.

Intelligence outcome of pediatric intensive care unit survivors: a systematic meta-analysis and meta-regression.

BACKGROUND: Long-term morbidity after pediatric intensive care unit (PICU) admission is a growing concern. Both critical illness and accompanying PICU treatments may impact neurocognitive development as assessed by its gold standard measure; intelligence. This meta-analysis and meta-regression quantifies intelligence outcome after PICU admission and explores risk factors for poor intelligence outcome. METHODS: PubMed, Embase, CINAHL and PsycINFO were searched for relevant studies, published from database inception until September 7, 2021. Using random-effects meta-analysis, we calculated the standardized mean difference in full-scale intelligence quotient (FSIQ) between PICU survivors and controls across all included studies and additionally distinguishing between PICU subgroups based on indications for admission. Relation between demographic and clinical risk factors and study's FSIQ effect sizes was investigated using random-effects meta-regression analysis. RESULTS: A total of 123 articles was included, published between 1973 and 2021, including 8,119 PICU survivors and 1,757 controls. We found 0.47 SD (7.1 IQ-points) lower FSIQ scores in PICU survivors compared to controls (95%CI -0.55 to -0.40, p < .001). All studied PICU subgroups had lower FSIQ compared to controls (range 0.38-0.88 SD). Later year of PICU admission (range 1972-2016) and longer PICU stay were related to greater FSIQ impairment (R2 = 21%, 95%CI -0.021 to -0.007, p < .001 and R2 = 2%, 95%CI -0.027 to -0.002, p = .03, respectively), whereas male sex and higher rate of survivors were related to smaller FSIQ impairment (R2 = 5%, 95%CI 0.001 to 0.014, p = .03 and R2 = 11%, 95%CI 0.006 to 0.022, p < .001, respectively). Meta-regression in PICU subgroups showed that later year of PICU admission was related to greater FSIQ impairment in children admitted after cardiac surgery and heart- or heart-lung transplantation. Male sex was related to smaller FSIQ impairment in children admitted after cardiac surgery. Older age at PICU admission and older age at follow-up were related to smaller FSIQ impairment in children admitted after heart- or heart-lung transplantation. CONCLUSIONS: PICU survivors, distinguished in a wide range of subgroups, are at risk of intelligence impairment. Length of PICU stay, female sex and lower rate of survivors were related to greater intelligence impairment. Intelligence outcome has worsened over the years, potentially reflecting the increasing percentage of children surviving PICU admission.

Long-Term Pulmonary Outcomes in Children Mechanically Ventilated for Severe Bronchiolitis.

OBJECTIVES: Bronchiolitis is a common indication for mechanical ventilation in the PICU. Both bronchiolitis and invasive mechanical ventilation may cause adverse long-term pulmonary outcomes. This study investigates children with a history of invasive mechanical ventilation for bronchiolitis, addressing: 1) the extent, 2) potential explanatory factors, and 3) possible impact on daily life activities of adverse long-term pulmonary outcomes. DESIGN: Single-center cohort study. SETTING: Outpatient PICU follow-up clinic. PATIENTS: Children 6-12 years old with a history of invasive mechanical ventilation for bronchiolitis (age < 2 yr). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Long-term pulmonary outcomes were assessed by a standardized questionnaire and by spirometry. Nineteen out of 74 included children (26%) had adverse long-term pulmonary outcomes, of whom the majority had asthma (14/74, 19%). By logistic regression analysis, we assessed whether background characteristics and PICU-related variables were associated with long-term pulmonary outcomes. In general, we failed to identify any explanatory factors associated with adverse long-term pulmonary outcomes. Nonetheless, atopic disease in family and longer duration of invasive mechanical ventilation (days) were associated with greater odds of having asthma at follow-up (odds ratio, 6.4 [95% CI, 1.2-36.0] and 1.3 [95% CI, 1.0-1.7], respectively). Adverse pulmonary outcome at follow-up was associated with more frequent use of pulmonary medication after PICU discharge. In comparison with those without adverse pulmonary outcomes, we did not identify any difference in frequency of sports performance or school absenteeism. CONCLUSIONS: In this single-center cohort, one-quarter of the children attending follow-up with a history of invasive mechanical ventilation for bronchiolitis had adverse, mostly previously undetected, long-term pulmonary outcomes at 6-12 years. Atopic disease in family and longer duration of invasive mechanical ventilation were associated with presence of asthma. The presence of adverse pulmonary outcomes was associated with more frequent use of pulmonary medication after PICU discharge.

Etiology, Pathophysiology and Mortality of Shock in Children in Low (Middle) Income Countries: A Systematic Review.

OBJECTIVES: Shock is a life-threatening condition in children in low- and middle-income countries (LMIC), with several controversies. This systematic review summarizes the etiology, pathophysiology and mortality of shock in children in LMIC. METHODS: We searched for studies reporting on children with shock in LMIC in PubMed, Embase and through snowballing (up to 1 October 2019). Studies conducted in LMIC that reported on shock in children (1 month-18 years) were included. We excluded studies only containing data on neonates, cardiac surgery patients or iatrogenic causes. We presented prevalence data, pooled mortality estimates and conducted subgroup analyses per definition, region and disease. Etiology and pathophysiology data were systematically collected. RESULTS: We identified 959 studies and included 59 studies of which six primarily studied shock. Definitions used for shock were classified into five groups. Prevalence of shock ranged from 1.5% in a pediatric hospital population to 44.3% in critically ill children. Pooled mortality estimates ranged between 3.9-33.3% for the five definition groups. Important etiologies included gastroenteritis, sepsis, malaria and severe anemia, which often coincided. The pathophysiology was poorly studied but suggests that in addition to hypovolemia, dissociative and cardiogenic shock are common in LMIC. CONCLUSIONS: Shock is associated with high mortality in hospitalized children in LMIC. Despite the importance few studies investigated shock and as a consequence limited data on etiology and pathophysiology of shock is available. A uniform bedside definition may help boost future studies unravelling shock etiology and pathophysiology in LMIC.

Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit.

Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of reactive oxygen species and myeloperoxidase during NETs formation in the airways) would increase mucus viscoelasticity. We collected human airway mucus from endotracheal tubes of healthy patients admitted for elective surgery and coincubated these samples with NETs from phorbol 12-myristate 13-acetate-stimulated neutrophils. Unstimulated neutrophils served as controls, and blocking experiments were performed with dornase alfa for extracellular DNA and the free radical scavenger dimethylthiourea for oxidation. Compared with controls, the coincubation of mucus with NETs resulted in 1) significantly increased mucus viscoelasticity (macrorheology) and 2) significantly decreased mesh pore size of the mucus and decreased movement of muco-inert nanoparticles through the mucus (microrheology), but 3) NETs did not cause visible changes in the microstructure of the mucus by scanning EM. Incubation with either dornase alfa or dimethylthiourea attenuated the observed changes in macrorheology and microrheology. This suggests that the release of NETs may contribute to airway mucus obstruction by increasing mucus viscoelasticity and that this effect is not solely due to the release of DNA but may in part be due to oxidative stress.

Early restrictive fluid resuscitation has no clinical advantage in experimental severe pediatric acute respiratory distress syndrome.

Intravenous fluids are widely used to treat circulatory deterioration in pediatric acute respiratory distress syndrome (PARDS). However, the accumulation of fluids in the first days of PARDS is associated with adverse outcome. As such, early fluid restriction may prove beneficial, yet the effects of such a fluid strategy on the cardiopulmonary physiology in PARDS are unclear. In this study, we compared the effect of a restrictive with a liberal fluid strategy on a hemodynamic response and the formation of pulmonary edema in an animal model of PARDS. Sixteen mechanically ventilated lambs (2-6 wk) received oleic acid infusion to induce PARDS and were randomized to a restrictive or liberal fluid strategy during a 6-h period of mechanical ventilation. Transpulmonary thermodilution determined extravascular lung water (EVLW) and cardiac output (CO). Postmortem lung wet-to-dry weight ratios were obtained by gravimetry. Restricting fluids significantly reduced fluid intake but increased the use of vasopressors among animals with PARDS. Arterial blood pressure was similar between groups, yet CO declined significantly in animals receiving restrictive fluids (P = 0.005). There was no difference in EVLW over time (P = 0.111) and lung wet-to-dry weight ratio [6.1, interquartile range (IQR) = 6.0-7.3 vs. 7.1, IQR = 6.6-9.4, restrictive vs. liberal, P = 0.725] between fluid strategies. Both fluid strategies stabilized blood pressure in this model, yet early fluid restriction abated CO. Early fluid restriction did not limit the formation of pulmonary edema; therefore, this study suggests that in the early phase of PARDS, a restrictive fluid strategy is not beneficial in terms of immediate cardiopulmonary effects.

Monitoring of micturition and bladder volumes can replace routine indwelling urinary catheters in children receiving intravenous opioids: a prospective cohort study.

In this prospective observational study, the incidence, risk factors and the time to event of urinary retention in children receiving intravenous opioids were evaluated. Urinary retention was confirmed by ultrasound following the inability to void for 8 h or earlier in patients experiencing discomfort. In total, 207 opioid episodes were evaluated, of which 199 (96.1%) concerned morphine, in 187 children admitted to the pediatric ward or pediatric intensive care unit. The median age was 7.6 years (IQR 0.9-13.8), and 123 (59.4%) were male. The incidence of urinary retention was 31/207 (15.0%) opioid episodes, in which 14/32 (43.8%) patients received continuous sedation for mechanical ventilation and 17/175 (9.7%) received no sedation. Multivariable logistic regression analysis showed a significant association with continuous sedation (OR 6.8, 95% CI 2.7-17.4, p 0.001) and highest daily fluid intake (OR 0.8 per 10% deviation of normal intake, 95% CI 0.7-0.9, p 0.01). Opioid dosage, age and gender were not significantly associated. Most events (28/31, 90.3%) occurred within 24 h.Conclusion: The incidence of urinary retention in children receiving intravenous opioids is low, indicating that placement of urinary catheters is not routinely necessary in these patients. However, micturition and bladder volumes must be monitored, especially in sedated children and during the first 24 h of opioid administration. What is Known: • Great variation exists in the routine placement of urinary catheters in children receiving IV opioids. What is New: • Confirmed by ultrasound, the incidence of urinary retention in children receiving intravenous opioids in this study was 15%, indicating that placement of urinary catheters is not routinely necessary in these patients. • Children receiving continuous sedation for invasive mechanical ventilation showed a sevenfold greater risk of developing urinary retention than non-sedated patients.

Burden of respiratory syncytial virus bronchiolitis on the Dutch pediatric intensive care units.

Respiratory syncytial virus (RSV) bronchiolitis causes substantial morbidity and mortality in young children, but insight into the burden of RSV bronchiolitis on pediatric intensive care units (PICUs) is limited. We aimed to determine the burden of RSV bronchiolitis on the PICUs in the Netherlands. Therefore, we identified all children ≤ 24 months of age with RSV bronchiolitis between 2003 and 2016 from a nationwide PICU registry. Subsequently we manually checked their patient records for correct diagnosis and collected patient characteristics, additional clinical data, respiratory support modes, and outcome. In total, 2161 children were admitted to the PICU for RSV bronchiolitis. The annual number of admissions increased significantly during the study period (ß 4.05, SE 1.27, p = 0.01), and this increase was mostly driven by increased admissions in children up to 3 months old. Concomitantly, non-invasive respiratory support significantly increased (ß 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (ß 6.69, SE 0.96, p < 0.01), whereas the use of invasive ventilation remained stable.Conclusion: The burden of severe RSV bronchiolitis on PICUs has increased in the Netherlands. Concomitantly, the use of non-invasive respiratory support, especially HFNC, has increased. What is Known: • RSV bronchiolitis is a major cause of childhood morbidity and mortality and may require pediatric intensive care unit admission. • The field of pediatric critical care for severe bronchiolitis has changed due to increased non-invasive respiratory support options. What is New: • The burden of RSV bronchiolitis for the Dutch PICUs has increased. These data inform future strategic PICU resource planning and implementation of RSV preventive strategies. • There was a significant increase in the use of high flow nasal cannula at the PICU, but the use of invasive mechanical ventilation did not decrease.

Perioperative apnea in infants with hypertrophic pyloric stenosis: A systematic review.

BACKGROUND: Infantile hypertrophic pyloric stenosis (IHPS) leads to excessive vomiting and metabolic alkalosis, which may subsequently cause apnea. Although it is generally assumed that metabolic derangements should be corrected prior to surgery to prevent apnea, the exact incidence of perioperative apneas in infants with IHPS and the association with metabolic alkalosis are unknown. We performed this systematic review to assess the incidence of apnea in infants with IHPS and to verify the possible association between apnea and metabolic alkalosis. METHODS: We searched MEDLINE, Embase, and Cochrane library to identify studies regarding infants with metabolic alkalosis, respiratory problems, and hypertrophic pyloric stenosis. We conducted a descriptive synthesis of the findings of the included studies. RESULTS: Thirteen studies were included for analysis. Six studies described preoperative apnea, three studies described postoperative apnea, and four studies described both. All studies were of low quality or had other research questions. We found an incidence of 27% of preoperative and 0.2%-16% of postoperative apnea, respectively. None of the studies examined the association between apnea and metabolic alkalosis in infants with IHPS. CONCLUSIONS: Infants with IHPS may have a risk to develop perioperative apnea. However, the incidence rates should be interpreted with caution because of the low quality and quantity of the studies. Therefore, further studies are required to determine the incidence of perioperative apnea in infants with IHPS. The precise underlying mechanism of apnea in these infants is still unknown, and the role of metabolic alkalosis should be further evaluated.