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Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

Background: Aerosol therapy is commonly used during treatment with high-flow nasal cannula (HFNC) in the intensive care unit (ICU). Heated humidification inside the HFNC tubing circuit leads to unwanted condensation, which may greatly limit the efficiency of drug delivery. In this study, we aimed to investigate whether a novel humidification system, which decouples temperature and humidity control, can improve the delivered dose., Methods: In a bench study setup, fluorescein sodium solution was nebulized using a vibrating-mesh nebulizer in an infant HFNC circuit to measure the delivered dose, with a conventional versus a novel decoupled humidifier. The deposition of fluorescein inside each breathing circuit component and a final collection filter at the end of the nasal cannula was collected and quantified with a UV-vis spectrometer. Droplet sizes at different sections of the breathing circuit were measured by laser diffraction. Three air flow rates: 5, 10 and 15 L/min, and two nebulizer positions: (1) at the humidifier and (2) after the inspiratory tube, were tested., Results: The delivered dose decreased with increasing flow rate for the conventional setup and was higher when the nebulizer was placed after the inspiratory tube. Turning off the conventional humidifier 10 minutes before and during nebulization did not improve the delivered dose. The decoupled humidifier achieved a significantly higher (p = .002) delivered dose than the conventional setup. The highest delivered dose obtained by the decoupled humidifier was 62.4% when the nebulizer was placed after the humidifier, while the highest dose obtained for the conventional humidifier was 36.3% by placing the nebulizer after the inspiratory tube., Conclusions: In this bench study, we found that the delivered dose for an infant HFNC nebulization setup could be improved significantly by decoupling temperature and humidity control inside the HFNC circuit, as it reduced drug deposition inside the breathing circuit., (Copyright © 2024 by Daedalus Enterprises.)

Noninvasive respiratory support delivered through a face mask has become a cornerstone treatment for adults and children with acute or chronic respiratory failure. However, an imperfect mask fit by using commercially available interfaces is frequently encountered, which may result in patient discomfort and treatment inefficiency or failure. To overcome this challenge, over the past decade, increasing attention has been given to the development of personalized face masks, which are custom-made to address the specific facial dimensions of an individual patient. With this scoping review, we aim to provide a comprehensive overview of the current advances and gaps in knowledge with regard to the personalization masks for CPAP and NIV. We performed a systematic search of the literature and identified and summarized a total of 23 studies. Most studies included were involved in the development of nasal masks. Studies that targeted adult respiratory care mainly focused on chronic (home) ventilation and included some clinical testing in a relevant subject population. In contrast, pediatric studies focused mostly on respiratory support in the acute setting, whereas testing was limited to bench or case studies only. Most studies were positive with regard to the performance (ie, comfort, level of air leak, and mask pressure applied to the skin) of personalized masks in bench testing or in human, healthy or patient, subjects. Advances in the field of 3-dimensional scanning and soft material printing were identified, but important gaps in knowledge remain. In particular, more insight into cushion materials, headgear design, clinical feasibility, and cost-effectiveness is needed before definite recommendations can be made with regard to implementation of large-scale clinical programs that personalize noninvasive respiratory support masks for adults and children., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2024 by Daedalus Enterprises.)

Purpose of Review: To review the evaluation and management of fluid overload in critically ill children., Recent Findings: Emerging evidence associates fluid overload, i.e. having a positive cumulative fluid balance, with adverse outcome in critically ill children. This is most likely the result of impaired organ function due to increased extravascular water content. The combination of a number of parameters, including physical, laboratory and radiographic markers, may aid the clinician in monitoring and quantifying fluid status, but all have important limitations, in particular to discriminate between intra- and extravascular water volume. Current guidelines advocate a restrictive fluid management, initiated early during the disease course, but are hampered by the lack of high quality evidence., Summary: Recent advances in early evaluation of fluid status and (tailored) restrictive fluid management in critically ill children may decrease complications of fluid overload, potentially improving outcome. Further clinical trials are necessary to provide the clinician with solid recommendations., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Background: Obtaining a properly fitting non-invasive ventilation (NIV) mask to treat acute respiratory failure is a major challenge, especially in young children and patients with craniofacial abnormalities. Personalization of NIV masks holds promise to improve pediatric NIV efficiency. As current customization methods are relatively time consuming, this study aimed to test the air leak and surface pressure performance of personalized oronasal face masks using 3D printed soft materials. Personalized masks of three different biocompatible materials (silicone and photopolymer resin) were developed and tested on three head models of young children with abnormal facial features during preclinical bench simulation of pediatric NIV. Air leak percentages and facial surface pressures were measured and compared for each mask., Results: Personalized NIV masks could be successfully produced in under 12 h in a semi-automated 3D production process. During NIV simulation, overall air leak performance and applied surface pressures were acceptable, with leak percentages under 30% and average surface pressure values mostly remaining under normal capillary pressure. There was a small advantage of the masks produced with soft photopolymer resin material., Conclusion: This first, proof-of-concept bench study simulating NIV in children with abnormal facial features, showed that it is possible to obtain biocompatible, personalized oronasal masks with acceptable air leak and facial surface pressure performance using a relatively short, and semi-automated production process. Further research into the clinical value and possibilities for application of personalized NIV masks in critically ill children is needed., (© 2024. The Author(s).)

Background: Exhaled volatile organic compounds (VOCs), particularly hydrocarbons from oxidative stress-induced lipid peroxidation, are associated with hyperoxia exposure. However, important heterogeneity amongst identified VOCs and concerns about their precise pathophysiological origins warrant translational studies assessing their validity as a marker of hyperoxia-induced oxidative stress. Therefore, this study sought to examine changes in VOCs previously associated with the oxidative stress response in hyperoxia-exposed lung epithelial cells., Methods: A549 alveolar epithelial cells were exposed to hyperoxia for 24 h, or to room air as normoxia controls, or hydrogen peroxide as oxidative-stress positive controls. VOCs were sampled from the headspace, analysed by gas chromatography coupled with mass spectrometry and compared by targeted and untargeted analyses. A secondary analysis of breath samples from a large cohort of critically ill adult patients assessed the association of identified VOCs with clinical oxygen exposure., Results: Following cellular hyperoxia exposure, none of the targeted VOCs, previously proposed as breath markers of oxidative stress, were increased, and decane was significantly decreased. Untargeted analysis did not reveal novel identifiable hyperoxia-associated VOCs. Within the clinical cohort, three previously proposed breath markers of oxidative stress, hexane, octane, and decane had no real diagnostic value in discriminating patients exposed to hyperoxia., Conclusions: Hyperoxia exposure of alveolar epithelial cells did not result in an increase in identifiable VOCs, whilst VOCs previously linked to oxidative stress were not associated with oxygen exposure in a cohort of critically ill patients. These findings suggest that the pathophysiological origin of previously proposed breath markers of oxidative stress is more complex than just oxidative stress from hyperoxia at the lung epithelial cellular level., (© 2024. The Author(s).)

Importance: Infection control guidelines have historically classified high-flow nasal oxygen and noninvasive ventilation as aerosol-generating procedures that require specialized infection prevention and control measures., Objective: To evaluate the current evidence that high-flow nasal oxygen and noninvasive ventilation are associated with pathogen-laden aerosols and aerosol generation., Data Sources: A systematic search of EMBASE and PubMed/MEDLINE up to March 15, 2023, and CINAHL and ClinicalTrials.gov up to August 1, 2023, was performed., Study Selection: Observational and (quasi-)experimental studies of patients or healthy volunteers supported with high-flow nasal oxygen or noninvasive ventilation were selected., Data Extraction and Synthesis: Three reviewers were involved in independent study screening, assessment of risk of bias, and data extraction. Data from observational studies were pooled using a random-effects model at both sample and patient levels. Sensitivity analyses were performed to assess the influence of model choice., Main Outcomes and Measures: The main outcomes were the detection of pathogens in air samples and the quantity of aerosol particles., Results: Twenty-four studies were included, of which 12 involved measurements in patients and 15 in healthy volunteers. Five observational studies on SARS-CoV-2 detection in a total of 212 air samples during high-flow nasal oxygen in 152 patients with COVID-19 were pooled for meta-analysis. There was no association between high-flow nasal oxygen and pathogen-laden aerosols (odds ratios for positive samples, 0.73 [95% CI, 0.15-3.55] at the sample level and 0.80 [95% CI, 0.14-4.59] at the patient level). Two studies assessed SARS-CoV-2 detection during noninvasive ventilation (84 air samples from 72 patients). There was no association between noninvasive ventilation and pathogen-laden aerosols (odds ratios for positive samples, 0.38 [95% CI, 0.03-4.63] at the sample level and 0.43 [95% CI, 0.01-27.12] at the patient level). None of the studies in healthy volunteers reported clinically relevant increases in aerosol particle production by high-flow nasal oxygen or noninvasive ventilation., Conclusions and Relevance: This systematic review and meta-analysis found no association between high-flow nasal oxygen or noninvasive ventilation and increased airborne pathogen detection or aerosol generation. These findings argue against classifying high-flow nasal oxygen or noninvasive ventilation as aerosol-generating procedures or differentiating infection prevention and control practices for patients receiving these modalities.

Competing Interests: Research time for Ms Stilma was based on a personal grant from NWO Netherlands Organization for Scientific Research (023.011.016), during the conduct of the study. Financial support for the rheology device was provided to Dr Bem by the CJ Vaillant Fund. The other authors have disclosed no conflicts of interest.

Nebulization of mRNA therapeutics can be used to directly target the respiratory tract. A promising prospect is that mucosal administration of lipid nanoparticle (LNP)-based mRNA vaccines may lead to a more efficient protection against respiratory viruses. However, the nebulization process can rupture the LNP vehicles and degrade the mRNA molecules inside. Here we present a novel nebulization method able to preserve substantially the integrity of vaccines, as tested with two SARS-CoV-2 mRNA vaccines. We compare the new method with well-known nebulization methods used for medical respiratory applications. We find that a lower energy level in generating LNP droplets using the new nebulization method helps safeguard the integrity of the LNP and vaccine. By comparing nebulization techniques with different energy dissipation levels we find that LNPs and mRNAs can be kept largely intact if the energy dissipation remains below a threshold value, for LNP integrity 5-10 J/g and for mRNA integrity 10-20 J/g for both vaccines., (© 2023. The Author(s).)

Competing Interests: I declare no competing interests.

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., Competing Interests: Dr. Lilien received funding through a PhD scholarship (Academic Medical Center Graduate School, Amsterdam UMC) through which this study and previous work was partly funded and from a KNAW Ter Meulen Grant/KNAW Medical Sciences Fund (Royal Netherlands Academy of Arts & Sciences). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Viral-induced lower respiratory tract infection (LRTI), mainly by respiratory syncytial virus (RSV), causes a major health burden among young children and has been associated with long-term respiratory dysfunction. Children with severe viral LRTI are frequently treated with oxygen therapy, hypothetically posing an additional risk factor for pulmonary sequelae. The main goal of this study was to determine the effect of concurrent hyperoxia exposure during the acute phase of viral LRTI on long-term pulmonary outcome. As an experimental model for severe RSV LRTI in infants, C57Bl/6J mice received an intranasal inoculation with the pneumonia virus of mice J3666 strain at post-natal day 7, and were subsequently exposed to hyperoxia (85% O 2 ) or normoxia (21% O 2 ) from post-natal day 10 to 17 during the acute phase of disease. Long-term outcomes, including lung function and structural development, were assessed 3 weeks post-inoculation at post-natal day 28. Compared to normoxic conditions, hyperoxia exposure in PVM-inoculated mice induced a transient growth arrest without subsequent catchup growth, as well as a long-term increase in airway resistance. This hyperoxia-induced pulmonary dysfunction was not associated with developmental changes to the airway or lung structure. These findings suggest that hyperoxia exposure during viral LRTI at young age may aggravate subsequent long-term pulmonary sequelae. Further research is needed to investigate the specific mechanisms underlying this alteration to pulmonary function.

Objectives: Airway mucus obstruction is a major challenge in children admitted to the paediatric intensive care unit (PICU). We aimed to evaluate the evidence and contemporary use of the mucolytic medication dornase alfa for non-cystic fibrosis conditions in the PICU., Methods: (1) We performed a systematic review with searches in PubMed, EMBASE, and the Cochrane Library. Study selection: for quality assessment and data synthesis, we included only randomised controlled trials (RCTs) that compared dornase alfa to standard care or placebo in critically-ill paediatric patients (<18 years of age) in the PICU. However, non-randomised controlled studies and case series are also discussed. Data extraction: data were extracted independently by multiple reviewers using data extraction forms. The primary outcome was duration of mechanical ventilation. Data synthesis: The GRADE approach was used for quality assessment. No meta-analysis could be performed. (2) A national cross-sectional survey among all seven PICUs in the Netherlands was also performed., Results: The systematic review yielded only one RCT, comparing dornase alfa with normal saline in children after cardiac surgery. In this study, dornase alfa led to a reduction in duration of mechanical ventilation by approximately 1 day (36% reduction). In addition, we found nine retrospective observational and case studies. The survey revealed high current use of dornase alfa in Dutch PICUs: 42% of the respondents reported prescribing dornase alfa at least once every week. Only 4% of the respondents reported having access to a local PICU dornase alfa protocol., Conclusions: The off-label use of dornase alfa in the PICU is frequent without strong evidence or local protocols, highlighting the need for further research on the effectiveness of this mucolytic agent., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2022. Re-use permitted under CC BY. Published by BMJ.)

Non-invasive ventilation (NIV) is increasingly used in the support of acute respiratory failure in critically ill children admitted to the pediatric intensive care unit (PICU). One of the major challenges in pediatric NIV is finding an optimal fitting mask that limits air leakage, in particular for young children and those with specific facial features. Here, we describe the development of a pediatric head-lung model, based on 3D anthropometric data, to simulate pediatric NIV in a 1-year-old child, which can serve as a tool to investigate the effectiveness of NIV masks. Using this model, the primary aim of this study was to determine the extent of air leakage during NIV with our recently described simple anesthetic mask with a 3D-printed quick-release adaptor, as compared with a commercially available pediatric NIV mask. The simple anesthetic mask provided a better seal resulting in lower air leakage at various positive pressure levels as compared with the commercial mask. These data further support the use of the simple anesthetic mask as a reasonable alternative during pediatric NIV in the acute setting. Moreover, the pediatric head-lung model provides a promising tool to study the applicability and effectiveness of customized pediatric NIV masks in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hovenier, Goto, Huysmans, van Gestel, Klein-Blommert, Markhorst, Dijkman and Bem.)

Purpose: Viral bronchiolitis is a major cause of pediatric intensive care unit (PICU) admission. Insight in the trends of bronchiolitis-associated PICU admissions is limited, but imperative for future PICU resource and capacity planning., Materials and Methods: We retrospectively studied trends in PICU admissions for bronchiolitis in six European sites, including three full national registries, between 2000 and 2019 and calculated population-based estimates per 100,000 children where appropriate. Information concerning risk factors for severe disease and use of invasive mechanical ventilation was also collected when available., Results: In total, there were 15,606 PICU admissions for bronchiolitis. We observed an increase in the annual number, rate and estimates per 100,000 children of PICU admissions for bronchiolitis at all sites over the last two decades, while the proportion of patients at high risk for severe disease remained relatively stable., Conclusions: The international increased burden of bronchiolitis for the PICU is concerning, and warrants further international attention and investigation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) causes a major burden of disease. The host response in RSV-LRTI is characterized by airway epithelial injury, inflammation and neutrophil influx, with the formation of neutrophil extracellular traps (NETs). However, the precise role of NETs in the pathophysiology of RSV-LRTI remains to be elucidated. Here, we used well-differentiated human airway epithelial cultures (HAE) of a pediatric and adult donor to study whether NETs cause airway epithelial injury and inflammation in the setting of RSV infection. The exposure of uninfected and RSV-infected HAE cultures to NETs, as produced by stimulation of neutrophils by a low dose of phorbol 12-myristate 13-acetate (PMA), did not induce or aggravate cell injury or inflammation. RSV infection of HAE cultures caused release of pro-inflammatory cytokines such as IL-6 and RANTES in both adult and pediatric cultures, but the differential gene expression for regulated cell death differed between culture donors. In this in vitro airway epithelial model, NETs in the setting of RSV infection did not cause or aggravate epithelial injury or inflammation.

Appropriate fluid management in mechanically ventilated critically ill children remains an important challenge and topic of active discussion in pediatric intensive care medicine. An increasing number of studies show an association between a positive fluid balance or fluid overload and adverse outcomes. However, to date, no international consensus regarding fluid management or removal strategies exists. The aim of this study was to obtain more insight into the current clinical practice of fluid therapy in mechanically ventilated critically ill children. On behalf of the section of cardiovascular dynamics of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) we conducted an anonymous survey among pediatric intensive care unit (PICU) specialists in Europe regarding fluid overload and management. A total of 107 study participants responded to the survey. The vast majority of respondents considers fluid overload to be a common phenomenon in mechanically ventilated children and believes this complication is associated with adverse outcomes, such as mortality and duration of respiratory support. Yet, only 75% of the respondents administers a lower volume of fluids (reduction of 20% of normal intake) to mechanically ventilated critically ill children on admission. During PICU stay, a cumulative fluid balance of more than 5% is considered to be an indication to reduce fluid intake and start diuretic treatment in most respondents. Next to fluid balance calculation, the occurrence of peripheral and/or pulmonary edema (as assessed including by chest radiograph and lung ultrasound) was considered an important clinical sign of fluid overload entailing further therapeutic action. In conclusion, fluid overload in mechanically ventilated critically ill children is considered an important problem among PICU specialists, but there is great heterogeneity in the current clinical practice to avoid this complication. We identify a great need for further prospective and randomized investigation of the effects of (restrictive) fluid strategies in the PICU., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Arrahmani, Ingelse, van Woensel, Bem and Lemson.)

Importance: Oxygen supplementation is a cornerstone treatment in pediatric critical care. Accumulating evidence suggests that overzealous use of oxygen, leading to hyperoxia, is associated with worse outcomes compared with patients with normoxia., Objectives: To evaluate the association of arterial hyperoxia with clinical outcome in critically ill children among studies using varied definitions of hyperoxia., Data Sources: A systematic search of EMBASE, MEDLINE, Cochrane Library, and ClinicalTrials.gov from inception to February 1, 2021, was conducted., Study Selection: Clinical trials or observational studies of children admitted to the pediatric intensive care unit that examined hyperoxia, by any definition, and described at least 1 outcome of interest. No language restrictions were applied., Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology guideline and Newcastle-Ottawa Scale for study quality assessment were used. The review process was performed independently by 2 reviewers. Data were pooled with a random-effects model., Main Outcomes and Measures: The primary outcome was 28-day mortality; this time was converted to mortality at the longest follow-up owing to insufficient studies reporting the initial primary outcome. Secondary outcomes included length of stay, ventilator-related outcomes, extracorporeal organ support, and functional performance., Results: In this systematic review, 16 studies (27 555 patients) were included. All, except 1 randomized clinical pilot trial, were observational cohort studies. Study populations included were post-cardiac arrest (n = 6), traumatic brain injury (n = 1), extracorporeal membrane oxygenation (n = 2), and general critical care (n = 7). Definitions and assessment of hyperoxia differed among included studies. Partial pressure of arterial oxygen was most frequently used to define hyperoxia and mainly by categorical cutoff. In total, 11 studies (23 204 patients) were pooled for meta-analysis. Hyperoxia, by any definition, showed an odds ratio of 1.59 (95% CI, 1.00-2.51; after Hartung-Knapp adjustment, 95% CI, 1.05-2.38) for mortality with substantial between-study heterogeneity (I2 = 92%). This association was also found in less heterogeneous subsets. A signal of harm was observed at higher thresholds of arterial oxygen levels when grouped by definition of hyperoxia. Secondary outcomes were inadequate for meta-analysis., Conclusions and Relevance: These results suggest that, despite methodologic limitations of the studies, hyperoxia is associated with mortality in critically ill children. This finding identifies the further need for prospective observational studies and importance to address the clinical implications of hyperoxia in critically ill children.

Objectives: Swift extubation is important to prevent detrimental effects of invasive mechanical ventilation but carries the risk of extubation failure. Accurate tools to assess extubation readiness are lacking. This study aimed to describe the effect of extubation on diaphragm activity in ventilated infants and children. Our secondary aim was to compare diaphragm activity between failed and successfully extubated patients., Design: Prospective, observational study., Setting: Single-center tertiary neonatal ICU and PICU., Patients: Infants and children receiving invasive mechanical ventilation longer than 24 hours., Interventions: None., Measurements and Main Results: Diaphragm activity was measured with transcutaneous electromyography, from 15 minutes before extubation till 180 minutes thereafter. Peak and tonic activity, inspiratory amplitude, inspiratory area under the curve, and respiratory rate were calculated from the diaphragm activity waveform. One hundred forty-seven infants and children were included (median postnatal age, 1.9; interquartile range, 0.9-6.7 wk). Twenty patients (13.6%) failed extubation within 72 hours. Diaphragm activity increased rapidly after extubation and remained higher throughout the measurement period. Pre extubation, peak (end-inspiratory) diaphragm activity and tonic (end-inspiratory) diaphragm activity were significantly higher in failure, compared with success cases (5.6 vs 7.0 μV; p = 0.04 and 2.8 vs 4.1 μV; p = 0.04, respectively). Receiver operator curve analysis showed the highest area under the curve for tonic (end-inspiratory) diaphragm activity (0.65), with a tonic (end-inspiratory) diaphragm activity greater than 3.4 μV having a combined sensitivity and specificity of 55% and 77%, respectively, to predict extubation outcome. After extubation, diaphragm activity remained higher in patients failing extubation., Conclusions: Diaphragm activity rapidly increased after extubation. Patients failing extubation had a higher level of diaphragm activity, both pre and post extubation. The predictive value of the diaphragm activity variables alone was limited. Future studies are warranted to assess the additional value of electromyography of the diaphragm in combined extubation readiness assessment., Competing Interests: Dr. van Kaam’s institution received funding from Vyaire. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Competing Interests: We declare no competing interests. We thank Stephane Leteurtre, the Groupe Francophone de Réanimation et d’Urgences pédiatriques, and the Dutch Pediatric Intensive Care Evaluation study group for previously collected data.

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 (β 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 (β 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (β 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., (© 2021. The Author(s).)

Background: There is a persistent concern over the risk of respiratory pathogen transmission, including SARS-CoV-2, via the formation of aerosols (ie, a suspension of microdroplets and residual microparticles after evaporation) generated during high-flow nasal cannula (HFNC) oxygen therapy in critically ill patients. This concern is fueled by limited available studies on this subject. In this study, we tested our hypothesis that HFNC treatment is not associated with increased aerosol formation as compared to conventional oxygen therapy., Methods: We used laser light scattering and a handheld particle counter to detect and quantify aerosols in healthy subjects and in adults with acute respiratory disease, including COVID-19, during HFNC or conventional oxygen therapy., Results: The use of HFNC was not associated with increased formation of aerosols as compared to conventional oxygen therapy in both healthy subjects ( n = 3) and subjects with acute respiratory disease, including COVID-19 ( n = 17)., Conclusions: In line with scarce previous clinical and experimental findings, our results indicate that HFNC itself does not result in overall increased aerosol formation as compared to conventional oxygen therapy. This suggests there is no increased risk of respiratory pathogen transmission to health care workers during HFNC., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)

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.

Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of global child morbidity and mortality. Every year, seasonal RSV outbreaks put high pressure on paediatric intensive care units (PICUs) worldwide, including in the Netherlands, and this burden appears to be increasing. Weather conditions have a strong influence on RSV activity, and climate change has been proposed as a potential important determinant of future RSV-related health care utilisation. In this national study spanning a total of 13 years with 2161 PICU admissions for RSV bronchiolitis, we aimed (1) to identify meteorological variables that were associated with the number of PICU admissions for RSV bronchiolitis in the Netherlands and (2) to determine if longitudinal changes in these variables occurred over time as a possible explanation for the observed increase in PICU burden. Poisson regression modelling was used to identify weather variables (aggregated in months and weeks) that predicted PICU admissions, and linear regression analysis was used to assess changes in the weather over time. Maximum temperature and global radiation best predicted PICU admissions, with global radiation showing the most stable strength of effect in both month and week data. However, we did not observe a significant change in these weather variables over the 13-year time period. Based on our study, we could not identify changing weather conditions as a potential contributing factor to the increased RSV-related PICU burden in the Netherlands.

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.

We measure aerosol persistence to assess the risk of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in public spaces. Direct measurement of aerosol concentrations, however, has proven to be technically difficult; we propose the use of handheld particle counters as a novel and easily applicable method to measure aerosol concentrations. This allows us to perform measurements in typical public spaces, each differing in volume, the number of people, and the ventilation rate. These data are used to estimate the relation between the aerosol persistence time and the risk of infection with SARS-CoV-2., (© 2020 Author(s).)

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Lung ultrasound (LUS) is an emerging tool that may be used in the diagnosis and follow-up of children with viral bronchiolitis. In this study, we describe LUS abnormalities in children receiving invasive mechanical ventilation (IMV) for severe bronchiolitis in the pediatric intensive care unit (PICU). Our aim was to semiquantify the loss of aeration and examine the association between serial LUS scores and oxygenation anomaly, as a marker of disease severity., Design: Prospective, observational study in a single-center PICU., Methods: LUS was performed by multiple observers using two different LUS scoring systems (counting B-lines and aeration score) in 17 patients in the PICU, generating 320 images. Oxygen saturation index (OSI) was the primary outcome marker to describe the severity of oxygenation anomaly., Results: Pulmonary aeration was moderately impaired with a homogeneous anterolateral pattern. LUS scores worsened after 24 hours, to improve in subsequent days. Both LUS scores were positively correlated with OSI on the first day of IMV (counting B-lines P = .034, r = .52 and LUS aeration score P = .017, r = .57), but not thereafter. There was considerable variability in the LUS scores despite moderate to high agreement between the observers., Conclusions: In children receiving IMV for severe bronchiolitis, pulmonary aeration is moderately impaired. LUS scores positively correlate with severity of oxygenation anomaly only in the acute phase of disease. We speculate that with the progression of disease other factors affect LUS patterns (eg, fluid overload, atelectasis), which may complicate the interpretation of LUS in follow-up of this specific cohort in the PICU., (© 2020 Wiley Periodicals LLC.)

Transmission of SARS-CoV-2 leading to COVID-19 occurs through exhaled respiratory droplets from infected humans. Currently, however, there is much controversy over whether respiratory aerosol microdroplets play an important role as a route of transmission. By measuring and modeling the dynamics of exhaled respiratory droplets, we can assess the relative contribution of aerosols to the spreading of SARS-CoV-2. We measure size distribution, total numbers, and volumes of respiratory droplets, including aerosols, by speaking and coughing from healthy subjects. Dynamic modeling of exhaled respiratory droplets allows us to account for aerosol persistence times in confined public spaces. The probability of infection by inhalation of aerosols when breathing in the same space can then be estimated using current estimates of viral load and infectivity of SARS-CoV-2. The current known reproduction numbers show a lower infectivity of SARS-CoV-2 compared to, for instance, measles, which is known to be efficiently transmitted through the air. In line with this, our study of transmission of SARS-CoV-2 suggests that aerosol transmission is a possible but perhaps not a very efficient route, in particular from non-symptomatic or mildly symptomatic individuals that exhibit low viral loads., (© 2020 Author(s).)

Clinical assessment of the work of breathing (WOB) remains a cornerstone in respiratory support decision-making in the pediatric intensive care unit (PICU). In this study, we determined the interobserver agreement of 30 observers (PICU physicians and nurses) on WOB and multiple signs of effort of breathing in 10 spontaneously breathing children admitted to the PICU. By reliability analysis, the agreement on overall WOB was poor to moderate, and only three separate signs of effort of breathing (breathing rate, stridor, and grunting) showed moderate-to-good interobserver reliability. We conclude that the interobserver agreement on the clinical WOB judgment among PICU physicians and nurses is low., Competing Interests: Conflict of Interest None declared., (© Thieme Medical Publishers.)

Background: Fluid overload is common in critically ill children and is associated with adverse outcome. Therefore, restricting fluid intake may be beneficial. This study aims to study the feasibility of a randomized controlled trial (RCT) comparing a conservative to a standard, more liberal, strategy of fluid management in mechanically ventilated pediatric patients with acute respiratory tract infection (ARTI). Methods: This is a feasibility study in a single, tertiary referral pediatric intensive care unit (PICU). Twenty-three children receiving mechanical ventilation for ARTI, without ongoing hemodynamic support, admitted to the PICU of the Emma Children's Hospital/Amsterdam UMC between 2016 and 2018 were included. Patients were randomized to a conservative (<70% of normal intake) or standard (>85% of normal intake) fluid strategy, which was kept throughout the period of mechanical ventilation. Results: Primary endpoints were adherence to fluid strategy and safety parameters such as calorie and protein intake. Secondary outcomes were cumulative fluid intake (CFI) and cumulative fluid balance (CFB) on day 3. In the conservative group, in 75% of the mechanical ventilation days patients achieved their target fluid intake. Median [25th-75th percentiles] calorie intake over all mechanical ventilation days was 67.9 [51.5-74.0] kcal/kg/day in the conservative vs. 67.2 [58.0-75.2] kcal/kg/day in the standard group ( p = 0.878). Protein intake was 1.6 [1.3-1.8] gr protein/kg in the conservative and 1.5 [1.2-1.7] gr protein/kg in the standard group ( p = 0.598). No adverse effects on hemodynamics or electrolyte imbalances were noted. Mean (±SD) CFI on day 3 was 262.3 (±58.9) ml/kg in the conservative group vs. 360.5 (±52.6) ml/kg in the standard fluid group ( p < 0.001), which did not result in a lower CFB. Conclusions: A conservative fluid strategy in mechanically ventilated children with ARTI seems feasible, without limiting metabolic needs. However, in our study a conservative fluid strategy surprisingly did not reduce the degree of fluid overload. This study aids the design and sample size calculation of a future larger multicenter RCT, in which we need to redefine the target fluid strategy, possibly by even further fluid restriction and early initiation of active diuresis. Clinical Trial Registration : ClinicalTrials.gov, identifier: NCT02989051., (Copyright © 2019 Ingelse, Geukers, Dijsselhof, Lemson, Bem and van Woensel.)