Current advances and gaps in knowledge on personalizing masks for non-invasive respiratory support: a scoping review.

Non-invasive 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 using commercially available interfaces is frequently encountered, which may result in patient discomfort and treatment inefficiency or failure. To overcome this challenge, over the last 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 regarding the personalization of ventilation masks. 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 targeting 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, while testing was limited to bench or case studies only. Most studies were positive regarding the performance (i.e. 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 3D 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 regarding implementation of large scale clinical programs that personalize non-invasive respiratory support masks for adults and children.

Evaluating fluid overload in critically ill children.

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.

HS-GC-MS analysis of volatile organic compounds after hyperoxia-induced oxidative stress: a validation study.

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.

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.

Development of personalized non-invasive ventilation masks for critically ill children: a bench study.

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.

The Changing Landscape of Respiratory Syncytial Virus Infections.

Respiratory syncytial virus (RSV), a negative-sense, enveloped RNA virus of the family Paramyxoviridae, subfamily Pneumovirinae, and genus Pneumovirus, is the single most important respiratory pathogen affecting infants and young children [...].

Generation of Aerosols by Noninvasive Respiratory Support Modalities: A Systematic Review and Meta-Analysis.

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.

Low energy nebulization preserves integrity of SARS-CoV-2 mRNA vaccines for respiratory delivery.

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.

Hyperoxia-induced lung injury in acute respiratory distress syndrome: what is its relative impact?

Over the past decade, the interest in oxygen toxicity has led to various observational studies and randomized clinical trials in critically ill patients, assessing the association with outcomes and the potential benefit of restrictive oxygenation targets. Yet to date, no consensus has been reached regarding the clinical impact of hyperoxia and hyperoxemia. In this perspective article, we explore the experimental and clinical evidence on hyperoxia-induced lung injury (HILI) and assess its relative impact in current critical care practice, specifically in patients who require oxygen therapy due to acute respiratory distress syndrome (ARDS). Here, we suggest that in current clinical practice in the setting of ARDS HILI may actually be of less importance than other ventilator-related factors.

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.

Long-Term Pulmonary Dysfunction by Hyperoxia Exposure during Severe Viral Lower Respiratory Tract Infection in Mice.

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% O2) or normoxia (21% O2) 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.

Reduced Air Leakage During Non-Invasive Ventilation Using a Simple Anesthetic Mask With 3D-Printed Adaptor in an Anthropometric Based Pediatric Head-Lung Model.

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.

Neutrophil Extracellular Traps Do Not Induce Injury and Inflammation in Well-Differentiated RSV-Infected Airway Epithelium.

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.

Current Practice of Fluid Maintenance and Replacement Therapy in Mechanically Ventilated Critically Ill Children: A European Survey.

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.