Background Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin–angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. Methods In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days–18 years), 26 adults (18–65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. Results Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. Conclusions Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS. Electronic supplementary material The online version of this article (10.1186/s13613-019-0529-4) contains supplementary material, which is available to authorized users.

Neutrophils are the predominant inflammatory cells recruited to the respiratory tract as part of the innate immune response to viral infections. Recent reports indicate the existence of distinct functional neutrophil subsets in the circulatory compartment of adults, following severe inflammatory conditions. Here, we evaluated the occurrence of neutrophil subsets in blood and broncho-alveolar lavage fluid during severe viral respiratory infection in infants based on CD16/CD62L expression. We show that during the course of severe respiratory infection infants may develop four heterogeneous neutrophil subsets in blood (mature, immature, progenitor, and suppressive neutrophils), each with distinct activation states. However, while isolated viral respiratory infection was characterized by a relative absence of suppressive neutrophils in both blood and lungs, only patients with bacterial co-infection were shown to produce suppressive neutrophils. These data suggest the occurrence of distinct and unique neutrophil subset responses during severe viral and (secondary) bacterial respiratory infection in infants.

Early fluid overload is an independent predictor of prolonged mechanical ventilation in young children with viral-lower respiratory tract disease. This study suggests that avoiding early fluid overload is a potential target to reduce duration of mechanical ventilation in these children. Prospective testing in a clinical trial is warranted to support this hypothesis.

The administration of an appropriate volume of intravenous fluids, while avoiding fluid overload, is a major challenge in the pediatric intensive care unit. Despite our efforts, fluid overload is a very common clinical observation in critically ill children, in particular in those with pediatric acute respiratory distress syndrome (PARDS). Patients with ARDS have widespread damage of the alveolar–capillary barrier, potentially making them vulnerable to fluid overload with the development of pulmonary edema leading to prolonged course of disease. Indeed, studies in adults with ARDS have shown that an increased cumulative fluid balance is associated with adverse outcome. However, age-related differences in the development and consequences of fluid overload in ARDS may exist due to disparities in immunologic response and body water distribution. This systematic review summarizes the current literature on fluid imbalance and management in PARDS, with special emphasis on potential differences with adult patients. It discusses the adverse effects associated with fluid overload and the corresponding possible pathophysiological mechanisms of its development. Our intent is to provide an incentive to develop age-specific fluid management protocols to improve PARDS outcomes.

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.

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

Background: 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 cardio-pulmonary physiology in PARDS is unclear. In this study, we compared the effect of a restrictive to a liberal fluid strategy on hemodynamic response and the formation of pulmonary edema in an animal model of PARDS. Methods: Sixteen mechanically ventilated lambs (2-6 weeks) received oleic acid infusion to induce PARDS and were randomized to a restrictive or liberal fluid strategy during a 6-hour period of mechanical ventilation. Transpulmonary thermodilution determined extravascular lung water (EVLW) and cardiac output (CO) Post-mortem lung wet-to-dry weight ratios were obtained by gravimetry. Results: Restricting fluids significantly reduced fluid intake, but increased 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 IQR 6.0-7.3 vs. 7.1 IQR 6.6-9.4 restrictive vs. liberal, p=0.725) between fluid strategies. Conclusions: 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 cardio-pulmonary effects.

Background In acute respiratory distress syndrome (ARDS), uncontrolled production of activators of coagulation and proinflammatory mediators results in a shift from an adequate local innate immune response to hypercoagulability and inflammation. This study aimed to investigate whether the protease inhibitors antithrombin (AT) and alpha-1 protease inhibitor (A1PI) may attenuate an exaggerated pulmonary immune response. Methods Lung injury was induced either by single intranasal administration of lipopolysaccharide (LPS) (5 mg/kg) in BALB/c mice or by combination of an intravenous injection of LPS (10 mg/kg) with subsequent injurious ventilation using high tidal volumes (12–15 ml/kg) for 4 h in RccHan Wistar rats. Animals received either a single bolus of AT (250 IU/kg) or A1PI (60 mg/kg) alone or in combination, with or without intravenous low-dose heparin (100 U/kg). Control animals received saline. Additional controls received neither LPS, nor ventilation, nor treatment. Endpoints were local and systemic markers of coagulation, e.g., thrombin–antithrombin complexes (TATc), and inflammation, e.g., interleukin-6. Results Both lung injury models resulted in a pronounced immune response within the pulmonary compartment shown by elevated levels of markers of coagulation and inflammation. The two-hit lung injury model also induced profound systemic coagulopathy and inflammation. Monotherapy with AT or A1PI did not reduce pulmonary coagulopathy or inflammation in any lung injury model. Nor did combination therapy with AT and A1PI result in a decrease of coagulation or inflammatory parameters. AT markedly reduced systemic levels of TATc in the two-hit lung injury model. Systemic inflammation was not affected by the different interventions. Additional administration of heparin did not lead to macroscopic bleeding incidences. Conclusions In two different murine models of acute lung injury, neither single therapy with AT or A1PI nor combination of both agents attenuates the pronounced pulmonary coagulation or inflammatory response.