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.

Neutrophil subset responses in infants with severe viral respiratory infection.

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 Prolongs Mechanical Ventilation in Children With Viral-Lower Respiratory Tract Disease.

OBJECTIVES: Viral-lower respiratory tract disease is common in young children worldwide and is associated with high morbidity. Acute respiratory failure due to viral-lower respiratory tract disease necessitates PICU admission for mechanical ventilation. In critically ill patients in PICU settings, early fluid overload is common and associated with adverse outcomes such as prolonged mechanical ventilation and increased mortality. It is unclear, however, if this also applies to young children with viral-lower respiratory tract disease induced acute respiratory failure. In this study, we aimed to investigate the relation of early fluid overload with adverse outcomes in mechanically ventilated children with viral-lower respiratory tract disease in a retrospective dataset. DESIGN: Retrospective cohort study. SETTING: Single, tertiary referral PICU. PATIENTS: One hundred thirty-five children (< 2 yr old) with viral-lower respiratory tract disease requiring mechanical ventilation admitted to the PICU of the Academic Medical Center, Amsterdam between 2008 and 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cumulative fluid balance on day 3 of mechanical ventilation was compared against duration of mechanical ventilation (primary outcome) and daily mean oxygen saturation index (secondary outcome), using uni- and multivariable linear regression. In 132 children, the mean cumulative fluid balance on day 3 was + 97.9 (49.2) mL/kg. Higher cumulative fluid balance on day 3 was associated with a longer duration of mechanical ventilation in multivariable linear regression (ß = 0.166; p = 0.048). No association was found between the fluid status and oxygen saturation index during the period of mechanical ventilation. CONCLUSIONS: 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.

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.

Lung ultrasound scoring in invasive mechanically ventilated children with severe bronchiolitis.

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.

Alkaline phosphatase in pulmonary inflammation-a translational study in ventilated critically ill patients and rats.

BACKGROUND: Alkaline phosphatase (AP), a dephosphorylating enzyme, is involved in various physiological processes and has been shown to have anti-inflammatory effects. AIM: To determine the correlation between pulmonary AP activity and markers of inflammation in invasively ventilated critically ill patients with or without acute respiratory distress syndrome (ARDS), and to investigate the effect of administration of recombinant AP on pulmonary inflammation in a well-established lung injury model in rats METHODS: AP activity was determined and compared with levels of various inflammatory mediators in bronchoalveolar lavage fluid (BALF) samples obtained from critically ill patients within 2 days of start of invasive ventilation. The endpoints of this part of the study were the correlations between AP activity and markers of inflammation, i.e., interleukin (IL)-6 levels in BALF. In RccHan Wistar rats, lung injury was induced by intravenous administration of 10 mg/kg lipopolysaccharide, followed by ventilation with a high tidal volume for 4 h. Rats received either an intravenous bolus of 1500 IU/kg recombinant AP or normal saline 2 h after intravenous LPS administration, right before start of ventilation. Endpoints of this part of the study were pulmonary levels of markers of inflammation, including IL-6, and markers of endothelial and epithelial dysfunction. RESULTS: BALF was collected from 83 patients; 10 patients had mild ARDS, and 15 had moderate to severe ARDS. AP activity correlated well with levels of IL-6 (r = 0.70), as well as with levels of other inflammatory mediators. Pulmonary AP activity between patients with and without ARDS was comparable (0.33 [0.14-1.20] vs 0.55 [0.21-1.42] U/L; p = 0.37). Animals with acute lung injury had markedly elevated pulmonary AP activity compared to healthy controls (2.58 [2.18-3.59] vs 1.01 [0.80-1.46] U/L; p < 0.01). Intravenous administration of recombinant AP did neither affect pulmonary inflammation nor endothelial and epithelial dysfunction. CONCLUSIONS: In ventilated critically ill patients, pulmonary AP activity correlates well with markers of pulmonary inflammation, such as IL-6 and IL-8. In animals with lung injury, pulmonary AP activity is elevated. Administration of recombinant AP does not alter pulmonary inflammation and endothelial or epithelial dysfunction in the acute phase of a murine lung injury model.

Less Is More?-A Feasibility Study of Fluid Strategy in Critically Ill Children With Acute Respiratory Tract Infection.

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.

Fluid restriction reduces pulmonary edema in a model of acute lung injury in mechanically ventilated rats.

Experimental acute lung injury models are often used to increase our knowledge on the acute respiratory distress syndrome (ARDS), however, existing animal models often do not take into account the impact of specific fluid strategies on the development of lung injury. In contrast, the current literature strongly suggests that fluid management strategies have a significant impact on clinical outcome of patients with ARDS. Thus, it is important to characterize the role of fluid management strategies in experimental models of lung injury. In this study we investigated the effect of two different fluid strategies on commonly used outcome variables in a short-term model of acute lung injury, in relation to age. Infant (2-3 weeks) and adult (3-4 months) Wistar rats received intratracheal instillations of lipopolysaccharide and 24 hours later were mechanically ventilated for 6 hours. During mechanical ventilation, rats from both age groups were randomized to either a standard or conservative intravenous fluid strategy. We found that the hemodynamic response in infant and adult rats was similar in both fluid strategies. Lung wet-to-dry ratios were lower in adult, but not in infant rats receiving the conservative fluid strategy as compared to the standard fluid strategy. There were age-related differences in markers of alveolar capillary barrier disruption and alveolar fluid clearance, yet these were unaffected by fluid strategy. Finally, we found significantly higher IL-1ß and TNF-α concentrations in the adult rats treated with the conservative as compared to the standard fluid regimen. In conclusion, the choice of fluid strategy in mechanically ventilated rats with experimental LPS-induced acute lung injury has a significant effect on pulmonary extravascular water, an important and well-recognized lung injury marker, and on the local pro-inflammatory cytokine profiles. We advocate the use of a more uniform, conservative, fluid strategy regimen in experimental models of acute lung injury.

Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study.

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.

Pediatric Acute Respiratory Distress Syndrome: Fluid Management in the PICU.

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.