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Objectives: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction., Design: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process., Methods: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate., Results: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified., Conclusions: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

Purpose: Much of the common practice in paediatric mechanical ventilation is based on personal experiences and what paediatric critical care practitioners have adopted from adult and neonatal experience. This presents a barrier to planning and interpretation of clinical trials on the use of specific and targeted interventions. We aim to establish a European consensus guideline on mechanical ventilation of critically children., Methods: The European Society for Paediatric and Neonatal Intensive Care initiated a consensus conference of international European experts in paediatric mechanical ventilation to provide recommendations using the Research and Development/University of California, Los Angeles, appropriateness method. An electronic literature search in PubMed and EMBASE was performed using a combination of medical subject heading terms and text words related to mechanical ventilation and disease-specific terms., Results: The Paediatric Mechanical Ventilation Consensus Conference (PEMVECC) consisted of a panel of 15 experts who developed and voted on 152 recommendations related to the following topics: (1) general recommendations, (2) monitoring, (3) targets of oxygenation and ventilation, (4) supportive measures, (5) weaning and extubation readiness, (6) normal lungs, (7) obstructive diseases, (8) restrictive diseases, (9) mixed diseases, (10) chronically ventilated patients, (11) cardiac patients and (12) lung hypoplasia syndromes. There were 142 (93.4%) recommendations with "strong agreement". The final iteration of the recommendations had none with equipoise or disagreement., Conclusions: These recommendations should help to harmonise the approach to paediatric mechanical ventilation and can be proposed as a standard-of-care applicable in daily clinical practice and clinical research.

Purpose: Although overall paediatric septic shock mortality is decreasing, refractory septic shock (RSS) is still associated with high mortality. A definition for RSS is urgently needed to facilitate earlier identification and treatment. We aim to establish a European society of paediatric and neonatal intensive care (ESPNIC) experts' definition of paediatric RSS., Methods: We conducted a two-round Delphi study followed by an observational multicentre retrospective study. One hundred and fourteen paediatric intensivists answered a clinical case-based, two-round Delphi survey, identifying clinical items consistent with RSS. Multivariate analysis of these items in a development single-centre cohort (70 patients, 30 % mortality) facilitated development of RSS definitions based on either a bedside or computed severity score. Both scores were subsequently tested in a validation cohort (six centres, 424 patients, 11.6 % mortality)., Results: From the Delphi process, the draft definition included evidence of myocardial dysfunction and high blood lactate levels despite high vasopressor treatment. When assessed in the development population, each item was independently associated with the need for extracorporeal life support (ECLS) or death. Resultant bedside and computed septic shock scores had high discriminative power against the need for ECLS or death, with areas under the receiver operating characteristics curve of 0.920 (95 % CI 0.89-0.94), and 0.956 (95 % CI 0.93-0.97), respectively. RSS defined by a bedside score equal to or higher than 2 and a computed score equal to or higher than 3.5 was associated with a significant increase in mortality., Conclusions: This ESPNIC definition of RSS accurately identifies children with the most severe form of septic shock., Competing Interests: Compliance with ethical standards Funding None. Conflicts of interest Dr. Javouhey reports grants from CSL Behring, personal fees from Gambro-Baxter, outside the submitted work. Dr. Tissieres reports grants from Merieux Foundation, non-financial support from Chiesi Inc, outside the submitted work. All other authors declare that they have no conflict of interest.

Purpose: A new acute respiratory distress syndrome (ARDS) definition has been recently issued: the so-called Berlin definition (BD) has some characteristics that could make it suitable for pediatrics. The European Society for Pediatric Neonatal Intensive Care (ESPNIC) Respiratory Section started a project to evaluate BD validity in early childhood. A secondary aim was reaching a consensus on clinical tools (risk factors list and illustrative radiographs) to help the application of BD., Methods: This was an international, multicenter, retrospective study enrolling 221 children [aged greater than 30 days and less than 18 months; median age 6 (range 2-13) months], admitted to seven European pediatric intensive care units (PICU) with acute lung injury (ALI) or ARDS diagnosed with the earlier definition., Results: Patients were categorized according to the two definitions, as follows: ALI, 36; ARDS, 185 (for the American-European Consensus Conference (AECC) definition); mild, 36; moderate, 97; severe ARDS, 88 (for BD). Mortality (13.9 % for mild ARDS; 11.3 % for moderate ARDS; 25 % for severe ARDS, p = 0.04) and the composite outcome extracorporeal membrane oxygenation (ECMO)/mortality (13.9 % for mild ARDS; 11.3 % for moderate ARDS; 28.4 % for severe ARDS, p < 0.01) were different across the BD classes, whereas they were similar using the previous definition. Mortality [HR 2.7 (95 % CI 1.1-7.1)] and ECMO/mortality [HR 3 (95 % CI 1.1-7.9)] were increased only for the severe ARDS class and remained significant after adjustment for confounding factors. PICU stay was not different across severity classes, irrespective of the definition used. There was significant concordance between raters evaluating radiographs [ICC 0.6 (95 % CI 0.2-0.8)] and risk factors [ICC 0.92 (95 % CI 0.8-0.97)]., Conclusions: BD validity for children is similar to that already reported in adults and mainly due to the introduction of a "severe ARDS" category. We provided clinical tools to use BD for clinical practice, research, and health services planning in pediatric critical care.

Purpose: Non-invasive positive pressure ventilation (NIV) is being increasingly used in paediatric critical care, although its use in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is still debated. No definite data are available for the prediction of NIV outcome in such selected populations. We aimed to identify which factors might affect NIV failure in paediatric ALI/ARDS patients., Methods: A retrospective cohort study using comprehensive predictivity analysis was performed. All children admitted to our paediatric intensive care unit over a 4-year period for ALI/ARDS were reviewed. Basic, clinical, physiological parameters and their change after 1 h of NIV were considered and subjected to univariate analysis. Candidate prognostic variables were then subjected to multicollinearity scrutiny and logistic regression. Finally, variables significant in the logistic regression were subjected to predictivity analysis., Results: The number of organ failures at admission (NOF) is a strong predictor of NIV failure (odds ratio 5.26; p = 0.004). Having only one organ failure provides a probability of NIV success of 85.7% (sensitivity 87%; specificity 49%). One NIV failure will be predicted and avoided for every four cases in which the presence of other organ failures is incorporated into the clinical decision., Conclusions: NOF significantly predicts the NIV failure. Children with no organ failures other than ALI/ARDS may safely be treated with NIV.

Purpose: Meconium aspiration syndrome (MAS) is a life-threatening neonatal lung injury, whose pathophysiology has been mainly studied in animal models. In such models, pancreatic secretory phospholipase A2 (sPLA2-IB) and proinflammatory cytokines present in meconium challenge the lungs, catabolising surfactant and harming the alveoli. Locally produced phospholipases might perpetuate the injury and influence clinical pictures and therapeutic approaches. Our aim is to verify whether pulmonary phospholipase A2 (sPLA2-IIA) is involved in the damage and to determine if phospholipases and their modulators are associated with MAS clinical pictures., Methods: We studied distinct phospholipases A2 and their modulators in broncho-alveolar lavage (BAL) fluids and in meconium of five MAS neonates and in five control neonates ventilated for extrapulmonary reasons., Results: MAS patients have higher amounts of pulmonary phospholipase (sPLA2-IIA; P = 0.016) and Clara cell secretory protein (CCSP; P = 0.032). The local production of such proteins by the lung is confirmed by their very low levels in meconium. sPLA2-IIA contributes to the higher total enzyme activity in MAS patients, as compared to controls (P = 0.008). Cytosolic phospholipase was not detected in meconium or alveolar fluid. sPLA2 activity and sPLA2-IIA concentrations are correlated with the TNFα and with the release of CCSP. sPLA2 total activity, sPLA2-IIA and TNFα concentrations in BAL fluids correlate with the oxygenation impairment and haemorrhagic lung oedema., Conclusions: Pulmonary sPLA2 is locally produced and contributes to the total sPLA2 activity during MAS. CCSP is also produced in trying to lower the inflammation. Both sPLA2 activity and sPLA2-IIA are significantly correlated with oxygenation impairment and haemorrhagic lung oedema.

Rationale: Limited data are available on predictors for surfactant retreatment in preterm infants with respiratory distress syndrome (RDS)., Objective: To study the pharmacokinetics of exogenous surfactant and the clinical parameters associated with surfactant redosing., Methods: Exogenous surfactant pharmacokinetics was studied in 125 preterm infants (birth weight 997 ± 432 g; gestational age 28.0 ± 2.6 weeks) with moderate to severe RDS requiring mechanical ventilation. Clinical and respiratory parameters were recorded hourly, and surfactant disaturated-phosphatidylcholine (DSPC) half-life, pool size, and endogenous synthesis were calculated by stable isotope tracing of surfactant DSPC isolated from serial tracheal aspirates. Univariate and multiple logistic regression were used to study the effects of clinical and surfactant kinetic variables on the need for redosing., Results: Fifty-three infants (42.4%) received one dose, 51 (40.8%) two doses, and 21 (16.8%) three doses. Median (interquartile range, IQR) DSPC half-life was 21 (13-39), 11 (7-17), and 10 (7-16) h after the first, second, and third dose, respectively (p = 0.07). Univariate analysis showed a significantly shorter DSPC half-life in infants requiring more surfactant doses. On logistic analysis, risk of redosing was higher with lower birth weight, worse radiological score, shorter DSPC half-life, and surfactant dose of 100 mg/kg, whilst it was lower with elective high-frequency ventilation at time of intubation, instead of conventional ventilation., Conclusions: When optimizing surfactant replacement therapy and its cost-benefit ratio, pharmacokinetics and clinical variables associated with need of redosing should be taken into account.

Background: Noninvasive high frequency oscillatory ventilation through nasal prongs (nHFOV) has been proposed as a new respiratory support in neonatology. We studied the effect of ventilation parameters and nasal prongs on nHFOV efficacy and mechanics., Methods: Customized sealed circuits connecting a SM3100A oscillator to a neonatal lung model were developed to evaluate the effect of applying HFOV via two different sized nasal prongs on delivered tidal volume and pressure. Measurements were made across a range of frequencies and pressures; amplitude was set to obtain visible lung oscillation., Results: Volume delivered by peak-to-peak oscillation, ventilation, and pressure significantly differed among the interfaces, being higher for large cannulae and the control circuit (p < 0.0001). The interposition of a large or small nasal prong reduced volume to 56 and 26%, ventilation to 32 and 9%, and mean pressure to 83 and 79%, respectively, of the values measured for the direct connection of the oscillator to the test lung. Volume and ventilation were inversely related to frequency, which was particularly evident with larger diameter circuits due to higher delivered tidal volume (R (2) > 0.9). Increasing ventilation was associated with larger tidal volume and nasal prong diameter (adjusted R (2) = 0.97)., Conclusions: nHFOV using common nasal prongs is technically possible. Efficiency of tidal volume delivery is significantly affected by prong diameter.

Objective: To verify the feasibility of non-invasive ventilation (NIV) in immunocompromised children affected by ARDS., Setting: University Hospital PICU., Patients: Twenty-three consecutive immunocompromised children treated with NIV for ARDS., Interventions: All consecutive patients received NIV through a face-mask or a helmet., Results: No differences were found regarding admission data and severity scores between NIV responders and non-responders. Early and sustained improvement in PaO2/FiO2 ratio were observed in 82 and 74% of cases, respectively. 13 out of 23 patients (54.5%) avoided intubation and were discharged from the PICU; ten patients required intubation: two of them survived and eight patients died (two refractory hypoxemia, three septic shock, three multi-organ failure). PICU and intra-hospital mortality was significantly higher for NIV-nonresponders (P < 0.001). PICU stay was significantly shorter for NIV responders (P = 0.03). NIV responders had significantly lower heart and respiratory rate at the end of treatment (P < 0.001 and P = 0.048, respectively)., Conclusions: NIV administration is feasible and well tolerated in immunocompromised children with ARDS. A short NIV trial can be used to verify the usefulness of the technique. A randomized controlled trial is needed to confirm the efficacy of NIV in immunocompromised children requiring ventilatory support for ARDS.

Background and Purposes: Bile acids have been implicated in some forms of acute lung injury, including meconium aspiration and bile acid pneumonia in neonates, or aspiration related ARDS in adults. Secretory phospholipase A2 (sPLA2) is now known as a key enzyme in the lung injury pathways and is supposed to be responsible for surfactant dysfunction. Our aim was to investigate the interaction between bile acids and sPLA2 in an extracellular environment representing an in vitro model of aspiration., Methods: In vitro study using broncho-alveolar lavage (BAL) of 23 neonates/infants (<6 m) with healthy lungs. BAL supernatants were assayed for sPLA2 activity in basal condition and after addition of randomly assigned concentrations of bile acids (BA) or normal saline. Samples coming from neonates were then challenged with poractant-alfa up to a phospholipid concentration equal to that found in babies after the surfactant treatment for respiratory distress syndrome. sPLA2 activity was again measured, being corrected for serum/supernatant urea ratio and for confounding factors., Results: High concentrations of BA (5 micromol/l) significantly increased (P = 0.012) sPLA2 activity, leading to increased surfactant catabolism. This finding was not observed with lower BA concentration and this is consistent with available literature data and may indicate an anionic activation of the enzyme by bile acids. Increased activity was significantly reverted by the addition of exogenous surfactant (P = 0.004) which was able to reduce sPLA2 activity almost to the baseline level., Conclusions: BA are likely to contribute to lung injury, causing surfactant inactivation through the increased sPLA2 activity. Other mechanisms cannot be excluded and require further studies to be clarified.

Purposes: Secretory phospholipase A2 hydrolyzes phosphoglycerides and it has been shown to be involved in alveolar inflammation and surfactant degradation. It plays an important role in acute lung injury but it has never been studied in newborn infants. We were aimed to investigate the phospholipase A2 activity in neonatal lung injury and its relationship with ventilatory findings., Setting: Third level university hospital NICU., Methods: We measured phospholipase activity in broncho-alveolar lavage fluid of 21 neonates with hyaline membrane disease, 10 with pneumonia or sepsis and 10 controls, ventilated for extrapulmonary reasons. Fluid was obtained before surfactant administration on the first day of life and phospholipase activity was measured using an ultrasensitive enzymatic method. Before lavage, lung mechanics in pressure controlled synchronized intermittent mandatory ventilation was analyzed., Results: Phospholipase A2 was higher in babies ventilated for sepsis/pneumonia compared to hyaline membrane disease and to control babies. Phospholipase correlated negatively with dynamic compliance, positively with inspired oxygen fraction, mean airway pressure and oxygenation index. These correlations still remained significant after multivariate analysis, adjusting for possible confounding factors. Phospholipase was not correlated with blood and alveolar pH, gestational age, birth weight, blood gases, Apgar score, tidal volume, surfactant need and ventilation time., Conclusions: These are the first data about phospholipase A2 in neonates. The enzyme plays a role in neonatal lung injury, especially in infection related respiratory failure. It is associated with lung stiffness, higher mean airway pressure and need for oxygen.