European survey on Paediatric Early Warning Systems, and other processes used to aid the recognition and response to children's deterioration on hospital wards.

BACKGROUND: Internationally, there is an increasing trend in using Rapid Response Systems (RRS) to stabilize in-patient deterioration. Despite a growing evidence base, there remains limited understanding of the processes in place to aid the early recognition and response to deteriorating children in hospitals across Europe. AIM/S: To describe the processes in place for early recognition and response to in-patient deterioration in children in European hospitals. STUDY DESIGN: A cross-sectional opportunistic multi-centre European study, of hospitals with paediatric in-patients, using a descriptive self-reported, web-based survey, was conducted between September 2021 and March 2022. The sampling method used chain referral through members of European and national societies, led by country leads. The survey instrument was an adaptation to the survey of Recognition and Response Systems in Australia. The study received ethics approval. Descriptive analysis and Chi-squared tests were performed to compare results in European regions. RESULTS: A total of 185 questionnaires from 21 European countries were received. The majority of respondents (n = 153, 83%) reported having written policies, protocols, or guidelines, regarding the measurement of physiological observations. Over half (n = 120, 65%) reported that their hospital uses a Paediatric Early Warning System (PEWS) and 75 (41%) reported having a Rapid Response Team (RRT). Approximately one-third (38%) reported that their hospital collects specific data about the effectiveness of their RRS, while 100 (54%) reported providing regular training and education to support it. European regional differences existed in PEWS utilization (North = 98%, Centre = 25%, South = 44%, p < .001) and process evaluation (North = 49%, Centre = 6%, South = 36%, p < .001). CONCLUSIONS: RRS practices in European hospitals are heterogeneous. Differences in the uptake of PEWS and RRS process evaluation emerged across Europe. RELEVANCE TO CLINICAL PRACTICE: It is important to scope practices for the safe monitoring and management of deteriorating children in hospital across Europe. To reduce variance in practice, a consensus statement endorsed by paediatric and intensive care societies could provide guidance and resources to support PEWS implementation and for the operational governance required for continuous quality improvement.

Epidemiology and Outcomes of Critically Ill Children at Risk for Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: Interventional trials aimed at pediatric acute respiratory distress syndrome prevention require accurate identification of high-risk patients. In this study, we aimed to characterize the frequency and outcomes of children meeting "at risk for pediatric acute respiratory distress syndrome" criteria as defined by the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Planned substudy of the prospective multicenter, international Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology study conducted during 10 nonconsecutive weeks (May 2016-June 2017). SETTING: Thirty-seven international PICUs. PATIENTS: Three-hundred ten critically ill children meeting Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We evaluated the frequency of children at risk for pediatric acute respiratory distress syndrome and rate of subsequent pediatric acute respiratory distress syndrome diagnosis and used multivariable logistic regression to identify factors associated with subsequent pediatric acute respiratory distress syndrome. Frequency of at risk for pediatric acute respiratory distress syndrome was 3.8% (95% CI, 3.4-5.2%) among the 8,122 critically ill children who were screened and 5.8% (95% CI, 5.2-6.4%) among the 5,334 screened children on positive pressure ventilation or high-flow oxygen. Among the 310 at-risk children, median age was 2.1 years (interquartile range, 0.5-7.3 yr). Sixty-six children (21.3%) were subsequently diagnosed with pediatric acute respiratory distress syndrome, a median of 22.6 hours (interquartile range, 9.8-41.0 hr) later. Subsequent pediatric acute respiratory distress syndrome was associated with increased mortality (21.2% vs 3.3%; p < 0.001) and longer durations of invasive ventilation and PICU care. Subsequent pediatric acute respiratory distress syndrome rate did not differ by respiratory support modality at the time of meeting at risk criteria but was independently associated with lower initial saturation:Fio2 ratio, progressive tachycardia, and early diuretic administration. CONCLUSIONS: The Pediatric Acute Lung Injury Consensus Conference "at-risk for pediatric acute respiratory distress syndrome" criteria identify critically ill children at high risk of pediatric acute respiratory distress syndrome and poor outcomes. Interventional trials aimed at pediatric acute respiratory distress syndrome prevention should target patients early in their illness course and include patients on high-flow oxygen and positive pressure ventilation.

Population Pharmacokinetics and Outcomes of Critically Ill Pediatric Patients Treated with Intravenous Colistin at Higher Than Recommended Doses.

Limited pharmacokinetic (PK) data suggest that currently recommended pediatric dosages of colistimethate sodium (CMS) by the Food and Drug Administration and European Medicines Agency may lead to suboptimal exposure, resulting in plasma colistin concentrations that are frequently <2 mg/liter. We conducted a population PK study in 17 critically ill patients 3 months to 13.75 years (median, 3.3 years) old who received CMS for infections caused by carbapenem-resistant Gram-negative bacteria. CMS was dosed at 200,000 IU/kg/day (6.6 mg colistin base activity [CBA]/kg/day; 6 patients), 300,000 IU/kg/day (9.9 mg CBA/kg/day; 10 patients), and 350,000 IU/kg/day (11.6 mg CBA/kg/day; 1 patient). Plasma colistin concentrations were determined using ultraperformance liquid chromatography combined with electrospray ionization-tandem mass spectrometry. Colistin PK was described by a one-compartment disposition model, including creatinine clearance, body weight, and the presence or absence of systemic inflammatory response syndrome (SIRS) as covariates (P < 0.05 for each). The average colistin plasma steady-state concentration (Css,avg) ranged from 1.11 to 8.47 mg/liter (median, 2.92 mg/liter). Ten patients had Css,avg of ≥2 mg/liter. The presence of SIRS was associated with decreased apparent clearance of colistin (47.8% of that without SIRS). The relationship between the number of milligrams of CBA per day needed to achieve each 1 mg/liter of plasma colistin Css,avg and creatinine clearance (in milliliters per minute) was described by linear regression with different slopes for patients with and without SIRS. Nephrotoxicity, probably unrelated to colistin, was observed in one patient. In conclusion, administration of CMS at the above doses improved exposure and was well tolerated. Apparent clearance of colistin was influenced by creatinine clearance and the presence or absence of SIRS.

Adherence to Lung-Protective Ventilation Principles in Pediatric Acute Respiratory Distress Syndrome: A Pediatric Acute Respiratory Distress Syndrome Incidence and Epidemiology Study.

OBJECTIVES: To describe mechanical ventilation management and factors associated with nonadherence to lung-protective ventilation principles in pediatric acute respiratory distress syndrome. DESIGN: A planned ancillary study to a prospective international observational study. Mechanical ventilation management (every 6 hr measurements) during pediatric acute respiratory distress syndrome days 0-3 was described and compared with Pediatric Acute Lung Injury Consensus Conference tidal volume recommendations (< 7 mL/kg in children with impaired respiratory system compliance, < 9 mL/kg in all other children) and the Acute Respiratory Distress Syndrome Network lower positive end-expiratory pressure/higher Fio2 grid recommendations. SETTING: Seventy-one international PICUs. PATIENTS: Children with pediatric acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Analyses included 422 children. On pediatric acute respiratory distress syndrome day 0, median tidal volume was 7.6 mL/kg (interquartile range, 6.3-8.9 mL/kg) and did not differ by pediatric acute respiratory distress syndrome severity. Plateau pressure was not recorded in 97% of measurements. Using delta pressure (peak inspiratory pressure - positive end-expiratory pressure), median tidal volume increased over quartiles of median delta pressure (p = 0.007). Median delta pressure was greater than or equal to 18 cm H2O for all pediatric acute respiratory distress syndrome severity levels. In severe pediatric acute respiratory distress syndrome, tidal volume was greater than or equal to 7 mL/kg 62% of the time, and positive end-expiratory pressure was lower than recommended by the positive end-expiratory pressure/Fio2 grid 70% of the time. In multivariable analysis, tidal volume nonadherence was more common with severe pediatric acute respiratory distress syndrome, fewer PICU admissions/yr, non-European PICUs, higher delta pressure, corticosteroid use, and pressure control mode. Adherence was associated with underweight stature and cuffed endotracheal tubes. In multivariable analysis, positive end-expiratory pressure/Fio2 grid nonadherence was more common with higher pediatric acute respiratory distress syndrome severity, ventilator decisions made primarily by the attending physician, pre-ICU cardiopulmonary resuscitation, underweight stature, and age less than 2 years. Adherence was associated with respiratory therapist involvement in ventilator management and longer time from pediatric acute respiratory distress syndrome diagnosis. Higher nonadherence to tidal volume and positive end-expiratory pressure recommendations were independently associated with higher mortality and longer duration of ventilation after adjustment for confounding variables. In stratified analyses, these associations were primarily influenced by children with severe pediatric acute respiratory distress syndrome. CONCLUSIONS: Nonadherence to lung-protective ventilation principles is common in pediatric acute respiratory distress syndrome and may impact outcome. Modifiable factors exist that may improve adherence.

Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy.

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi-allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD-EU register database and an in-house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi-allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients.

Energy transmission in mechanically ventilated children: a translational study.

BACKGROUND: Recurrent delivery of tidal mechanical energy (ME) inflicts ventilator-induced lung injury (VILI) when stress and strain exceed the limits of tissue tolerance. Mechanical power (MP) is the mathematical description of the ME delivered to the respiratory system over time. It is unknown how ME relates to underlying lung pathology and outcome in mechanically ventilated children. We therefore tested the hypothesis that ME per breath with tidal volume (Vt) normalized to bodyweight correlates with underlying lung pathology and to study the effect of resistance on the ME dissipated to the lung. METHODS: We analyzed routinely collected demographic, physiological, and laboratory data from deeply sedated and/or paralyzed children < 18 years with and without lung injury. Patients were stratified into respiratory system mechanic subgroups according to the Pediatric Mechanical Ventilation Consensus Conference (PEMVECC) definition. The association between MP, ME, lung pathology, and duration of mechanical ventilation as a primary outcome measure was analyzed adjusting for confounding variables and effect modifiers. The effect of endotracheal tube diameter (ETT) and airway resistance on energy dissipation to the lung was analyzed in a bench model with different lung compliance settings. RESULTS: Data of 312 patients with a median age of 7.8 (1.7-44.2) months was analyzed. Age (p <  0.001), RR p <  0.001), and Vt <  0.001) were independently associated with MPrs. ME but not MP correlated significantly (p <  0.001) better with lung pathology. Competing risk regression analysis adjusting for PRISM III 24 h score and PEMVECC stratification showed that ME on day 1 or day 2 of MV but not MP was independently associated with the duration of mechanical ventilation. About 33% of all energy generated by the ventilator was transferred to the lung and highly dependent on lung compliance and airway resistance but not on endotracheal tube size (ETT) during pressure control (PC) ventilation. CONCLUSIONS: ME better related to underlying lung pathology and patient outcome than MP. The delivery of generated energy to the lung was not dependent on ETT size during PC ventilation. Further studies are needed to identify injurious MErs thresholds in ventilated children.

Effect of Endotracheal Tube Size, Respiratory System Mechanics, and Ventilator Settings on Driving Pressure.

OBJECTIVES: We sought to investigate factors that affect the difference between the peak inspiratory pressure measured at the Y-piece under dynamic flow conditions and plateau pressure measured under zero-flow conditions (resistive pressure) during pressure controlled ventilation across a range of endotracheal tube sizes, respiratory mechanics, and ventilator settings. DESIGN: In vitro study. SETTING: Research laboratory. PATIENTS: None. INTERVENTIONS: An in vitro bench model of the intubated respiratory system during pressure controlled ventilation was used to obtain the difference between peak inspiratory pressure measured at the Y-piece under dynamic flow conditions and plateau pressure measured under zero-flow conditions across a range of endotracheal tubes sizes (3.0-8.0 mm). Measurements were taken at combinations of pressure above positive end-expiratory pressure (10, 15, and 20 cm H2O), airway resistance (no, low, high), respiratory system compliance (ranging from normal to extremely severe), and inspiratory time at constant positive end-expiratory pressure (5 cm H2O). Multiple regression analysis was used to construct models predicting resistive pressure stratified by endotracheal tube size. MEASUREMENTS AND MAIN RESULTS: On univariate regression analysis, respiratory system compliance (ß -1.5; 95% CI, -1.7 to -1.4; p < 0.001), respiratory system resistance (ß 1.7; 95% CI, 1.5-2.0; p < 0.001), pressure above positive end-expiratory pressure (ß 1.7; 95% CI, 1.4-2.0; p < 0.001), and inspiratory time (ß -0.7; 95% CI, -1.0 to -0.4; p < 0.001) were associated with resistive pressure. Multiple linear regression analysis showed the independent association between increasing respiratory system compliance, increasing airway resistance, increasing pressure above positive end-expiratory pressure, and decreasing inspiratory time and resistive pressure across all endotracheal tube sizes. Inspiratory time was the strongest variable associated with a proportional increase in resistive pressure. The contribution of airway resistance became more prominent with increasing endotracheal tube size. CONCLUSIONS: Peak inspiratory pressures measured during pressure controlled ventilation overestimated plateau pressure irrespective of endotracheal tube size, especially with decreased inspiratory time or increased airway resistance.

Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients.

The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC0-∞) of plasma concentrations on day 1 ranged between 123.8 to 663.9 µg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.

Characteristics of Bordetella pertussis infection among infantsand children admitted to paediatric intensive care units in Greece: A multicentre, 11-year study.

AIM: To describe children with pertussis who required intensive care. METHODS: This is a retrospective analysis of pertussis admissions to all (six) national intensive care units in Greece from 2003 to 2013. RESULTS: A total of 31 children were included, 28 of whom were younger than 12 months old. Cough was the most prominent symptom, being present in 27 of 31 (87%) patients, and on admission, only 7 (22.6%) satisfied the case definition. Mechanical ventilation was initiated in 13 (42%) patients. Six patients died because of respiratory failure (two) or multi-organ system failure (four). The patients who died had significantly higher white blood cell counts (WBC) (77 800-31 600, P = 0.031) and neutrophils (29 016-12 795, P = 0021) than those who survived and lower minimum values of serum sodium (125-133, P = 0002). They also had a longer duration of hospitalisation prior to their paediatric intensive care unit admission (6-1 days, P = 0022). Three patients were diagnosed with pulmonary hypertension, and only one of them survived. Age, gender and immunisation status did not differ between survivors and non-survivors. Two patients received exchange blood transfusion, and survival benefit was not apparent. CONCLUSION: Young infants are at risk of severe pertussis, resulting in serious complications or death. Elevated WBC and low serum sodium are associated with higher mortality. Despite advances in life support and treatment of organ failure in childhood critical illness, pertussis still has substantial mortality.

At the Beach: To Jump or Not to Jump?

Splenic injury due to blunt abdominal trauma is an emergency condition in pediatrics. We present a case of a 10-year-old girl who presented to the emergency department 12 hours after a fall from height with abdominal pain, vomiting, and left upper quadrant tenderness and was found to have splenic rupture. Because of extensive bleeding and hemodynamic instability, emergency exploratory laparotomy was performed. Splenic bleeding lacerations were controlled by sutures and tamponade, and ipsilateral intrathoracic hemorrhagic fluid was drained with a good recovery. In this article, we emphasize the importance of early recognition, proper imaging, and splenic conservation where possible in pediatric blunt trauma.

Suicidality Prevalence in a Pediatric Psychiatric Clinic: Relation to Social and Environmental Risk Factors.

Suicidality is a growing public health problem in children and adolescents. The aim of this retrospective data analysis study was to estimate the prevalence of suicidality in pediatric patients admitted to an academic Pediatric Psychiatric Clinic (PPC) and to analyze social and environmental risk factors associated with suicide. Suicidal ideation was assessed by the Self-Injurious Thoughts and Behaviors Interview. Using established psychometric scales, social and stressful events were analyzed. During the four-year study, 249 episodes of care were experienced by 152 individuals (mean age 15.2 ± 2 years, girls/boys 107/45). Twenty-eight patients (11.2%) were admitted from the Pediatric Intensive Care Unit and the Department of Pediatrics, 162 (65.1%) from the Pediatric Emergency Department, and 59 (23.7%) from other Hospitals (p = 0.003). A significant longitudinal increase in admissions to PPC, with increasing trends of suicidal ideation, suicide attempts, and suicidality, was recorded. Suicidal behavior, bullying, internet addiction, friends quarreling, and family problems were risk factors for suicide attempts and suicidality. Our results have implications for prevention programs, highlighting an increasing need for care for suicide attempts and suicidal ideation, related to specific stressful events and contextual socio-environmental status.

The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis.

Zinc is a structural component of proteins, functions as a catalytic co-factor in DNA synthesis and transcription of hundreds of enzymes, and has a regulatory role in protein-DNA interactions of zinc-finger proteins. For many years, zinc has been acknowledged for its anti-oxidative and anti-inflammatory functions. Furthermore, zinc is a potent inhibitor of caspases-3, -7, and -8, modulating the caspase-controlled apoptosis and necroptosis. In recent years, the immunomodulatory role of zinc in sepsis and COVID-19 has been investigated. Both sepsis and COVID-19 are related to various regulated cell death (RCD) pathways, including apoptosis and necroptosis. Lack of zinc may have a negative effect on many immune functions, such as oxidative burst, cytokine production, chemotaxis, degranulation, phagocytosis, and RCD. While plasma zinc concentrations decline swiftly during both sepsis and COVID-19, this reduction is primarily attributed to a redistribution process associated with the inflammatory response. In this response, hepatic metallothionein production increases in reaction to cytokine release, which is linked to inflammation, and this protein effectively captures and stores zinc in the liver. Multiple regulatory mechanisms come into play, influencing the uptake of zinc, the binding of zinc to blood albumin and red blood cells, as well as the buffering and modulation of cytosolic zinc levels. Decreased zinc levels are associated with increasing severity of organ dysfunction, prolonged hospital stay and increased mortality in septic and COVID-19 patients. Results of recent studies focusing on these topics are summarized and discussed in this narrative review. Existing evidence currently does not support pharmacological zinc supplementation in patients with sepsis or COVID-19. Complementation and repletion should follow current guidelines for micronutrients in critically ill patients. Further research investigating the pharmacological mechanism of zinc in programmed cell death caused by invasive infections and its therapeutic potential in sepsis and COVID-19 could be worthwhile.

The Impact of Estimated Energy and Protein Balances on Extrauterine Growth in Preterm Infants.

BACKGROUND: Nutritional support of preterm infants remains a field of debate in the literature and clinical practice varies significantly. Adequate nutrition should promote growth and aim for optimal later neurodevelopment. However, it is often impaired by prematurity-associated morbidity and the physiologic immaturity of preterm infants. This study assessed the impact of energy and macronutrient provision on growth velocity and outcome and explored differences attributed to the heterogeneity of the preterm population. METHODS: We retrospectively collected clinical and nutritional data from neonates hospitalized in two separate Neonatal Intensive Care Units (NICUs). Estimated energy and protein balance were calculated based on the ESPGHAN guidelines and their association with the growth outcome was explored. Growth assessment was based on somatometry Delta (Δ) z-scores at discharge. RESULTS: In total, 174 neonates were included in the study. By day 14, most preterm infants were exclusively enterally fed, whereas there were infants in the <28 and 28-31+6 subgroups fed exclusively parenterally. Energy balance was positive for all gestational age (GA) subgroups except for those born <28 weeks. Protein balance was consistently positive for extremely premature but negative for late preterms. Cumulative substrates provisions were strong predictors of a positive energy or protein balance in the <34 weeks GA preterms on days 14 (ROC analyses, p < 0.001) and 7 (p < 0.05). A higher GA (p = 0.013) and enteral nutrition (p = 0.005) were additional predictors of a positive energy balance. All GA subgroups had a negative Δ z-score of weight at discharge. In the <34 GA subcohorts, a positive protein balance on day 14 (p = 0.009) and a short time to regain birth weight (exp(B) 3.1 (p = 0.004)) were independently associated with a positive Δ z-score of weight at discharge. CONCLUSIONS: Early achievement of a positive energy and protein balance, based on the ESPGHAN guidelines, is crucial to ensure optimal postnatal growth and prevent extrauterine growth restriction, a relatively common occurrence in preterm infants.