Acute respiratory failure due to pulmonary exacerbation in children with cystic fibrosis admitted in a pediatric intensive care unit: outcomes and factors associated with mortality.

BACKGROUND: Children with advanced pulmonary disease due to cystic fibrosis (CF) are at risk of acute respiratory failure due to pulmonary exacerbations leading to their admission to pediatric intensive care units (PICU). The objectives of this study were to determine short and medium-term outcomes of children with CF admitted to PICU for acute respiratory failure due to pulmonary exacerbation and to identify prognosis factors. METHODS: This retrospective monocentric study included patients less than 18 years old admitted to the PICU of a French university hospital between 2000 and 2020. Cox proportional hazard regression methods were used to determine prognosis factors of mortality or lung transplant. RESULTS: Prior to PICU admission, the 29 patients included (median age 13.5 years) had a severe lung disease (median Forced Expiratory Volume in 1 s percentage predicted at 29%). Mortality rates were respectively 17%, 31%, 34%, 41% at discharge and at 3, 12 and 36 months post-discharge. Survival rates free of lung transplant were 34%, 32%, 24% and 17% respectively. Risk factors associated with mortality or lung transplant using the univariate analysis were female sex and higher pCO2 and chloride levels at PICU admission, and following pre admission characteristics: home respiratory and nutritional support, registration on lung transplant list and Stenotrophomonas Maltophilia bronchial colonization. CONCLUSION: Children with CF admitted to PICU for acute respiratory failure secondary to pulmonary exacerbations are at high risk of death, both in the short and medium terms. Lung transplant is their main chance of survival and should be considered early.

Neurologic Outcomes and Quality of Life in Children After Extracorporeal Membrane Oxygenation.

RATIONALE: Use of life support with extracorporeal membrane oxygenation (ECMO) is associated with brain injury. However, the consequences of these injuries on subsequent neurologic development and health-related quality of life (HRQoL) are poorly described in children. OBJECTIVES: The aim of this preliminary study was to describe short- and long-term neurologic outcomes in survivors of ECMO, as well as their HRQoL. DESIGN: Retrospective identified cohort with contemporary evaluations. SETTING: Necker Children's Hospital academic PICU. PATIENTS: Forty survivors who underwent ECMO (October 2014 to January 2020) were included in follow-up assessments in May 2021. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: We first reviewed the outcomes of ECMO at the time of PICU discharge, which included a summary of neurology, radiology, and Pediatric Overall/Cerebral Performance Category (POPC/PCPC) scores. Then, in May 2021, we interviewed parents and patients to assess HRQoL (Pediatric Quality of Life Inventory [PedsQL]) and POPC/PCPC for children 3 years old or older, and Denver II test (DTII) for younger children. An evaluation of DTII in the youngest patients 1 year after ECMO decannulation was also added. Median age at ECMO was 1.4 years (interquartile range [IQR], 0.4-6 yr). Thirty-five children (88%) underwent a venoarterial ECMO. At PICU discharge, 15 of 40 patients (38%) had neurologic impairment. Assessment of HRQoL was carried out at median of 1.6 years (IQR, 0.7-3.3 yr) after PICU discharge. PedsQL scores were over 70 of 100 for all patients (healthy peers mean results: 80/100), and scores were like those published in patients suffering with chronic diseases. In May 2021, seven of 15 patients had a normal DTII, and 36 of 40 patients had a POPC/PCPC score less than or equal to 3. CONCLUSIONS: None of our patients presented severe disability at long term, and HRQoL evaluation was reassuring. Considering the risk of neurologic impairment after ECMO support, a systematic follow-up of these high-risk survivor patients would be advisable.

Accuracy of tidal volume delivery by paediatric intensive care ventilators: A bench-model study.

BACKGROUND: Tidal volume (Vt) delivery during mechanical ventilation is influenced by gas compression, humidity, and temperature. OBJECTIVES: This bench study aimed at assessing the accuracy of Vt delivery by paediatric intensive care ventilators according to the humidification system. Secondary objectives were to assess the following: (i) the accuracy of Vt delivery in ventilators with an integrated Y-piece pneumotachograph and (ii) the ability of ventilators to deliver and maintain a preset positive end-expiratory pressure. METHODS: Six latest-generation intensive care ventilators equipped with a paediatric mode were tested on the ASL5000 test lung in four simulated paediatric bench models (full-term neonate, infant, preschool-age chile, and school-age child), under volume-controlled mode with a heated humidifier (HH) or a heat moisture exchanger, with various loading conditions. Three ventilators equipped with a Y-piece pneumotachograph were tested with or without the pneumotachograph in the neonatal and infant models. "Accurate Vt" delivery was defined as a volume error (percentage of the preset Vt under body temperature and pressure and saturated water vapour conditions) being ≤10 % of the absolute preset value. RESULTS: Vt accuracy varied significantly across ventilators but was acceptable in almost all the ventilators and all the models, except the neonatal model. The humidification system had an impact on Vt delivery in the majority of the tested conditions (p < 0.05). The use of an HH was associated with a better Vt accuracy in four ventilators (V500, V800, R860, and ServoU) and allowed to achieve an acceptable level of volume error in the neonatal model as compared to the use of heat moisture exchanger. The use of an integrated pneumotachograph was associated with lower volume error in only one ventilator (p < 0.01). All the tested ventilators were able to maintain adequate positive end-expiratory pressure levels. CONCLUSION: The humidification system affects Vt accuracy of paediatric intensive care ventilators, especially in the youngest patients for whom the HH should be preferred.

Pleural and transpulmonary pressures to tailor protective ventilation in children.

This review aims to: (1) describe the rationale of pleural (PPL) and transpulmonary (PL) pressure measurements in children during mechanical ventilation (MV); (2) discuss its usefulness and limitations as a guide for protective MV; (3) propose future directions for paediatric research. We conducted a scoping review on PL in critically ill children using PubMed and Embase search engines. We included peer-reviewed studies using oesophageal (PES) and PL measurements in the paediatric intensive care unit (PICU) published until September 2021, and excluded studies in neonates and patients treated with non-invasive ventilation. PL corresponds to the difference between airway pressure and PPL Oesophageal manometry allows measurement of PES, a good surrogate of PPL, to estimate PL directly at the bedside. Lung stress is the PL, while strain corresponds to the lung deformation induced by the changing volume during insufflation. Lung stress and strain are the main determinants of MV-related injuries with PL and PPL being key components. PL-targeted therapies allow tailoring of MV: (1) Positive end-expiratory pressure (PEEP) titration based on end-expiratory PL (direct measurement) may be used to avoid lung collapse in the lung surrounding the oesophagus. The clinical benefit of such strategy has not been demonstrated yet. This approach should consider the degree of recruitable lung, and may be limited to patients in which PEEP is set to achieve an end-expiratory PL value close to zero; (2) Protective ventilation based on end-inspiratory PL (derived from the ratio of lung and respiratory system elastances), might be used to limit overdistention and volutrauma by targeting lung stress values < 20-25 cmH2O; (3) PPL may be set to target a physiological respiratory effort in order to avoid both self-induced lung injury and ventilator-induced diaphragm dysfunction; (4) PPL or PL measurements may contribute to a better understanding of cardiopulmonary interactions. The growing cardiorespiratory system makes children theoretically more susceptible to atelectrauma, myotrauma and right ventricle failure. In children with acute respiratory distress, PPL and PL measurements may help to characterise how changes in PEEP affect PPL and potentially haemodynamics. In the PICU, PPL measurement to estimate respiratory effort is useful during weaning and ventilator liberation. Finally, the use of PPL tracings may improve the detection of patient ventilator asynchronies, which are frequent in children. Despite these numerous theoritcal benefits in children, PES measurement is rarely performed in routine paediatric practice. While the lack of robust clincal data partially explains this observation, important limitations of the existing methods to estimate PPL in children, such as their invasiveness and technical limitations, associated with the lack of reference values for lung and chest wall elastances may also play a role. PPL and PL monitoring have numerous potential clinical applications in the PICU to tailor protective MV, but its usefulness is counterbalanced by technical limitations. Paediatric evidence seems currently too weak to consider oesophageal manometry as a routine respiratory monitoring. The development and validation of a noninvasive estimation of PL and multimodal respiratory monitoring may be worth to be evaluated in the future.

Systemic corticosteroids for the treatment of acute episodes of rhabdomyolysis in lipin-1-deficient patients.

Mutations in the LPIN1 gene constitute a major cause of severe rhabdomyolysis (RM). The TLR9 activation prompted us to treat patients with corticosteroids in acute conditions. In patients with LPIN1 mutations, RM and at-risk situations that can trigger RM have been treated in a uniform manner. Since 2015, these patients have also received intravenous corticosteroids. We retrospectively compared data on hospital stays by corticosteroid-treated patients vs. patients not treated with corticosteroids. Nineteen patients were hospitalized. The median number of admissions per patient was 21 overall and did not differ when comparing the 10 corticosteroid-treated patients with the 9 patients not treated with corticosteroids. Four patients in the non-corticosteroid group died during a RM (mean age at death: 5.6 years). There were no deaths in the corticosteroid group. The two groups did not differ significantly in the number of RM episodes. However, for the six patients who had RM and occasionally been treated with corticosteroids, the median number of RM episodes was significantly lower when intravenous steroids had been administered. The peak plasma creatine kinase level and the area under the curve were or tended to be higher in patients treated with corticosteroids-even after the exclusion of deceased patients or focusing on the period after 2015. The median length of stay (10 days overall) was significantly longer for corticosteroid-treated patients but was similar after the exclusion of deceased patients. The absence of deaths and the higher severity of RM observed among corticosteroid-treated patients could suggest that corticotherapy is associated with greater survival.

Beta-lactam exposure and safety in intermittent or continuous infusion in critically ill children: an observational monocenter study.

The aim of this study was to assess the pharmacokinetic (PK) exposure and clinical toxicity for three beta-lactams: cefotaxime, piperacillin/tazobactam, and meropenem, depending on two lengths of infusion: continuous and intermittent, in critically ill children. This single center observational prospective study was conducted in a pediatric intensive care unit. All hospitalized children who had one measured plasma concentration of the investigated antibiotics were included. Plasma antibiotic concentrations were interpreted by a pharmacologist, using a Bayesian approach based on previously published population pharmacokinetic models in critically ill children. Exposure was considered optimal, low, or high according to the PK target 100% fT> 4 × MIC and a trough concentration below the toxic concentration (50 mg.L-1 for cefotaxime, 150 mg.L-1 for piperacillin, and 44 mg.L-1 for meropenem). Between May 2019 and January 2020, 80 patients were included and received 106 antibiotic courses: 74 (70%) were administered in intermittent infusion (II) and 32 (30%) in continuous infusion (CI). Compared to II, CI provided more optimal PK exposure (n = 22/32, 69% for CI versus n = 35/74, 47% for II, OR 1.2, 95%CI 1.01-1.5, p = 0.04), less underexposure (n = 4/32, 13% for CI versus n = 36/74, 49% for II, OR 0.7, 95%CI 0.6-0.84, p < 0.001), and more overexposure (n = 6/32, 19% for CI versus n = 3/74, 4% for II, OR 1.2, 95%CI 1.03-1.3, p = 0.01). Five adverse events have been reported during the study period, although none has been attributed to beta-lactam treatment. CONCLUSION: CI provided a higher probability to attain an optimal PK target compared to II, but also a higher risk for overexposure. Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion. WHAT IS KNOWN: • Since beta-lactams are time-dependent antibiotics, the probability to attain the pharmacokinetic target is higher with continuous infusion compared to that with intermittent infusion. • In daily practice, continuous or extended infusions are rarely used despite recent guidelines, and toxicity is hardly reported. WHAT IS NEW: • Continuous infusion provided a higher probability to attain an optimal pharmacokinetic target compared to intermittent infusion, but also a higher risk of overexposure. • Regular therapeutic drug monitoring is recommended in critically ill children receiving beta-lactams, regardless of the length of infusion.

Visiting Policies and Parental Presence During PICU Admission: A Survey in French Units.

OBJECTIVES: To describe the policies about parent visiting and involvement in care during admission to French PICUs. DESIGN: A structured questionnaire was emailed to the chief of each of 35 French PICUs. Data about visiting policies, involvement in care, evolution of policies, and general characteristics were collected from April 2021 to May 2021. A descriptive analysis was conducted. SETTING: Thirty-five PICUs in France. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-nine of 35 (83%) PICUs replied. Twenty-four-hour access for parents was reported for all PICUs responding. Other allowed visitors were grandparents (21/29, 72%) and siblings (19/29, 66%) with professional support. Simultaneous visits were restricted to two visitors in 83% (24/29) of PICUs. Family presence was always permitted during medical rounds for 20 of 29 (69%) PICUs. Most of the units rarely or never allowed parental presence during the most invasive procedures, such as central venous catheter placement (18/29, 62%) and intubation (22/29, 76%). CONCLUSIONS: Unrestricted access to the PICU, for both parents, was available in all responding French units. There were, however, restrictions on the number of visitors and the presence of other family members at the bedside. Moreover, permission for parental presence during care procedures was heterogenous, and mainly restricted. National guidelines and educational programs are needed to support family wishes and promote acceptance by healthcare providers in French PICUs.

Severe and fatal neonatal infections linked to a new variant of echovirus 11, France, July 2022 to April 2023.

We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3-5 days-old and had severe sepsis and liver failure. This new variant, detected in France since April 2022, is still circulating and has caused more fatal neonatal enterovirus infections in 2022 and 2023 (8/496; 1.6%, seven associated with echovirus 11) compared with 2016 to 2021 (7/1,774; 0.4%). National and international alerts are warranted.

Piperacillin Population Pharmacokinetics and Dosing Regimen Optimization in Critically Ill Children Receiving Continuous Renal Replacement Therapy.

We aimed to develop a piperacillin population pharmacokinetic (PK) model in critically ill children receiving continuous renal replacement therapy (CRRT) and to optimize dosing regimens. The piperacillin plasma concentration was quantified by high-performance liquid chromatography. Piperacillin PK was investigated using a nonlinear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration according to the target of 100% interdose interval time in which concentration is one to four times above the MIC (100% fT > 1 to 4× MIC). A total of 32 children with a median (interquartile range [IQR]) postnatal age of 2 years (0 to 11), body weight (BW) of 15 kg (6 to 38), and receiving CRRT were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. BW and residual diuresis (Qu) explained some between-subject variabilities on volume of distribution (V), where [Formula: see text], and clearance (CL), where [Formula: see text], where CLpop and Vpop are 6.78 L/h and 55.0 L, respectively, normalized to a 70-kg subject and median residual diuresis of 0.06 mL/kg/h. Simulations with intermittent and continuous administrations for 4 typical patients with different rates of residual diuresis (0, 0.1, 0.25, and 0.5 mL/kg/h) showed that continuous infusions were appropriate to attain the PK target for patients with residual diuresis higher than 0.1 mL/kg/h according to BW and MIC, while for anuric patients, less frequent intermittent doses were mandatory to avoid accumulation. Optimal exposure to piperacillin in critically ill children on CRRT should be achieved by using continuous infusions with escalating doses for high-MIC bacteria, except for anuric patients who require less frequent intermittent doses.

Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis.

INTRODUCTION: Pulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease. METHODS: Four patients received methionine supplementation and were followed for respiratory, hepatic, growth and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species production by patient monocytes before and after methionine supplementation was also studied. RESULTS: Methionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or noninvasive ventilation could be weaned off within 60 days. In addition, liver dysfunction, inflammation and growth delay improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes. CONCLUSION: Methionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.

What are the clues for an inherited metabolic disorder in Reye syndrome? A single Centre study of 58 children.

OBJECTIVES: Reye Syndrome is an acute encephalopathy with increased liver enzymes and blood ammonia, without jaundice. The prevalence of an underlying inherited metabolic disorder (IMD) is unclear, nor the clinical or biological factors directing toward this diagnosis. Our aims were to define these clues in a large series of patients. PATIENTS AND METHODS: We retrospectively studied all patients with Reye admitted in our institution from 1995. We defined 3 groups: Group 1 with a confirmed IMD, Group 2 considered as free of IMD, Group 3 unclassified. Statistical analysis compared patients in Groups 1 and 2, to find criteria for a diagnosis of IMD. RESULTS: Fifty-eight children were included; 41 (71%) had a confirmed IMD, 12 (20%) were free of IMD, and 5 remained unclassified. IMDs included Urea Cycle Disorders (51%), Fatty-Acid Oxidation Disorders (24%), ketogenesis defects (5%), other mitochondrial energy metabolism defects (10%), NBAS mutation (7%), Glycosylation Disorders (2%). In Group 2, the trigger was a viral infection, or a drug, deferasirox in three children. Univariate analysis showed that onset before 2 years-old, recurrent Reye and the association with rhabdomyolysis were significantly associated with IMD. Blood ammonia was a poor discriminating marker. All children were admitted into the intensive care unit, 23% needed continuous venovenous hemodialysis and one died from brain oedema. CONCLUSION: Metabolic tests should be performed early in all cases of Reye, regardless of triggers. As they can be inconclusive, we suggest to systematically go to Next-Generation Sequencing study. These children should be transferred early to a specialized unit.

Amiodarone/N-desethylamiodarone population pharmacokinetics in paediatric patients.

The population pharmacokinetics of amiodarone and its active metabolite, N-desethylamiodarone (DEA) were investigated in paediatric patients with arrhythmias, mainly supraventricular tachycardias. A total of 55 patients from the Department of Pediatric Intensive Care and Pediatric Cardiology at Necker-Enfants malades Hospital (Paris, France) provided 72 concentrations for both amiodarone and DEA following repeated oral or intravenous administration. Blood samples drawn for biological analyses were used for drug concentrations. Plasma amiodarone concentrations were measured by a liquid chromatography method coupled with mass spectrometry and the data were modelled using the software Monolix 2019R2. Parent pharmacokinetics was described with a 2-compartment open model and the metabolite formation was connected to the central parent compartment. Parameter estimates scaled allometrically on bodyweight (normalized to 70 kg) were, respectively (% relative standard errors, RSEs), 6.32 (31%) and 7.14 L/h (26%) for elimination (CL) and intercompartmental clearances and 167 (31%) and 3930 (32%) L for V1 and V2 . Oral bioavailability was 0.362 (21.5%). The clearance between subject variability (ω, square root of the variance) was 0.462 (RSE 21%). The proportional residual variabilities were respectively 0.453 (RSE 13%) and 0.423 (RSE 12%) for amiodarone and DEA respectively. The terminal half-lives were 34 and 14.5 days for amiodarone and DEA, respectively. A dosage schedule was established for 3 weight bands in 2 time periods. The high pharmacokinetic variability suggests that therapeutic drug monitoring might be useful to improve individual efficacy and safety.

Therapeutic Drug Monitoring of Antibiotics in Critically Ill Children: An Observational Study in a Pediatric Intensive Care Unit.

BACKGROUND: Septic critically ill children are at a high risk of inadequate antibiotic exposure, requiring them to undergo therapeutic drug monitoring (TDM). The aim of this study was to describe the use of TDM for antibiotics in critically ill children. METHODS: The authors conducted a single-center observational study between June and December 2019, with all children treated with antibiotics in a pediatric intensive care unit located in a French university hospital. Standard clinical and laboratory data were recorded. Blood samples were collected for routine laboratory tests, and plasma antibiotic levels were assayed using validated analytical methods. RESULTS: A total of 209 children received antibiotics. TDM was performed in 58 patients (27.8%) who had a greater mean organ dysfunction (according to the International Pediatric Sepsis Consensus Conference) (3 versus 1 in the non-TDM group; P < 0.05) and were treated with antibiotics for longer. A total of 208 samples were analyzed. The median [interquartile range] assay turnaround time was 3 (1-5) days, and 48 (46.2%) of the 104 initial antibiotic concentration values were below the pharmacokinetic/pharmacodynamic targets. A total of 34 (46%) of the 74 off-target TDM measurements available before the end of the antibiotic treatment prompted dose adjustment. This dose adjustment increased the proportion of on-target TDM measurements (70% versus 20% without adjustment). Subsequent measurements of the minimum inhibitory concentration showed that the use of the European Committee on Antimicrobial Susceptibility Testing's epidemiological cutoff values led to underestimation of pharmacokinetic/pharmacodynamic target attainment in 10 cases (20%). CONCLUSIONS: TDM seems to be an effective means of optimizing antibiotic exposure in critically ill children. This requires timely plasma antibiotic assays and minimum inhibitory concentration measurements. It is important to define which patients should undergo TDM and how this monitoring should be managed.

Management of severe inaugural diabetic ketoacidosis in paediatric intensive care: retrospective comparison of two protocols.

The best protocol for severe inaugural diabetic ketoacidosis (DKA) in children remains unclear. We compared two protocols by assessing effects during the first 24 h on osmolality, serum sodium, and glucose variations, which are associated with the risk of cerebral oedema, the most dreaded complication of DKA. We also recorded complications. We retrospectively included children aged 28 days to 18 years and admitted for severe DKA to either of two paediatric intensive care units (PICUs) in Paris (France). The two protocols differed regarding hydration volume, glucose intake, and sodium intake. From 17 June 2010 to 17 June 2015, 93 patients were included, 29 at one PICU, and 64 at the other. We compared severe glycaemic drops (> 5.5 mmol/L/h), mean glycaemia variations, serum sodium, serum osmolality, and the occurrence of cerebral oedema (CE) during the first 24 h after PICU admission. Severe glycaemic drops occurred in 70% of patients, with no between-group difference. Blood glucose, serum sodium, and serum osmolality variations were comparable. Seven (7.5%) patients were treated for suspected CE, (4 [10.3%)] and 3 [6.3%]) in each PICU; none had major residual impairments. CONCLUSION:  The two paediatric DKA-management protocols differing in terms of fluid-volume, glucose, and sodium intakes had comparable effects on clinical and laboratory-test changes within 24 h. Major drops in glycaemia and osmolality were common with both protocols. No patients had residual neurological impairments. WHAT IS KNOWN: • Cerebral oedema is the most severe complication of diabteic ketoacidosis in children.The risk of cerebral oedema is dependant on both patient related and treatment-related factors. • The optimal protocol for managing severe inaugural diabetic ketoacidosis in children remains unclear, and few studies have targeted this specific population. WHAT IS NEW: • Two management protocols that complied with ISPAD guidelines but differed regarding the amounts of fluids, glucose, and sodium administered produced similar outcomes in children with severe inaugural diabetic ketoacidosis. • Cerebral oedema was rare with both protocols and caused no lasting impairments.

Acute Heart Failure in Multisystem Inflammatory Syndrome in Children in the Context of Global SARS-CoV-2 Pandemic.

BACKGROUND: Cardiac injury and myocarditis have been described in adults with coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children as defined by the US Centers for Disease Control and Prevention. METHODS: Over a 2-month period, contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state. RESULTS: Thirty-five children were identified and included in the study. Median age at admission was 10 years (range, 2-16 years). Comorbidities were present in 28%, including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one-third; 80% required inotropic support with 28% treated with extracorporeal membrane oxygenation. Inflammation markers were suggestive of cytokine storm (interleukin-6 median, 135 pg/mL) and macrophage activation (D-dimer median, 5284 ng/mL). Mean BNP (B-type natriuretic peptide) was elevated (5743 pg/mL). Thirty-one of 35 patients (88%) tested positive for SARS-CoV-2 infection by polymerase chain reaction of nasopharyngeal swab or serology. All patients received intravenous immunoglobulin, with adjunctive steroid therapy used in one-third. Left ventricular function was restored in the 25 of 35 of those discharged from the intensive care unit. No patient died, and all patients treated with extracorporeal membrane oxygenation were successfully weaned. CONCLUSIONS: Children may experience an acute cardiac decompensation caused by severe inflammatory state after SARS-CoV-2 infection (multisystem inflammatory syndrome in children). Treatment with immunoglobulin appears to be associated with recovery of left ventricular systolic function.

Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

Pediatric Acute Alcohol Intoxication Admitted to the ICU: A Review of 102 Cases in France.

OBJECTIVES: To describe the profile and clinical outcomes of children (<18 yr) admitted to intensive care for acute alcohol intoxication, with special attention to complications and to the subgroup that required intubation. DESIGN: Retrospective observational study. SETTING: Seven pediatric and three adult ICUs in France. PATIENTS: Children 1-17 yr admitted to intensive care for acute alcohol intoxication between January 1, 2010, and December 30, 2017. INTERVENTIONS: The study was observational and patients received standard care. MEASUREMENTS AND MAIN RESULTS: We included 102 patients, with 71 males (69.6%) and 31 females (30.4%). Mean age was not different between males and females (14.0 ± 3.0 yr [range, 2-17 yr] and 14.2 ± 1.3 yr [range, 11-17 yr]; p = 0.67); six children were younger than 10 years. Mean blood alcohol concentration was not significantly different in males and females (2.42 ± 0.86 and 2.20 ± 0.54 g/L, respectively; p = 0.51). Of the 102 patients, 58 (57%) required intubation. Factors significantly associated with requiring intubation were lower Glasgow Coma Scale score (p = 0.002), lower body temperature (p = 0.045), and higher blood alcohol concentration (p = 0.012); vascular filling, and electrolyte disturbances were not associated with needing intubation. Mean intubation time was 9.7 ± 5.2 hours. Among the 59 patients with Glasgow Coma Scale score less than 8, 12 did not require intubation. The most common metabolic disturbance was a high lactate level (48%), followed by hypokalemia (27.4%); 59 (58.2%) patients had hyperglycemia and three had hypoglycemia. CONCLUSIONS: Male adolescents make up the majority of pediatric patients admitted to intensive care for acute alcohol intoxication. A need for intubation was associated with a worse Glasgow Coma Scale, lower body temperature, and higher blood alcohol concentration. Intubation was usually required for less than 12 hours. Other acute medical complications reported in adults with acute alcohol intoxication, such as electrolyte disturbances and aspiration pneumonia, were rare in our pediatric patients.

Estimation of piperacillin clearance with different glomerular filtration rate formulas in critically ill children.

AIMS: Glomerular filtration rate (GFR) is difficult to assess in critically ill children using gold standard method and alternatives are needed. This study aimed to determine the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children, using a published piperacillin pharmacokinetics (PK) population model. METHODS: All children hospitalized in the paediatric intensive care unit of a single institution who were receiving piperacillin were included. PK were described using the nonlinear mixed effect modelling software MONOLIX. In the initial PK model, GFR was estimated according to the Schwartz 1976 formula. We evaluated a set of 12 additional validated formulas, developed using plasma creatinine and/or cystatin C concentrations, in the building model to assess the lowest between-subject variability for piperacillin clearance. RESULTS: We included 20 children with a median (range) postnatal age of 1.9 (0.1-19) years, body weight of 12.5 (3.5-69) kg. Estimated GFR according to the Schwartz 1976 formula was 160.5 (38-315) mL min-1 1.73 m-2 . Piperacillin clearance was best predicted by the Bouvet combined formula. CONCLUSION: The combined Bouvet formula was the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children.

Mortality and Neurologic Sequelae in Influenza-Associated Encephalopathy: Retrospective Multicenter PICU Cohort in France.

OBJECTIVES: To describe and estimate the mortality rate of severe influenza-associated encephalopathy/encephalitis among children admitted to PICUs. DESIGN: Multicenter retrospective study. SETTING: Twelve French PICUs. PATIENTS: All children admitted for influenza-associated encephalopathy/encephalitis between 2010 and 2018 with no severe preexisting chronic neurologic disorders and no coinfection potentially responsible for the disease. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We collected the clinical presentation; laboratory, electroencephalographic, and MRI findings; and treatments used in the PICU. The primary outcome was mortality. The secondary outcomes included sequelae at discharge and last follow-up. We included 41 patients with a median (interquartile range) age of 4.7 years (2.5-8.2 yr). The main reasons for admission were altered consciousness (59%) and status epilepticus (34%); 48% of patients had meningitis, and one third had acute necrotizing encephalopathy on MRI. Mechanical ventilation was required in 73% of patients and hemodynamic support in 24%. The use of specific treatments was variable; steroids were given to 49% of patients. Seven patients (17%) died in the PICU. Median (interquartile range) PICU stay length was 7 days (2-13 d), and total hospital length of stay was 23 days (7-33 d). On hospital discharge, 49% (n = 20) had neurologic sequelae, with 27% (n = 11) having severe disabilities defined by modified Rankin Score greater than or equal to 4. CONCLUSIONS: Children requiring PICU admission for influenza-associated encephalopathy/encephalitis have high mortality and morbidity rates. The management remains highly variable due to the lack of guidelines.

Therapeutic plasma exchange for life-threatening pediatric disorders.

INTRODUCTION: Therapeutic plasma exchange (TPE) is acknowledged to be an effective treatment in life-threatening pediatric disorders. Apheresis for pediatric diseases has been poorly investigated, and most studies to date featured small numbers of patients and lacked control groups. The objective of the present study was to evaluate the tolerance of TPE in pediatric patients. MATERIALS AND METHODS: A retrospective cohort study via a web-based electronic case report form including pediatric patients referred for TPE between January 2005 and December 2014. RESULTS: A total of 78 patients (median [range] age: 9.8 [0.53-17.93]) and 731 TPE procedures were analyzed. The indications were antibody-mediated rejection (n = 33; 42%) and desensitization therapy (n = 5; 6%) after solid organ or hematopoietic stem cell transplantation, thrombotic microangiopathy (n = 17; 22%), pediatric inflammatory diseases (n = 16; 21%), kidney diseases (n = 6; 8%), and hyperviscosity syndrome (n = 1; 1%). On average, each patient underwent six procedures during the first session [range: 1-19]. In the 2 weeks following the start of a session, 72 patients (92%) presented a total of 311 adverse events (AEs) potentially related to TPE. The risk of AEs was not related to the indication for TPE, the intensity of care, venous access, plasma substitute use, or body weight. None of the deaths was related to the TPE. CONCLUSION: We studied one of the largest retrospective pediatric cohorts described to date. Our experience of TPE children's TPE feasibility concerned specific, life-threatening conditions and otherwise treatment-refractory diseases.