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BACKGROUND & AIMS: The association between nutritional status at pediatric intensive care unit (PICU) admission with clinical outcomes remains unclear. We conducted this systematic review to summarize the overall impact of PICU admission body mass index (BMI) on clinical outcomes. METHODS: We searched the following medical databases from inception through May 2020: PubMed, Excerpta Medica database (Embase), Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library, and Web of Science. We included studies on patients ≤18 years old admitted to a PICU that investigated the effect of BMI on mortality, PICU or hospital length of stay (LOS), or duration of mechanical ventilation (MV). Classification of underweight, overweight, and obese were based on each study's criteria. RESULTS: There was a total of 21,558 patients from 20 included studies. 12,936 (60.0%), 2965 (13.8%), 2182 (10.1%), 3348 (15.5%) were normal weight, underweight, overweight, and obese patients, respectively. Relative to normal weight patients, underweight (OR 1.32, 95% CI 0.89-1.98; p = 0.171) and overweight/obese patients (OR 1.10, 95% CI 0.86-1.42; p = 0.446) did not have an increase risk in mortality. There was also no difference in duration of MV, PICU and hospital LOS between all three weight categories. Included studies were heterogeneous and lacked standardized nutritional categorization. Sensitivity analysis including only studies that used BMI z-scores as nutritional classification (n = 5) revealed that underweight patients had higher odds of mortality compared to patients with normal weight (OR 1.61, 95% CI 1.35-1.92; p < 0.001); studies that used percentiles as classification did not reveal any differences in mortality. Sensitivity analysis including only studies containing mixed PICU cohorts (i.e., excluding specialized cohorts e.g., congenital heart surgeries, burns) revealed higher mortality odds in underweight patients (OR 1.53, 95% CI 1.25-1.87; p < 0.001) and overweight/obese patients (OR 1.51, 95% CI 1.14-2.01; p = 0.004) relative to normal weight patients. CONCLUSIONS: Our systematic review did not reveal any association between PICU admission BMI status and outcomes in critically ill children. Further investigation with standardized nutrition status classification on admission, stratified by patient subgroups, is needed to clarify the association between nutritional status and clinical outcomes of PICU patients.

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Objectives: This study aimed to identify alterations in pharmacokinetics in children on extracorporeal membrane oxygenation (ECMO), identify knowledge gaps, and inform future pharmacology studies. Data Sources: We systematically searched the databases MEDLINE, CINAHL, and Embase from earliest publication until November 2018 using a controlled vocabulary and keywords related to "ECMO" and "pharmacokinetics," "pharmacology," "drug disposition," "dosing," and "pediatrics." Study Selection: Inclusion criteria were as follows: study population aged <18 years, supported on ECMO for any indications, received any medications while on ECMO, and reported pharmacokinetic data. Data Extraction: Clearance and/or volume of distribution values were extracted from included studies. Data Synthesis: Forty-one studies (total patients = 574) evaluating 23 drugs met the inclusion criteria. The most common drugs studied were antimicrobials (n = 13) and anticonvulsants (n = 3). Twenty-eight studies (68%) were conducted in children <1 year of age. Thirty-three studies (80%) were conducted without intra-study comparisons to non-ECMO controls. Increase in volume of distribution attributable to ECMO was demonstrated for nine (56%) drugs: cefotaxime, gentamicin, piperacillin/tazobactam, fluconazole, micafungin, levetiracetam, clonidine, midazolam, and sildenafil (range: 23-345% increase relative to non-ECMO controls), which may suggest the need for higher initial dosing. Decreased volume of distribution was reported for two drugs: acyclovir and ribavirin (50 and 69%, respectively). Decreased clearance was reported for gentamicin, ticarcillin/clavulanate, bumetanide, and ranitidine (range: 26-95% decrease relative to non-ECMO controls). Increased clearance was reported for caspofungin, micafungin, clonidine, midazolam, morphine, and sildenafil (range: 25-455% increase relative to non-ECMO controls). Conclusions: There were substantial pharmacokinetic alterations in 70% of drugs studied in children on ECMO. However, studies evaluating pharmacokinetic changes of many drug classes and those that allow direct comparisons between ECMO and non-ECMO patients are still lacking. Systematic evaluations of pharmacokinetic alterations of drugs on ECMO that incorporate multidrug opportunistic trials, physiologically based pharmacokinetic modeling, and other methods are necessary for definitive dose recommendations. Trial Registration Prospero Identifier: CRD42019114881.

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BACKGROUND: Outcome in severe acute necrotizing encephalopathy of childhood is poor, with high mortality (30%) and moderate to severe disability in survivors despite the use of intravenous corticosteroids or immunoglobulins. Increased blood interleukin 6 level correlates with poor outcome. METHODS: We report the early use of tocilizumab, a monoclonal antibody against the interleukin 6 receptor, in three patients (aged five, eight, and 10 years) with severe acute necrotizing encephalopathy. RESULTS: All three patients experienced a rapid neurological deterioration associated with febrile viral illnesses and met criteria for severe acute necrotizing encephalopathy with a high risk for death or severe disability. Intravenous methylprednisolone and tocilizumab were administered at 18 to 32 hours of encephalopathy in addition to supportive medical therapy. No side effects were observed with this therapeutic strategy. The two patients with influenza A(H1N1)pdm09 virus-related acute necrotizing encephalopathy had a short illness with excellent clinical and radiological recovery. The patient with influenza B virus-related acute necrotizing encephalopathy and florid hemorrhagic brain lesions had a slow recovery with eventual mild disability despite focal encephalomalacia on follow-up neuroimaging. CONCLUSIONS: The early use of interleukin 6 blockade in acute necrotizing encephalopathy is safe and may have a role in improving outcomes and preventing disability.

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Importance: The global patterns and distribution of case-fatality rates (CFRs) in pediatric severe sepsis and septic shock remain poorly described. Objective: We performed a systematic review and meta-analysis of studies of children with severe sepsis and septic shock to elucidate the patterns of CFRs in developing and developed countries over time. We also described factors associated with CFRs. Data Sources: We searched PubMed, Web of Science, Excerpta Medica database, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Central systematically for randomized clinical trials and prospective observational studies from earliest publication until January 2017, using the keywords "pediatric," "sepsis," "septic shock," and "mortality." Study Selection: Studies involving children with severe sepsis and septic shock that reported CFRs were included. Retrospective studies and studies including only neonates were excluded. Data Extraction and Synthesis: We conducted our systematic review and meta-analysis in close accordance to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled case-fatality estimates were obtained using random-effects meta-analysis. The associations of study period, study design, sepsis severity, age, and continents in which studies occurred were assessed with meta-regression. Main Outcomes and Measures: Meta-analyses to provide pooled estimates of CFR of pediatric severe sepsis and septic shock over time. Results: Ninety-four studies that included 7561 patients were included. Pooled CFRs were higher in developing countries (31.7% [95% CI, 27.3%-36.4%]) than in developed countries (19.3% [95% CI, 16.4%-22.7%]; P < .001). Meta-analysis of CFRs also showed significant heterogeneity across studies. Continents that include mainly developing countries reported higher CFRs (adjusted odds ratios: Africa, 7.89 [95% CI, 6.02-10.32]; P < .001; Asia, 3.81 [95% CI, 3.60-4.03]; P < .001; South America, 2.91 [95% CI, 2.71-3.12]; P < .001) than North America. Septic shock was associated with higher CFRs than severe sepsis (adjusted odds ratios, 1.47 [95% CI, 1.41-1.54]). Younger age was also a risk factor (adjusted odds ratio, 0.95 [95% CI, 0.94-0.96] per year of increase in age). Earlier study eras were associated with higher CFRs (adjusted odds ratios for 1991-2000, 1.24 [95% CI, 1.13-1.37]; P < .001) compared with 2011 to 2016. Time-trend analysis showed higher CFRs over time in developing countries than developed countries. Conclusions and Relevance: Despite the declining trend of pediatric severe sepsis and septic shock CFRs, the disparity between developing and developed countries persists. Further characterizations of vulnerable populations and collaborations between developed and developing countries are warranted to reduce the burden of pediatric sepsis globally.

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