TLRs sense components of microorganisms and are critical host mediators of inflammation during infection. Different TLR agonists can profoundly alter inflammatory effects of one another, and studies suggest that the sequence of exposure to TLR agonists may importantly impact on responses during infection. We tested the hypothesis that synergy, priming, and tolerance between TLR agonists follow a pattern that can be predicted based on differential engagement of the MyD88-dependent (D) and the MyD88-independent (I) intracellular signaling pathways. Inflammatory effects of combinations of D and I pathway agonists were quantified in vivo and in vitro. Experiments used several D-specific agonists, an I-specific agonist (poly(I:C)), and LPS, which acts through both the D and I pathways. D-specific agonists included: peptidoglycan-associated lipoprotein, Pam3Cys, flagellin, and CpG DNA, which act through TLR2 (peptidoglycan-associated lipoprotein and Pam3Cys), TLR5, and TLR9, respectively. D and I agonists were markedly synergistic in inducing cytokine production in vivo in mice. All of the D-specific agonists were synergistic with poly(I:C) in vitro in inducing TNF and IL-6 production by mouse bone marrow-derived macrophages. Pretreatment of bone marrow-derived macrophages with poly(I:C) led to a primed response to subsequent D-specific agonists and vice versa, as indicated by increased cytokine production, and increased NF-κB translocation. Pretreatment with a D-specific agonist augmented LPS-induced IFN-β production. All D-specific agonists induced tolerance to one another. Thus, under the conditions studied here, simultaneous and sequential activation of both the D and I pathways causes synergy and priming, respectively, and tolerance is induced by agonists that act through the same pathway.

AIMTo synthesize the available evidence focusing on morbidities in pediatric survivors of critical illness that fall within the defined construct of postintensive care syndrome (PICS) in adults, including physical, neurocognitive and psychological morbidities.METHODSA comprehensive search was conducted in MEDLINE, EMBASE, the Cochrane Library, PsycINFO, and CINAHL using controlled vocabulary and key word terms to identify studies reporting characteristics of PICS in pediatric intensive care unit (PICU) patients. Two reviewers independently screened all titles and abstracts and performed data extraction. From the 3176 articles identified in the search, 252 abstracts were identified for full text review and nineteen were identified for inclusion in the review. All studies reporting characteristics of PICS in PICU patients were included in the final synthesis.RESULTSNineteen studies meeting inclusion criteria published between 1995 and 2016 were identified and categorized into studies reporting morbidities in each of three categories-physical, neurocognitive and psychological. The majority of included articles reported prospective cohort studies, and there was significant variability in the outcome measures utilized. A synthesis of the studies indicate that morbidities encompassing PICS are well-described in children who have survived critical illness, often resolving over time. Risk factors for development of these morbidities include younger age, lower socioeconomic status, increased number of invasive procedures or interventions, type of illness, and increased benzodiazepine and narcotic administration.CONCLUSIONPICS-related morbidities impact a significant proportion of children discharged from PICUs. In order to further define PICS in children, more research is needed using standardized tools to better understand the scope and natural history of morbidities after hospital discharge. Improving our understanding of physical, neurocognitive, and psychological morbidities after critical illness in the pediatric population is imperative for designing interventions to improve long-term outcomes in PICU patients.

Toll-like receptor 2 (TLR2) activation induces cellular and organ inflammation, and affects lung function. Since deranged endothelial function and coagulation pathways contribute to sepsis-induced organ failure, we studied the effects of bacterial lipoprotein TLR2 agonists, including peptidoglycan-associated lipoprotein, Pam3Cys, and murein lipoprotein, on endothelial function and coagulation pathways in vitro and in vivo. TLR2 agonist treatment induced diverse human endothelial cells (EC) to produce IL-6 and IL-8, and to express E-selectin on their surface, including human umbilical vein EC (HUVEC), human lung microvascular EC, and human coronary artery EC. Treatment of HUVEC with TLR2 agonists caused increased monolayer permeability and had multiple coagulation effects, including increased production of plasminogen-activator inhibitor 1 (PAI-1) and tissue factor, and decreased production of tissue plasminogen activator (tPA) and tissue factor pathway inhibitor. TLR2 agonist treatment also increased HUVEC expression of TLR2 itself. PAL induced IL-6 production by EC from wild-type, but not from TLR2 knockout mice, indicating TLR2 specificity. Mice were challenged with TLR2 agonists, and lungs and plasmas were assessed for markers of leukocyte trafficking and coagulopathy. Wild-type mice, but not TLR2 mice, that were challenged intravenously with TLR2 agonists had increased lung levels of myeloperoxidase and mRNAs for E-selectin, P-selectin, and MCP-1, and had increased plasma PAI-1 and E-selectin levels. Intratracheally administered TLR2 agonist caused increased lung fibrin levels. These studies show that TLR2 activation by bacterial lipoproteins broadly affects endothelial function and coagulation pathways, suggesting that TLR2 activation contributes in multiple ways to endothelial activation, coagulopathy, and vascular leakage in sepsis.

Objective: Quetiapine is an atypical antipsychotic that has been used off-label for the treatment of intensive care unit (ICU) delirium in the adult population, with studies demonstrating both efficacy and a favorable safety profile. Although there is a potential role for quetiapine in the treatment of pediatric ICU delirium, there has been no systematic reporting to date of safety in this patient population. Methods: Pharmacy records were used to identify 55 consecutive pediatric ICU patients who were diagnosed with delirium and received quetiapine. A comprehensive retrospective medical chart review was performed to collect data on demographics, dosing, and side effects. Results: Fifty patients treated between January 2013 and November 2014 were included, and five patients were excluded from the study. Subjects ranged in age from 2 months to 20 years. Median daily dose was 1.3 mg/kg/day, and median duration of treatment was 12 days. There were three episodes of QTc prolongation that were clinically nonsignificant with no associated dysrhythmia: Two resolved over time without intervention, and one resolved with decrease in quetiapine dosage. There were no episodes of extrapyramidal symptoms or neuroleptic malignant syndrome. Conclusions: In this population of critically ill youth, short-term use of quetiapine as treatment for delirium appears to be safe, without serious adverse events. Further research is required to assess efficacy and evaluate for long-term effects. A prospective, randomized, placebo-controlled study of quetiapine in managing pediatric delirium is necessary.

Objectives: To determine the feasibility of implementing an ICU diary in the pediatric critical care setting and to understand the perceptions held by family members who receive the diaries after PICU discharge. Design: Observational pilot study. Setting: PICU in a tertiary academic hospital in the United States. Participants: Critically ill pediatric patients admitted to the PICU and their families. Interventions: The addition of a PICU diary to a patient’s routine care. Measurements and Main Results: Twenty families of critically ill children admitted to the PICU were enrolled in the PICU diary pilot study between May 2017 and March 2018. Patients who had an anticipated length of stay of at least 3 days and whose families were English-speaking were included. The median age of patients was 6 years, ranging from newborns to 18 years old, and the median length of stay was 11.5 days (interquartile range, 8.5–41 d). A total of 453 diary entries were written in 19 diaries over 433 PICU days, the majority of which were composed by bedsides nurses (63%). Follow-up surveys sent to parents 2 weeks after PICU discharge revealed that of the parents who had contributed to the diary, most enjoyed doing so (7/8). Nine of 12 parents had reviewed the diary at least once since discharge, and all parent respondents found the diary to be a beneficial aspect of their experience after PICU discharge. Conclusions: The use of ICU diaries in the PICU setting is feasible and perceived as beneficial by families of critically ill children. Future studies are needed to better understand if PICU diaries may objectively improve psychologic outcomes of patients and family members after PICU admission.