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Use of magnetic resonance imaging (MRI) as a tool to aid in neuroprognostication after cardiac arrest (CA) has been described, yet details of specific indications, timing, and sequences are unknown. We aim to define the current practices in use of brain MRI in prognostication after pediatric CA.A survey was distributed to pediatric institutions participating in three international studies. Survey questions related to center demographics, clinical practice patterns of MRI after CA, neuroimaging resources, and details regarding MRI decision support.Response rate was 31% (44 of 143). Thirty-four percent (15 of 44) of centers have a clinical pathway informing the use of MRI after CA. Fifty percent (22 of 44) of respondents reported that an MRI is obtained in nearly all patients with CA, and 32% (14 of 44) obtain an MRI in those who do not return to baseline neurological status. Poor neurological examination was reported as the most common factor (91% [40 of 44]) determining the timing of the MRI. Conventional sequences (T1, T2, fluid-attenuated inversion recovery, and diffusion-weighted imaging/apparent diffusion coefficient) are routinely used at greater than 97% of centers. Use of advanced imaging techniques (magnetic resonance spectroscopy, diffusion tensor imaging, and functional MRI) were reported by less than half of centers.Conventional brain MRI is a common practice for prognostication after CA. Advanced imaging techniques are used infrequently. The lack of standardized clinical pathways and variability in reported practices support a need for higher-quality evidence regarding the indications, timing, and acquisition protocols of clinical MRI studies.

Families and clinicians have limited validated tools available to assist in estimating long-term outcomes early after pediatric cardiac arrest. Blood-based brain-specific biomarkers may be helpful tools to aid in outcome assessment.To analyze the association of blood-based brain injury biomarker concentrations with outcomes 1 year after pediatric cardiac arrest.The Personalizing Outcomes After Child Cardiac Arrest multicenter prospective cohort study was conducted in pediatric intensive care units at 14 academic referral centers in the US between May 16, 2017, and August 19, 2020, with the primary investigators blinded to 1-year outcomes. The study included 120 children aged 48 hours to 17 years who were resuscitated after cardiac arrest, had pre-cardiac arrest Pediatric Cerebral Performance Category scores of 1 to 3 points, and were admitted to an intensive care unit after cardiac arrest.Cardiac arrest.The primary outcome was an unfavorable outcome (death or survival with a Vineland Adaptive Behavior Scales, third edition, score of70 points) at 1 year after cardiac arrest. Glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal esterase L1 (UCH-L1), neurofilament light (NfL), and tau concentrations were measured in blood samples from days 1 to 3 after cardiac arrest. Multivariate logistic regression and area under the receiver operating characteristic curve (AUROC) analyses were performed to examine the association of each biomarker with outcomes on days 1 to 3.Among 120 children with primary outcome data available, the median (IQR) age was 1.0 (0-8.5) year; 71 children (59.2%) were male. A total of 5 children (4.2%) were Asian, 19 (15.8%) were Black, 81 (67.5%) were White, and 15 (12.5%) were of unknown race; among 110 children with data on ethnicity, 11 (10.0%) were Hispanic, and 99 (90.0%) were non-Hispanic. Overall, 70 children (58.3%) had a favorable outcome, and 50 children (41.7%) had an unfavorable outcome, including 43 deaths. On days 1 to 3 after cardiac arrest, concentrations of all 4 measured biomarkers were higher in children with an unfavorable vs a favorable outcome at 1 year. After covariate adjustment, NfL concentrations on day 1 (adjusted odds ratio [aOR], 5.91; 95% CI, 1.82-19.19), day 2 (aOR, 11.88; 95% CI, 3.82-36.92), and day 3 (aOR, 10.22; 95% CI, 3.14-33.33); UCH-L1 concentrations on day 2 (aOR, 11.27; 95% CI, 3.00-42.36) and day 3 (aOR, 7.56; 95% CI, 2.11-27.09); GFAP concentrations on day 2 (aOR, 2.31; 95% CI, 1.19-4.48) and day 3 (aOR, 2.19; 95% CI, 1.19-4.03); and tau concentrations on day 1 (aOR, 2.44; 95% CI, 1.14-5.25), day 2 (aOR, 2.28; 95% CI, 1.31-3.97), and day 3 (aOR, 2.04; 95% CI, 1.16-3.57) were associated with an unfavorable outcome. The AUROC models were significantly higher with vs without the addition of NfL on day 2 (AUROC, 0.932 [95% CI, 0.877-0.987] vs 0.871 [95% CI, 0.793-0.949]; P = .02) and day 3 (AUROC, 0.921 [95% CI, 0.857-0.986] vs 0.870 [95% CI, 0.786-0.953]; P = .03).In this cohort study, blood-based brain injury biomarkers, especially NfL, were associated with an unfavorable outcome at 1 year after pediatric cardiac arrest. Additional evaluation of the accuracy of the association between biomarkers and neurodevelopmental outcomes beyond 1 year is needed.

Pediatric neurocritical care survivorship is frequently accompanied by functional impairments. Lack of prognostic biomarkers is a barrier to early identification and management of impairment. We explored the association between blood biomarkers and functional impairment in children with acute acquired brain injury. This study is a secondary analysis of a randomized control trial evaluating early versus usual care rehabilitation in the pediatric intensive care unit (PICU). Forty-four children (17 [39%] female, median age 11 [interquartile range 6–13] years) with acute acquired brain injury admitted to the PICU were studied. A single center obtained serum samples on admission days 0, 1, 3, 5, and the day closest to hospital discharge. Biomarkers relevant to brain injury (neuron specific enolase [NSE], S100b), inflammation (interleukin [IL-6], C-reactive protein), and regeneration (brain-derived neurotrophic factor [BDNF], vascular endothelial growth factor [VEGF]) were collected. Biomarkers were analyzed using a Luminex® bioassay. Functional status scale (FSS) scores were abstracted from the medical record. New functional impairment was defined as a (worse) FSS score at hospital discharge compared to pre-PICU (baseline). Individual biomarker fluorescence index (FI) values for each sample collection day were correlated with new functional impairment using Spearman rank correlation coefficient (ρ). Trends in repeated measures of biomarker FI over time were explored graphically, and the association between repeated measures of biomarker FI and new functional impairment was analyzed using covariate adjusted linear mixed-effect models. Functional impairment was inversely correlated with markers of regeneration and plasticity including BDNF at day 3 (ρ = − 0.404, p = .015), day 5 (ρ = − 0.549, p = 0.005) and hospital discharge (ρ = − 0.420, p = 0.026) and VEGF at day 1 (ρ = − 0.282, p = 0.008) and hospital discharge (ρ = − 0.378, p = 0.047), such that lower levels of both markers at each time point were associated with greater impairment. Similarly, repeated measures of BDNF and VEGF were inversely correlated with new functional impairment (B = − 0.001, p = 0.001 and B = − 0.001, p = 0.003, respectively). NSE, a biomarker of acute brain injury, showed a positive correlation between day 0 levels and new functional impairment (ρ = 0.320, p = 0.044). Blood-based biomarkers of regeneration and plasticity may hold prognostic utility for functional impairment among pediatric patients with neurocritical illness and warrant further investigation.

s: Few feasibility, safety, and efficacy data exist regarding ICU-based rehabilitative services for children. We hypothesized that early protocolized assessment and therapy would be feasible and safe versus usual care in pediatric neurocritical care patients.Randomized controlled trial.Three tertiary care PICUs in the United States.Fifty-eight children between the ages of 3-17 years with new traumatic or nontraumatic brain insult and expected ICU admission greater than 48 hours.Early protocolized (consultation of physical therapy, occupational therapy, and speech and language therapy within 72 hr ICU admission, n = 26) or usual care (consultation per treating team, n = 32).Primary outcomes were consultation timing, treatment type, and frequency of deferrals and safety events. Secondary outcomes included patient and family functional and quality of life outcomes at 6 months. Comparing early protocolized (n = 26) and usual care groups (n = 32), physical therapy was consulted during the hospital admission in 26 of 26 versus 28 of 32 subjects (p = 0.062) on day 2.4 ± 0.8 versus 7.7 ± 4.8 (p = 0.001); occupational therapy in 26 of 26 versus 23 of 32 (p = 0.003), on day 2.3 ± 0.6 versus 6.9 ± 4.8 (p = 0.001); and speech and language therapy in 26 of 26 versus 17 of 32 (p = 0.011) on day 2.3 ± 0.7 versus 13.0 ± 10.8 (p = 0.026). More children in the early protocolized group had consults and treatments occur in the ICU versus ward for all three services (all p0.001). Eleven sessions were discontinued early: nine during physical therapy and two during occupational therapy, none impacting patient outcome. There were no group differences in functional or quality of life outcomes.A protocol for early personalized rehabilitation by physical therapy, occupational therapy, and speech and language therapy in pediatric neurocritical care patients could be safely implemented and led to more ICU-based treatment sessions, accelerating the temporal profile and changing composition of interventions versus usual care, but not altering the total dose of rehabilitation.

With decreasing mortality in PICUs, a growing number of survivors experience long-lasting physical impairments. Early physical rehabilitation and mobilization during critical illness are safe and feasible, but little is known about the prevalence in PICUs. We aimed to evaluate the prevalence of rehabilitation for critically ill children and associated barriers.National 2-day point prevalence study.Eighty-two PICUs in 65 hospitals across the United States.All patients admitted to a participating PICU for greater than or equal to 72 hours on each point prevalence day.None.The primary outcome was prevalence of physical therapy- or occupational therapy-provided mobility on the study days. PICUs also prospectively collected timing of initial rehabilitation team consultation, clinical and patient mobility data, potential mobility-associated safety events, and barriers to mobility. The point prevalence of physical therapy- or occupational therapy-provided mobility during 1,769 patient-days was 35% and associated with older age (adjusted odds ratio for 13-17 vs3 yr, 2.1; 95% CI, 1.5-3.1) and male gender (adjusted odds ratio for females, 0.76; 95% CI, 0.61-0.95). Patients with higher baseline function (Pediatric Cerebral Performance Category, ≤ 2 vs2) less often had rehabilitation consultation within the first 72 hours (27% vs 38%; p0.001). Patients were completely immobile on 19% of patient-days. A potential safety event occurred in only 4% of 4,700 mobility sessions, most commonly a transient change in vital signs. Out-of-bed mobility was negatively associated with the presence of an endotracheal tube (adjusted odds ratio, 0.13; 95% CI, 0.1-0.2) and urinary catheter (adjusted odds ratio, 0.28; 95% CI, 0.1-0.6). Positive associations included family presence in children less than 3 years old (adjusted odds ratio, 4.55; 95% CI, 3.1-6.6).Younger children, females, and patients with higher baseline function less commonly receive rehabilitation in U.S. PICUs, and early rehabilitation consultation is infrequent. These findings highlight the need for systematic design of rehabilitation interventions for all critically ill children at risk of functional impairments.

Objective To describe the pathophysiology associated with multiple organ dysfunction syndrome in children. Data sources Literature review, research data, and expert opinion. Study selection Not applicable. Data extraction Moderated by an experienced expert from the field, pathophysiologic processes associated with multiple organ dysfunction syndrome in children were described, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Data synthesis Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.

Purpose of review This review is being published to update the literature on the function of the adaptive immune system in critical illness, specifically sepsis and acute lung injury. We have focused on the role of T cells in these syndromes. Recent findings The adaptive immune response becomes dysfunctional during sepsis and acute lung injury in very similar ways. Many of the abnormalities contribute to morbidity and mortality. Immunoparalysis captures the breadth of the dysfunction in that T-cell functions are broadly suppressed after the early proinflammatory stages of illness. Lymphocyte apoptosis, decreased antigen responsiveness, decreased and altered cytokine expression, upregulation of inhibitory molecules, and expansion of the suppressive regulatory T-cell population are mechanisms involved. Each of these abnormalities can be reversed with improvement in experimental outcomes. Summary Immunoparalysis of the adaptive immune system occurs in sepsis and acute lung injury, and is critical to the outcome. Blocking the inhibited pathways and immunostimulant cytokines improved lymphocyte function and outcome. Many such blocking agents are already effective for other diseases and could be used for immunoparalysis. Unfortunately, there is no diagnostic marker yet. In order to provide the right therapy at the right time, advancements in immunomonitoring are necessary.

Summary Background The dynamic nature of healthcare ensures that early career nurses enter an uncertain and complex world of practice and consequently require support to develop their practice, build confidence and reach their potential. The New Zealand Nurse Entry to Practice programme for registered nurses in their first year of practice has been operating since 2005 to enable safe and confident practice, improve the quality of care, and positively impact on recruitment and retention. This academic and clinical programme was offered as a partnership between a university and a clinical provider with postgraduate academic credits gained. Aim The aim of this study was to explore the perceived impact of postgraduate university education for early career nurses in one regional health area of New Zealand. Methods Participants were registered nurses who had completed the early career nurse programme and their clinical preceptors. The research was conducted via an online survey of 248 nurses and three focus groups to explore how the programme was experienced and its impact on knowledge and practice. Results Early career nurses and their preceptors found that the programme enables improved knowledge and skills of patient assessment, application of critical thinking to clinical practice, perceived improvement in patient care delivery and outcomes, enhanced interprofessional communication and knowledge sharing, and had a positive impact on professional awareness and career planning. Conclusions This clinical–academic partnership positively impacted on the clinical practice and transition experience of early career nurses and was closely aligned to an organization's strategic plan for nursing workforce development.

New graduate nurses are the future of nursing and the education they receive as they transition into the workforce as a newly registered nurse is critical for building a suitably qualified nursing workforce that will adequately serve the future population. Variation exists in education programmes for new graduate nurses in their first year of practice which is known to impact on transition experience. A qualitative study using focus groups and semi-structured interviews was undertaken to explore the experiences and perceptions of New Graduate Nurses undertaking a new graduate programme and Directors of Nursing supporting them to complete the programme which may or may not have been inclusive of a postgraduate course (Masters Level). The findings of this study are in line with previous research and support the value of new graduate programmes but did reveal a lack of consensus in regards to the structure and content of such programmes. This study revealed some commonalities and challenges between the differing programmes but has identified the need for further research to establish the impact of postgraduate education in the first year of practice and how this impacts on nursing practice and patient care. There are numerous terms in the literature with reference to new graduate programmes; transition to practice programme, nurse entry to practice programme, first year of clinical practice programme, new graduate programme and early career nursing programme. For the purpose of this article the term Nurse Entry to Practice (NETP) will be used in reference to any form of new graduate programme.

Septic shock heterogeneity has important implications for clinical trial implementation and patient management. We previously addressed this heterogeneity by identifying three putative subclasses of children with septic shock based exclusively on a 100-gene expression signature. Here we attempted to prospectively validate the existence of these gene expression-based subclasses in a validation cohort.Prospective observational study involving microarray-based bioinformatics.Multiple pediatric intensive care units in the United States.Separate derivation (n = 98) and validation (n = 82) cohorts of children with septic shock.None other than standard care.Gene expression mosaics of the 100 class-defining genes were generated for 82 individual patients in the validation cohort. Using computer-based image analysis, patients were classified into one of three subclasses ("A," "B," or "C") based on color and pattern similarity relative to reference mosaics generated from the original derivation cohort. After subclassification, the clinical database was mined for phenotyping. Subclass A patients had higher illness severity relative to subclasses B and C as measured by maximal organ failure, fewer intensive care unit-free days, and a higher Pediatric Risk of Mortality score. Patients in subclass A were characterized by repression of genes corresponding to adaptive immunity and glucocorticoid receptor signaling. Separate subclass assignments were conducted by 21 individual clinicians using visual inspection. The consensus classification of the clinicians had modest agreement with the computer algorithm.We have validated the existence of subclasses of children with septic shock based on a biologically relevant, 100-gene expression signature. The subclasses have relevant clinical differences.

The mortality of septic shock in the pediatric population has improved over the last 2 decades with better supportive care however it still remains unacceptably high. Exaggerated inflammatory responses early in septic shock have been associated with poor outcomes. Regulation of the magnitude of the early inflammatory response is not well understood. The earliest aspect of the inflammatory response to pathogens is the innate immune response which is important to pathogen containment. Elements of the innate immune system activate the adaptive immune system in an antigen-specific way which leads to pathogen-specific protection and lasting immunologic memory to prevent subsequent infection. Pattern recognition receptors (PRRs) are evolutionarily conserved receptors on multiple types of innate immune cells and are capable of responding to highly conserved components of pathogens called pathogen associated molecular patterns (PAMPs). Numerous PRRs have been defined and are present on the cell surface as well as in the cytosol. These receptors fall into several classes called Toll-like receptors which are expressed on the cell surface or on the endosomal plasma membrane, C type lectin receptors and scavenger receptors which are only present on the cell surface. Other PRRs are present in the cytosol and including NOD-like receptors which can aggregate to form inflammasomes and RIG1 like receptors. Pathogenic microorganisms are extremely diverse however there are some common patterns repeated in components of structures such as the cell wall. PRRs can respond to PAMPs comprised of proteins, lipids, and carbohydrates, DNA and RNA. Numerous PAMPs have been described for many classes of pathogenic microorganisms such as Gram negative bacteria, Gram positive bacteria, viruses, fungi, and protozoa. The interactions between PRRs and PAMPs comprise the earliest immune responses to foreign substances and are critical for pathogen containment and amplification of the full repertoire of the immune response. There are developmental differences in the immune systems of infants and children compared to adults. The innate immune system matures much earlier than the adaptive immune response and as a result infants and young children may be more reliant on their innate immune system. For this reason it important to fully understand the key elements of the innate immune response including the many categories of PRRs and their cognate PAMPs. As these interactions are very early in the immune response, they are particularly relevant targets for therapeutic intervention. Below is a discussion of the major classes of PRRs, their expression, ligands, and signaling pathways as well as the major classes of PAMPs that activate them.

Objective To develop a clinically feasible stratification strategy for pediatric septic shock, using gene expression mosaics and a 100-gene signature representing the first 24 hrs of admission to the pediatric intensive care unit. Design Prospective, observational study involving microarray-based bioinformatics. Setting Multiple pediatric intensive care units in the United States. Patients Ninety-eight children with septic shock. Interventions None other than standard care. Measurements and main results Patients were classified into three previously published, genome-wide, expression-based subclasses (subclasses A, B, and C) having clinically relevant phenotypic differences. The class-defining 100-gene signature was depicted for each individual patient, using mosaics generated by the Gene Expression Dynamics Inspector (GEDI). Composite mosaics were generated representing the average expression patterns for each of the three subclasses. Nine individual clinicians served as blinded evaluators. Each evaluator was shown the 98 individual patient mosaics and asked to classify each patient into one of the three subclasses, using the composite mosaics as the reference point. The respective sensitivities, specificities, positive predictive values, and negative predictive values of the subclassification strategy were ≥ 4% across the three subclasses. The classification strategy also generated positive likelihood ratios of ≥ 6.8 and negative likelihood ratios of ≤ .2 across the three subclasses. The κ coefficient across all possible interevaluator comparisons was 0.81. Conclusions We have provided initial evidence (proof of concept) for a clinically feasible and robust stratification strategy for pediatric septic shock based on a 100-gene signature and gene expression mosaics.

Angiopoietin (angpt) 1 and angpt-2 are circulating proteins first ascribed opposing roles in embryonic angiogenesis. Both bind the tyrosine kinase with immunoglobulin-like loop and epidermal growth factor homology domains (Tie) 2 receptor on endothelial cells, but angpt-1 is a Tie-2 agonist, whereas angpt-2 antagonizes Tie-2 signaling. In the developed vasculature, angpt-1 protects against vascular leak, whereas angpt-2 promotes increased vascular permeability. Because alterations in vascular permeability are common in septic shock, we obtained plasma from critically ill children within 24 h of diagnosis of the systemic inflammatory response syndrome (SIRS, n = 20), sepsis (n = 20), or septic shock (n = 61), as well as 15 healthy controls. Plasma levels of angpt-1 and angpt-2 were measured via a commercially available enzyme-linked immunosorbent assay. Plasma angpt-2 levels were significantly elevated in children with septic shock when compared with healthy children, as well as critically ill children with either SIRS or sepsis, and circulating angpt-2 levels seemed to correlate with disease severity and outcome. In addition, plasma angpt-1 levels were significantly decreased in critically ill children with septic shock compared with critically ill children with either SIRS or sepsis. Given the contrasting effects of angpt-2 and angpt-1 on the vascular endothelium, these two factors may play an important role in the pathophysiology of septic shock in children, and further studies are warranted.

Electrolyte emergencies and acute renal failure are common problems in pediatric critical care. With improved understanding of electrolyte disturbances and more pediatric specific treatment available for acute renal failure, this field is constantly changing. The initial emergency management and ongoing care of these problems require special consideration and often individualized treatment. This article addresses the pathophysiology and treatment of electrolyte emergencies and acute renal failure. Special circumstances seen in the pediatric critical care setting are reviewed in greater detail with disease-specific treatment considerations. In addition, a review of renal replacement therapy and its use in acute renal failure is given. This article will provide a review of, and treatment strategy for, the variety of electrolyte emergencies and causes of acute renal failure facing the critical care patient.

Induction of the antiviral cytokine interferon alpha/beta (IFN-alpha/beta) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. We injected mice with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand and known IFN-alpha/beta inducer as well as nuclear factor kappaB (NF-kappaB) activator to simulate very early antiviral pathways. We then challenged mice with an in vivo septic shock model characterized by slowly evolving bacterial infection to simulate bacterial superinfection early during a viral infection. Our data demonstrated robust induction of IFN-alpha in serum within 24 h of PIC injection with IFN-alpha/beta-dependent major histocompatibility antigen class II up-regulation on peritoneal macrophages. PIC pretreatment before septic shock resulted in augmented tumor necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with septic shock alone. Intact IFN-alpha/beta signaling was necessary for augmentation of the inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in vitro. To assess the NF-kappaB contribution to PIC-modulated inflammatory responses to septic shock, we treated with parthenolide, an NF-kappaB inhibitor before PIC and septic shock. Parthenolide did not inhibit IFN-alpha induction by PIC. Inhibition of NF-kappaB by parthenolide did reduce IFN-alpha-mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease.

Antipyrine metabolism is a "gold standard" measure of mixed cytochrome P450 (CYP) mediated drug metabolism in humans. Cytokines (e.g., interleukin-6) and nitric oxide reduce CYP 450 activity in vitro and in vivo. Because interleukin-6 and nitric oxide production increases in children with sepsis-induced multiple organ failure, we hypothesized impaired CYP 450 mediated drug metabolism in this population.Fifty-one consecutive children with sepsis and six critically ill children without sepsis were enrolled and given 18 mg/kg antipyrine per NG. Plasma antipyrine elimination rate, elimination half-life, and apparent oral clearance were measured and calculated. Plasma interleukin-6 and nitrite plus nitrate levels were measured and organs failing scored on days 1-3 of sepsis.Children with sepsis had a twofold reduction in antipyrine clearance. Children with persistent failure of three or more organs had a fourfold reduction in antipyrine clearance. Antipyrine clearance was inversely correlated to circulating interleukin-6 and nitrite plus nitrate levels and to number of organ failures.Interpretation CYP 450 mediated drug metabolism is decreased in children with sepsis, related in part to the degree of inflammation and organ failure. For drugs metabolized by CYP 450 enzymes there is an urgent need to reevaluate the use of standard drug dosage schedules in the sepsis population

Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock/trauma, however, modeling this process in mice with a single shock or septic event is inconsistent. One explanation is that hemorrhage is often just a “priming insult,” thus, secondary stimuli may be required to “trigger” ALI. To test this we carried out studies in which we assessed the capacity of hemorrhage alone or hemorrhage followed by septic challenge (CLP) to induce ALI. Lung edema, bronchoalveolar lavage interleukin (IL)-6, alveolar congestion, as well as lung IL-6, macrophage inflammatory protein (MIP)-2, and myeloperoxidase (MPO) activity were all increased in mice subjected to CLP at 24 but not 72 hours following hemorrhage. This was associated with a marked increase in the susceptibility of these mice to septic mortality. Peripheral blood neutrophils derived from 24 hours post-hemorrhage, but not Sham animals, exhibited an ex vivo decrease in apoptotic frequency and an increase in respiratory burst capacity, consistent with in vivo “priming.” Subsequently, we observed that adoptive transfer of neutrophils from hemorrhaged but not sham-hemorrhage animals to neutropenic recipients reproduce ALI when subsequently septically challenged, implying that this priming was mediated by neutrophils. We also found marked general increases in lung IL-6, MIP-2, and MPO in mice deficient for toll-like receptor (TLR-4) or the combined lack of TLR-4/FasL. However, the TLR-4 defect markedly attenuated neutrophil influx into the lung while not altering the change in local cytokine/chemokine expression. Alternatively, the combined loss of FasL and TLR-4 did not inhibit the increase in MPO and exacerbated lung IL-6/MIP-2 levels even further.

SummaryCytokines increase endothelial tissue factor (TF) and tissue plasminogen activator inhibitor type -1 (PAI-1) expression in vitro. Tissue factor interacts with factor VII to facilitate thrombosis and PAI-1 inhibits fibrinolysis by endogenous plasminogen activators.Because cytokine release is increased in children with sepsisinduced multiple organ failure (MOF), we hypothesized a cytokine associated increase in circulating TF and PAI-1 antigen release, and systemic activity in these patients.One hundred and seven consecutive children, who met the criteria for sepsis, and 10 critically ill children without sepsis, were enrolled in the study. Plasma TF and PAI-1 antigen and activity levels, Interleukin-6 antigen levels (IL-6), nitrite + nitrate levels (marker of nitric oxide production) and number of organs failing were measured on days 1-3 of sepsis.Increased TF and PAI-1 antigen, and PAI-1 activity levels were associated with increasing IL-6 and nitrite + nitrate levels (p A shift to an anti-fibrinolytic endothelium phenotype characterizes children who develop sepsis-induced MOF and mortality. Children with coagulopathy have a shift to a pro-coagulant phenotype. These findings support potential therapeutic roles for PAI-1 and TF pathway inhibitors in reversal of this devastating pathophysiologic process.

Infectious diseases are among the most common pediatric illnesses and are frequently encountered in the pediatric intensive care unit. Tropical infections, on the other hand, are relatively uncommon in children in developed countries, except those with pertinent travel histories or recent immigration. Clinicians who participate in mission work and disaster relief work also encounter these diseases as they are endemic in many developing nations. For the most part these infections do not result in critical illness however some do and this chapter will focus on a few of the more common infections with potential to be acutely life threatening. The epidemiology, pathophysiology, clinical manifestations, and current clinical management are presented for severe malaria, dengue fever, typhoid, and leptospirosis.

Underlying viral infections can heighten sensitivity and worsen cytokine-mediated disease following secondary inflammatory challenges. Mechanisms for this are poorly understood. The impact of the innate response to lymphocytic choriomeningitis virus (LCMV) infection on sensitivity to endotoxin (LPS) was investigated. Compared with uninfected mice, infection with LCMV for 2-days-sensitized mice to LPS by approximately 2-fold for lethality and by 2- to 6-fold for serum TNF-alpha levels. Priming for LPS-induced TNF-alpha was also seen with splenic and peritoneal leukocytes isolated from infected mice and challenged with LPS ex vivo. The effect on TNF-alpha production was present in the absence of IFN-gamma, its major producers NK and T cells, and the major pathways for its induction through IL-12 and the signal transducer and activator of transcription 4 (STAT4), and therefore was IFN-gamma independent. Early LCMV infection induces high concentrations of the type 1 IFNs, IFN-alphabeta. Administration of recombinant IFN-alpha alone heightened the TNF-alpha response to LPS. Innate IFN-alphabeta and IFN-gamma responses to LCMV exist in a delicate balance. To reduce priming for LPS-induced TNF-alpha during LCMV, deficiencies in both the IFN-alphabeta and IFN-gamma receptors or STAT1, a transcription factor downstream to both IFNs, were required. These data demonstrate that early viral infection can enhance sensitivity to bacterial products, and that this sensitization can occur in part as a result of endogenously expressed IFN-alphabeta. This work also raises issues about potential complications associated with IFN-alphabeta therapies.

Background Provision of medications in-hand at discharge improves adherence with recommended therapy. Objectives Among patients discharged from our emergency departments(ED)/urgent cares(UC) with an acute asthma exacerbation, we aimed to provide oral corticosteroid (OCS) in-hand so families did not have to fill a prescription after discharge. Methods Our multidisciplinary team created a key driver diagram to make explicit our theory for improvement. Key drivers included effective decision support, readily available medication with standard dispensing process, and provider education. Multiple plan-do-study-act cycles were conducted to address key drivers. Our primary outcome was provision of OCS in-hand at time of discharge and our secondary outcome was change to dexamethasone as preferred OCS in ED. Proportion of patients with a return visit within 7 days who required additional OCS was tracked as a balancing measure to ensure there were no unintended consequences. Results Statistical process control charts illustrated special cause variation in both our primary (2% to 96%, figure 1) and secondary (17% to 95%, figure 2) outcome measures. Our balancing measure remained was stable demonstrating only common cause variation (figure 3). Conclusions Using improvement methodology, we increased the proportion of patients seen in the ED/UC who received OCS in-hand at discharge from 2% to 96% without any increase in 7 day returns requiring additional OCS. This practice change within one division had a ripple effect across multiple care sites, including inpatient change to dexamethasone and a standardized process for outpatient follow-up. Future work will focus on standardization of key decisions across ED/UC in collaboration with all key stakeholders.

Induction of high systemic levels of type 1 interferons (IFNs) IFN-alpha and IFN-beta is a hallmark of many viral infections. In addition to their potent antiviral effects, these cytokines mediate a number of immunoregulatory functions and can promote IFN-gamma expression in T cells. However, during viral infections of mice IFN-gamma production is not always observed at the same time as systemic IFN-alpha/beta production and when, elicited at these times, is IFN-alpha/beta-independent. We demonstrate that type 1 interferons not only fail to induce, but also act to inhibit, IFN-gamma expression by both NK and T cells. The mechanism of inhibition is dependent upon the IFN-alpha/beta receptor and the signal transducer and activator of transcription 1 (STAT1). In the absence of STAT1, not only are the IFN-alpha/beta-mediated inhibitory effects completely abrogated, but the cytokines themselves can induce IFN-gamma expression. These results indicate that endogenous biochemical pathways are in place to negatively regulate NK and T cell IFN-gamma expression elicited by IFN-alpha/beta or other stimuli, at times of innate responses to viral infections. They also show that type 1 interferon signaling can occur through STAT1-dependent and independent mechanisms and suggest that efficient induction of IFN-gamma expression by IFN-alpha/beta requires STAT1 regulation. Such immunoregulatory pathways may be critical for shaping the endogenous innate and virus-specific adaptive immune responses to viral infections.

To determine the circulating anti-inflammatory cytokine interleukin 10 (IL-10) response during the development of sepsis-induced multiple organ failure in children.Prospective study.University pediatric ICU.Fifty-three consecutive children with sepsis and 15 critically ill children without sepsis.Plasma IL-10, interleukin 6 (IL-6), and nitrite+nitrate (stable end products of nitric oxide) levels and an organ failure index (OFI indicating the number of failing organ systems) were determined in 53 children on days 1 to 3 of sepsis and in control children on day 1. The effect of exogenous human IL-10 or neutralizing IL-10 antibody on supernatant IL-6 levels in ex vivo whole blood culture from 17 children on day 1 of sepsis.Children with three or more organ failures had higher plasma IL-10 levels than children with less than 3 organ failures (days 1 and 3; p0.05). Children who developed sequential pulmonary/hepatic/renal failure had higher IL-10 levels (days 1 to 3; p0.05). Nonsurvivors had higher IL-10 levels (day 3; p0.05). IL-10 levels correlated with IL-6 levels (days 1 and 2) and nitrite+nitrate levels (days 1 and 3; p0.05). Whole blood samples incubated ex vivo with exogenous recombinant human IL-10 had decreased supernatant IL-6 levels (p0.05) and neutralizing IL-10 antibody showed no significant effect.A persistent compensatory anti-inflammatory cytokine response characterizes sepsis-induced multiple organ failure. Administration of exogenous IL-10 may inhibit the early proinflammatory response; however, identification of individual immune responsiveness and possibility of persistent infection could be important to rational use in the later stages of pediatric sepsis.

To determine whether plasma nitrite and nitrate concentrations are associated with the development of sepsis-induced multiple organ failure.Prospective study.University children's hospital.Fifty-three consecutive children meeting criteria for sepsis and not receiving exogenous sources of nitric oxide.Plasma nitrite and nitrate concentrations were measured, and the number of organs failing was scored using an organ failure index on the first 3 days of sepsis.Children with three or more organs failing on day 3 of sepsis had higher plasma nitrite and nitrate concentrations than children who had resolution of failure of three or more organs by day 3 of sepsis (days 2 and 3) and children who never had three organs failing in the first 3 days of sepsis (days 1, 2, and 3). Children who developed sequential pulmonary/hepatic/renal organ failure had significantly higher plasma nitrite and nitrate concentrations (days 1, 2, and 3). Nonsurvivors had significantly higher plasma nitrite and nitrate concentrations (days 2 and 3) than survivors. Plasma nitrite and nitrate concentrations on day 1 predicted the development of persistent failure of three of more organs and sequential multiple organ failure but not mortality.Increased plasma nitrite and nitrate concentrations are associated with the development of multiple organ failure in pediatric sepsis.

To examine the relationship of circulating proinflammatory and anti-inflammatory cytokine concentrations to nitric oxide and organ failure in pediatric sepsis.Prospective study.Pediatric intensive care unit (ICU), children's Hospital of Pittsburgh, University of Pittsburgh.Nineteen patients with a diagnosis of sepsis admitted to the pediatric ICU. Twelve uninfected critically iII patients served as controls.None.Plasma interleukin (IL)-10, IL-6, and nitrite/nitrate concentrations were measured and compared with an index of organ failure daily for 3 days after presentation with the sepsis syndrome. Children with increased plasma IL-6 concentrations (n = 6) had increased plasma nitrite/nitrate concentrations (p0.01 on each day), increased organ failure scores (p.05 on days 1 and 3), and the highest plasma IL-10 concentrations (p.05 on days 1 and 3, p = .054 on day 2) when compared with children with sepsis and undetectable IL-6 concentrations. Children with sepsis and detectable IL-6 concentrations, and children with undetectable IL-6 concentrations, both had increased nitrite/nitrate concentrations (p.005 on days 1 through 3) and increased IL-10 concentrations (p.05 on days 1 and 2) compared with controls. Children with increased IL-6 concentrations had higher organ failure on each day (p.01), and children with undetectable IL-6 concentrations had higher organ failure on days 1 and 2 only (p.005) when compared with controls. Organ failure improved over time in the children with undetectable IL-6 concentrations (p.005).Increased plasma nitrite/nitrates and increased organ failure scores occurred in the children with sepsis who had an exaggerated proinflammatory state, despite a pronounced anti-inflammatory response. When the anti-inflammatory response predominated and the proinflammatory state was dampened, organ failure status improved.

Acute kidney injury (AKI) independently increases morbidity and mortality in children admitted to the hospital. Renal replacement therapy (RRT) is an essential therapy in the setting of AKI and fluid overload. The decision to initiate RRT is complex and often complicated by concerns related to patient hemodynamic and thermodynamic instability. The choice of which RRT modality to use depends on numerous criteria that are both patient and treatment center specific. Surprisingly, despite decades of use, no randomized, controlled trial study involving RRT in pediatrics has been performed. Because of these factors, clear-cut consensus is lacking regarding key questions surrounding RRT delivery. In this paper, we will summarize existing data concerning RRT use in children. We discuss the major modalities and the data-driven specifics of each, followed by controversies in RRT. As no standard of care is in widespread use for RRT in AKI or in multiorgan disease, we conclude in this paper that prospective studies of RRT are needed to identify best practice guidelines.

Recent data suggest that extracellular Hsp60 modulates the host innate immune response. We analyzed plasma Hsp60 levels in children admitted to a level III tertiary care PICU with septic shock.Blood samples were obtained from children meeting criteria for septic shock (n = 63), critically ill children without septic shock (n = 10), and healthy controls (n = 24).Not applicable.Hsp60 levels were measured in the plasma using a commercially available ELISA. Differences between groups were analyzed with a Kruskal-Wallis one way ANOVA due to the non-parametric nature of the data. A p valueor = 0.05 was considered significant.Extracellular Hsp60 levels were significantly higher in children with septic shock (median, 16.7 ng/mL) compared to both critically ill children without septic shock (median, 0 ng/mL) and healthy controls (median, 0 ng/mL, p0.001).Extracellular Hsp60 levels are significantly elevated in children with septic shock compared with both healthy controls and critically ill children without sepsis. Extracellular Hsp60 may play a role in the pathogenesis of sepsis in children.

Suppressor of Cytokine Signaling (SOCS) proteins are recently identified inhibitors/regulators of cytokine/growth factor signaling pathways. We have previously shown that SOCS-3 is upregulated in mice after sepsis induced by cecal ligation and puncture; however, the contribution of SOCS-1 to septic morbidity and mortality is unclear. In the present study, we characterized SOCS-1 expression in different tissues and delineated putative mechanisms effecting SOCS-1 expression in thymus from septic mice. We observed no difference in SOCS-1 expression in blood, peritoneal leukocytes, lung, and spleen taken from sham or septic animals at 24 h after surgery. In contrast, SOCS-1 expression in thymus declined significantly after sepsis and this down-regulation of SOCS-1 was associated with increased thymocyte apoptosis as well as augmented Bax recruitment to the mitochondria. Administration of RU-38486, a steroid receptor antagonist, reversed the above effects in the septic thymus. Furthermore, SOCS-1+/− mice showed a significant higher mortality when compared to SOCS-1+/+ mice after sepsis. Together, these results show that sepsis increases steroid-induced thymic lymphoid cell apoptosis, which is associated with reduced SOCS-1 expression and increased Bax translocation to mitochondria. Survival data suggests that SOCS-1 protein may play an important role in sepsis.

Although studies have shown increased evidence of death receptor-driven apoptosis in intestinal lymphoid cells, splenocytes, and the liver following the onset of polymicrobial sepsis, little is known about the mediators controlling this process or their pathologic contribution. We therefore attempted to test the hypothesis that the hydrodynamic administration of small interfering RNA (siRNA) against the death receptor, Fas or caspase-8, should attenuate the onset of morbidity and mortality seen in sepsis, as produced by cecal ligation and puncture (CLP). We initially show that in vivo administration of green fluorescent protein (GFP) siRNA in GFP transgenic mice results in a decrease in GFP fluorescence in most tissues. Subsequently, we also found that treating septic nontransgenic mice with siRNA targeting Fas or caspase-8 but not GFP (used as a control here) decreased the mRNA, in a sustained fashion up to 10 days, and protein expression of Fas and caspase-8, respectively. In addition, transferase-mediated dUTP (deoxyuridine triphosphate) nick end labeling (TUNEL) and active caspase-3 analyses revealed a decrease in apoptosis in the liver and spleen but not the thymus following siRNA treatment. Indices of liver damage were also decreased. Finally, the injection of Fas or caspase-8 given not only 30 minutes but up to 12 hours after CLP significantly improved the survival of septic mice.

Prior studies have shown that hemorrhage (Hem) can serve as a priming stimulus for acute lung injury (ALI) triggered by subsequent septic challenge (cecal ligation and puncture, CLP). Furthermore, we have reported that in vivo antibody neutralization of the chemokines, macrophage inflammatory chemokine-2 (MIP-2) and keratinocyte-derived chemokine (KC), immediately after Hem appears to differentially effect the onset of ALI. However, although we hypothesize that this is due to divergent effects of MIP-2 and KC on Hem-induced neutrophil (PMN) priming, this has not been tested. To examine this hypothesis, PMN donor mice were Sham-Hem or Hem for 90 min at 35 +/- 5 mmHg and were then administered anti-MIP- 2 (Hem/anti-MIP2), anti-KC (Hem/anti-KC), or nonspecific immunoglobulin (Ig) G (Hem/IgG) during resuscitation (Ringer's lactate = four times the amount of drawn blood volume). Twenty-four hours post-Hem, the peripheral blood PMN were purified from these donor animals and were introduced into PMN-depleted recipient mice [depleted by prior anti-Gr1 (mouse PMN-specific marker) antibody treatment]. One hour after PMN transfer, recipient mice were subjected to CLP, euthanized 24 h later, and plasma as well as lung tissue samples were collected. PMN influx was assessed by myeloperoxidase assay (MPO; microU/mg protein) and histologically (IL-6, MIP-2, KC, and IL-10 levels) by enzyme-linked immunoabsorbant assay (ELISA; ng/mg). The results show that donor PMN from Hem/IgG but not Sham-Hem mice produce increased PMN influx (increased MPO, increased % esterase+ cells in tissue) into the lung and local tissue inflammation (increased IL-6/MIP-2, decreased IL-10) in PMN-depleted CLP recipient mice, which was attenuated in mice receiving cells from Hem/anti-MIP-2 but not Hem/anti-KC treated donors. Interestingly, although Hem/anti-MIP-2 donor PMN produced comparable effects on blood IL-6/MIP-2 levels, they were ineffective in altering the change in plasma IL-10/KC levels induce by Hem. Taken together, these data demonstrate that Hem-induced priming of PMN not only mediates ALI in the mouse, but also that this process is differentially effected by MIP2 and KC, despite the fact that both signal through CXCR2.

OBJECTIVE To examine the relationships between procalcitonin, bacterial infection, sepsis-induced multiple organ failure, and mortality rate in children. DESIGN Cohort study. SETTING A multidisciplinary, tertiary-care pediatric intensive care unit. PATIENTS Seventy-eight children meeting criteria for sepsis or septic shock and 12 critically ill children without sepsis. INTERVENTIONS Venous or arterial blood sampling. MEASUREMENTS AND MAIN RESULTS Demographic, epidemiologic, and outcome data were recorded. Plasma from children with sepsis were collected on days 1 and 3, and procalcitonin concentrations were measured by immunoluminometric assay. Organ failure index scores were determined, and multiple organ failure was defined as organ failure index > or = 3. Persistent multiple organ failure was defined by presence of multiple organ failure on day 3. Procalcitonin concentrations (median [25th percentile-75th percentile]) were increased among children with sepsis on day 1 (2.4 ng/mL [0.2-24.2], p < .01) but not on day 3 (0.8 ng/mL [0.1-8.1], p = nonsignificant) vs. controls (0.2 ng/mL [0.1-0.5]). This increase in procalcitonin concentration was particularly robust among children with bacterial sepsis on day 1 (7.1 ng/mL [0.9-44.8], p < .001) and on day 3 (2.9 ng/mL [0.1-32.4], p < .05). Procalcitonin concentrations were not increased among children with fungal, viral, or culture-negative sepsis vs. controls. Procalcitonin concentrations were persistently increased over time among patients with bacterial sepsis who had persistent multiple organ failure (p < .05) and who died (p < .01) but not among patients with nonbacterial sepsis. CONCLUSIONS Procalcitonin is persistently increased among children with poor outcome from bacterial sepsis. Further study is needed to better delineate this differential procalcitonin response to bacterial vs. nonbacterial sepsis and to characterize any mechanistic role that procalcitonin might play in the development of bacterial sepsis-induced multiple organ failure and mortality.

The systemic inflammatory response is elicited in a multitude of clinical scenarios including infection, tissue injury (surgical or traumatic), ischemia-reperfusion, post-cardiopulmonary bypass, as well as autoimmune phenomena. There are many factors capable of modulating the magnitude and quality of the immune response during critical illness/injury. Some factors precede critical illness/injury such as chronic poor nutrition, chronic stress (physiologic and/or psychologic), and underlying infectious disease (chronic and acute). Other factors become important modulators during a critical illness/injury including acute stress, infection, tissue injury, poor nutrition, and pharmacologic agents not usually associated with immunomodulation.

The Fas-Fas ligand system is important for apoptosis of activated immune cells. Perturbation of this system occurs in diseases with dysregulated inflammation. Increased soluble Fas (sFas) occurs in systemic inflammatory response syndrome (SIRS) and can block apoptosis. Increased shedding of FasL (sFasL) occurs in viral infection and hepatitis. Although dysregulated inflammation is associated with sepsis-induced multiple organ failure (MOF) in children, a role for Fas has not been established. We hypothesize that 1) sFas will be increased in children with severe and persistent sepsis-induced MOF and will correlate with inflammatory markers suggesting a role for sFas in inflammatory dysregulation in severe sepsis, and 2) sFasL will be increased when viral sepsis or sepsis-induced liver failure-associated MOF is present in children. Plasma sFas, sFasL, IL-6, IL-10, nitrite + nitrates, and organ failure scores were measured on d 1 and d 3 in 92 children with severe sepsis and 12 critically ill control children. sFas levels were increased in severe sepsis, continued to increase in persistent MOF and nonsurvivors, and were correlated with serum inflammatory markers (IL-6, IL-10, nitrite + nitrate levels). In contrast, sFasL was not increased in severe sepsis and did not correlate with inflammation. sFasL was, however, increased in liver failure-associated MOF and in nonsurvivors, and was associated with viral infection. At autopsy, hepatocyte destruction and lymphocyte infiltration were associated with increased sFas and sFasL levels. sFas may interfere with activated immune cell death and contribute to dysregulation of inflammation, worsening outcome from severe sepsis. sFasL may contribute to hepatic injury and the development of liver failure-associated MOF.