Estimating risk of prolonged mechanical ventilation after liver transplantation in children: PROVE-ALT score.

BACKGROUND: Children at high risk for prolonged mechanical ventilation (PMV) after liver transplantation (LT) need to be identified early to optimize pulmonary support, allocate resources, and improve surgical outcomes. We aimed to develop and validate a metric that can estimate risk for Prolonged Ventilation After LT (PROVE-ALT). METHODS: We identified preoperative risk factors for PMV by univariable analysis in a retrospective cohort of pediatric LT recipients between 2011 and 2017 (n = 205; derivation cohort). We created the PROVE-ALT score by mapping multivariable logistic regression coefficients as integers, with cutoff values using the Youden Index. We validated the score by C-statistic in a retrospectively collected separate cohort of pediatric LT recipients between 2018 and 2021 (n = 133, validation cohort). RESULTS: Among total 338 patients, 21% (n = 72) were infants; 49% (n = 167) had cirrhosis; 8% (n = 27) required continuous renal replacement therapy (CRRT); and 32% (n = 111) required management in hospital (MIH) before LT. Incidence of PMV post-LT was 20% (n = 69) and 3% (n = 12) required tracheostomy. Independent risk factors (OR [95% CI]) for PMV were cirrhosis (3.8 [1-14], p = .04); age <1-year (8.2 [2-30], p = .001); need for preoperative CRRT (6.3 [1.2-32], p = .02); and MIH before LT (12.4 [2.1-71], p = .004). PROVE-ALT score ≥8 [Range = 0-21] accurately predicted PMV in the validation cohort with 73% sensitivity and 80% specificity (AUC: 0.81; 95% CI: 0.71-0.91). CONCLUSION: PROVE-ALT can predict PMV after pediatric LT with a high degree of sensitivity and specificity. Once externally validated in other centers, PROVE-ALT will empower clinicians to plan patient-specific ventilation strategies, provide parental anticipatory guidance, and optimize hospital resources.

Pediatric Swine Model of Methicillin-Resistant Staphylococcus aureus Sepsis-Induced Coagulopathy, Disseminated Microvascular Thrombosis, and Organ Injuries.

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant Staphylococcus aureus (MRSA), there is a paucity of published Gram-positive pediatric sepsis models. Large animal models replicating sepsis-induced coagulopathy are needed to test new therapeutics before human clinical trials. HYPOTHESIS: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours. METHODS AND MODELS: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA (n = 6) (USA300, Texas Children's Hospital 1516 strain) at 1 × 109 colony forming units/kg or saline (n = 4). Fluid resuscitation was given for heart rate greater than 50% or mean arterial blood pressure less than 30% from baseline. Acetaminophen and dextrose were provided as indicated. Point-of-care complete blood count, prothrombin time (PT), activated thromboplastin time, d-dimer, fibrinogen, and specialized coagulation assays were performed at pre- and post-injection, at 0, 24, 48, 60, and 70 hours. Piglets were euthanized and necropsies performed. RESULTS: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors V, VII, protein C, antithrombin, and a disintegrin and metalloproteinase with thrombospondin-1 motifs (13th member of the family) (ADAMTS-13) decreased significantly in septic piglets compared with control. Histopathologic examination showed minor focal organ injuries including microvascular thrombi and necrosis in the kidney and liver of septic piglets. INTERPRETATIONS AND CONCLUSIONS: We established a 70-hour swine model of MRSA sepsis-induced coagulopathy with signs of consumptive coagulopathy, disseminated microvascular thrombosis, and early organ injuries with histological minor focal organ injuries. This model is clinically relevant to pediatric sepsis and can be used to study dysregulated host immune response and coagulopathy to infection, identify potential early biomarkers, and to test new therapeutics.

Aberrant Fibrin Clot Structure Visualized Ex Vivo in Critically Ill Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

OBJECTIVES: Disseminated fibrin-rich microthrombi have been reported in patients who died from COVID-19. Our objective is to determine whether the fibrin clot structure and function differ between critically ill patients with or without COVID-19 and to correlate the structure with clinical coagulation biomarkers. DESIGN: A cross-sectional observational study. Platelet poor plasma was used to analyze fibrin clot structure; the functional implications were determined by quantifying clot turbidity and porosity. SETTING: ICU at an academic medical center and an academic laboratory. PATIENTS: Patients admitted from July 1 to August 1, 2020, to the ICU with severe acute respiratory syndrome coronavirus 2 infection confirmed by reverse transcription-polymerase chain reaction or patients admitted to the ICU with sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood was collected from 36 patients including 26 ICU patients with COVID-19 and 10 ICU patients with sepsis but without COVID-19 at a median of 11 days after ICU admission (interquartile range, 3-16). The cohorts were similar in age, gender, body mass index, comorbidities, Sequential Organ Failure Assessment (SOFA) score, and mortality. More patients with COVID-19 (100% vs 70%; p = 0.003) required anticoagulation. Ex vivo fibrin clots formed from patients with COVID-19 appeared to be denser and to have smaller pores than those from patients with sepsis but without COVID-19 (percent area of fluorescent fibrin 48.1% [SD, 16%] vs 24.9% [SD, 18.8%]; p = 0.049). The turbidity and flow-through assays corroborated these data; fibrin clots had a higher maximum turbidity in patients with COVID-19 compared with patients without COVID-19 (0.168 vs 0.089 OD units; p = 0.003), and it took longer for buffer to flow through these clots (216 vs 103 min; p = 0.003). In patients with COVID-19, d-dimer levels were positively correlated with percent area of fluorescent fibrin (ρ = 0.714, p = 0.047). Denser clots (assessed by turbidity and thromboelastography) and higher SOFA scores were independently associated with delayed clot lysis. CONCLUSIONS: We found aberrant fibrin clot structure and function in critically ill patients with COVID-19. These findings may contribute to the poor outcomes observed in COVID-19 patients with widespread fibrin deposition.

Secretion of von Willebrand Factor and Suppression of ADAMTS-13 Activity by Markedly High Concentration of Ferritin.

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.

Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs.

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (n = 7) and ADI-PEG20 treated (n = 8) pigs during the postprandial period. In addition, blood pressure was monitored by telemetry, and multiple tissues were collected to determine arginine concentration. Plasma arginine was depleted immediately after ADI-PEG20 administration, with an increase in plasma citrulline concentration (P < 0.01). The depletion of arginine did not affect (P > 0.10) blood pressure, whole body protein synthesis, or urea production. Despite the lack of circulating arginine in ADI-PEG20-treated pigs, most tissues were able to maintain concentrations similar (P > 0.10) to those in Control animals. The kinetics of citrulline and arginine indicated the high citrulline turnover and regeneration of arginine through the citrulline recycling pathway. ADI-PEG20 administration resulted in an absolute and almost instantaneous depletion of circulating arginine, thus reducing global availability without affecting cardiovascular parameters and protein metabolism. The citrulline produced from the deimination of arginine was in turn utilized by the citrulline recycling pathway restoring local tissue arginine availability.NEW & NOTEWORTHY Pegylated arginine deiminase depletes circulating arginine, but the citrulline generated is utilized by multiple tissues to regenerate arginine and sustain local arginine availability. Preempting the arginine depletion that occurs as result of sepsis and trauma with arginine deiminase offers the possibility of maintaining tissue arginine availability despite negligible plasma arginine concentrations.

T-cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disorder of immune hyperactivation that has been described as a cytokine storm. Sepsis due to known or suspected infection has also been viewed as a cytokine storm. Although clinical similarities between these syndromes suggest similar immunopathology and may create diagnostic uncertainty, distinguishing them is critical as treatments are widely divergent. We examined T-cell profiles from children with either HLH or sepsis and found that HLH is characterized by acute T-cell activation, in clear contrast to sepsis. Activated T cells in patients with HLH were characterized as CD38high/HLA-DR+ effector cells, with activation of CD8+ T cells being most pronounced. Activated T cells were type 1 polarized, proliferative, and displayed evidence of recent and persistent activation. Circulating activated T cells appeared to be broadly characteristic of HLH, as they were seen in children with and without genetic lesions or identifiable infections and resolved with conventional treatment of HLH. Furthermore, we observed even greater activation and type 1 polarization in tissue-infiltrating T cells, described here for the first time in a series of patients with HLH. Finally, we observed that a threshold of >7% CD38high/HLA-DR+ cells among CD8+ T cells had strong positive and negative predictive value for distinguishing HLH from early sepsis or healthy controls. We conclude that the cytokine storm of HLH is marked by distinctive T-cell activation whereas early sepsis is not, and that these 2 syndromes can be readily distinguished by T-cell phenotypes.

Modulating the rate of fibrin formation and clot structure attenuates microvascular thrombosis in systemic inflammation.

Systemic inflammation can lead to coagulopathy and disseminated intravascular coagulation (DIC). In prior studies, the recombinant A2 domain of human von Willebrand factor (VWF; A2 protein) attenuated DIC and decreased mortality in lipopolysaccharide (LPS)-treated mice. Here, we performed studies to dissect the mechanism by which the A2 protein moderates DIC. We used confocal microscopy to analyze the fibrin clot structure in plasma from healthy humans and endotoxemic mice, turbidity assays to examine fibrin polymerization, and a murine model for LPS-induced DIC and introduced a loss-of-function mutation into the A2 protein for fibrin. The mutation of the residue E1567 located in the α2 helix of the folded A2 domain of VWF inhibited binding activity for fibrin, possibly mapping a novel region containing a putative binding site for fibrin. The A2 protein increased the initial rate of change of fibrin polymerization, intercalated into the fibrin network, and modified the resultant clot structure in vitro. Furthermore, ex vivo experiments using plasma from mice with endotoxemia treated with the A2 protein revealed an increased rate of fibrin formation and an altered clot structure as compared with plasma from nontreated sick animals. Moreover, and in contrast to the A2 mutant, the A2 protein improved survival and reduced fibrin deposition and microvascular thrombosis in mice with endotoxemia-induced DIC. Importantly, in vivo and in vitro studies indicated that the A2 protein did not affect experimental thrombosis. Thus, we provide evidence for a novel treatment to attenuate systemic inflammation-induced coagulopathy/DIC via targeting fibrin formation, without an increased risk for bleeding.

Thrombocytopenia-Associated Multiple Organ Failure.

Thrombocytopenia-associated multiple organ failure is a clinical phenotype encompassing a spectrum of syndromes associated with disseminated microvascular thromboses. Autopsies performed in patients that died with thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, or disseminated intravascular coagulation reveal specific findings that can differentiate these 3 entities. Significant advancements have been made in our understanding of the pathologic mechanisms of these syndromes. Von Willebrand factor and ADAMTS-13 play a central role in thrombotic thrombocytopenic purpura. Shiga toxins and the complement pathway drive the hemolytic uremic syndrome pathology. Tissue factor activity is vital in the development of disseminated intravascular coagulation.

Surviving sepsis campaign international guidelines for the management of septic shock and sepsis-associated organ dysfunction in children.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 49 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 52 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

Surviving Sepsis Campaign International Guidelines for the Management of Septic Shock and Sepsis-Associated Organ Dysfunction in Children.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for children (including infants, school-aged children, and adolescents) with septic shock and other sepsis-associated organ dysfunction. DESIGN: A panel of 49 international experts, representing 12 international organizations, as well as three methodologists and three public members was convened. Panel members assembled at key international meetings (for those panel members attending the conference), and a stand-alone meeting was held for all panel members in November 2018. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. Teleconferences and electronic-based discussion among the chairs, co-chairs, methodologists, and group heads, as well as within subgroups, served as an integral part of the guideline development process. METHODS: The panel consisted of six subgroups: recognition and management of infection, hemodynamics and resuscitation, ventilation, endocrine and metabolic therapies, adjunctive therapies, and research priorities. We conducted a systematic review for each Population, Intervention, Control, and Outcomes question to identify the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak, or as a best practice statement. In addition, "in our practice" statements were included when evidence was inconclusive to issue a recommendation, but the panel felt that some guidance based on practice patterns may be appropriate. RESULTS: The panel provided 77 statements on the management and resuscitation of children with septic shock and other sepsis-associated organ dysfunction. Overall, six were strong recommendations, 52 were weak recommendations, and nine were best-practice statements. For 13 questions, no recommendations could be made; but, for 10 of these, "in our practice" statements were provided. In addition, 49 research priorities were identified. CONCLUSIONS: A large cohort of international experts was able to achieve consensus regarding many recommendations for the best care of children with sepsis, acknowledging that most aspects of care had relatively low quality of evidence resulting in the frequent issuance of weak recommendations. Despite this challenge, these recommendations regarding the management of children with septic shock and other sepsis-associated organ dysfunction provide a foundation for consistent care to improve outcomes and inform future research.

Role of Damage-Associated Molecular Patterns and Uncontrolled Inflammation in Pediatric Sepsis-Induced Multiple Organ Dysfunction Syndrome.

The incidence of multiple organ dysfunction syndrome (MODS) in sepsis varies from 17 to 73% and furthermore, increases the risk of death by 60% when controlled for the number of dysfunctional organs. Several MODS phenotypes exist, each unique in presentation and pathophysiology. Common to the phenotypes is the stimulation of the immune response by pathogen-associated molecular patterns (PAMPs), or danger-associated molecular patterns (DAMPs) causing an unremitting inflammation. Two of the MODS phenotypes are discussed in detail, thrombocytopenia-associated multiple organ failure (TAMOF) and the hyperinflammatory phenotype-macrophage activating syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH). In the end, we will briefly review the role of mitochondrial dysfunction as a significant contributor to the pathogenesis of MODS.

Central Venous Catheter-Related Deep Vein Thrombosis in the Pediatric Cardiac Intensive Care Unit.

BACKGROUND: Central venous catheter (CVC) use is common in the management of critically ill children, especially those with congenital heart disease. CVCs are known to augment the risk of deep vein thrombosis (DVT), but data on CVC-associated DVTs in the pediatric cardiac intensive care unit (CICU) are limited. In this study, we aim to identify the incidence of and risk factors for CVC-related DVT in this high-risk population, as its complications are highly morbid. MATERIALS AND METHODS: The PC4 database and a radiologic imaging database were retrospectively reviewed for the demographics and outcomes of patients admitted to the Texas Children's Hospital CICU requiring CVC placement, as well as the incidence of DVT and its complications. RESULTS: Between January 2017 and December 2017, 1215 central lines were placed over 851 admissions. DVT was diagnosed in 8% of admissions with a CVC, 29% of which demonstrated thrombus in the inferior vena cava. The risk factors significantly associated with DVT included the presence of >1 line, higher total line hours, longer intubation times, and extended CICU stay. A diagnosis of low cardiac output syndrome, sepsis, central line-associated bloodstream infection, and cardiac catheterization were also significant risk factors. Interestingly, cardiac surgery with cardiopulmonary bypass appeared to be protective of clot development. DVT was a highly significant risk factor for mortality in these patients. CONCLUSIONS: CVC-related DVTs in critically ill children with congenital heart disease are associated with higher risks of morbidity and mortality, highlighting the need for well-designed studies to determine the best preventative and treatment strategies and to establish guidelines for appropriate monitoring and follow-up of these patients.

Hepatobiliary Dysfunction and Disseminated Intravascular Coagulation Increase Risk of Mortality in Pediatric Hemophagocytic Lymphohistiocytosis.

OBJECTIVES: Hemophagocytic lymphohistiocytosis poses significant challenges due to limited tools to guide clinical decisions in a population at high risk of death. We sought to assess whether disseminated intravascular coagulation and hepatobiliary dysfunction, significant comorbidities seen in critical care settings, would identify hemophagocytic lymphohistiocytosis patients with increased risk of mortality. DESIGN: Retrospective chart review. SETTING: Single-center PICU. PATIENTS: All patients admitted to a tertiary care children's hospital diagnosed with hemophagocytic lymphohistiocytosis from 2005 to 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-three patients were diagnosed with hemophagocytic lymphohistiocytosis with median age of 61 months. The 5-year overall survival was 51% (22/43). Univariate analyses revealed ferritin levels greater than 10,000 (ng/mL), international normalized ratio greater than 1.5, or platelet counts less than 100,000/µL at initiation of dexamethasone were individually associated with mortality. Development of disseminated intravascular coagulation, hepatobiliary dysfunction, or both increased the likelihood of death in hemophagocytic lymphohistiocytosis patients (relative risk; 95% CI) (6; 1.4-34; p < 0.05), (4.1; 1.8-10; p < 0.05), and (7.5; 1.8-42; p < 0.05). Of 12 autopsies performed, 75% had at least one active infection, 66% had chronic lymphopenia, 50% had lymphocyte depletion in the spleen, thymus, or bone marrow, 42% had evidence of microvascular thrombosis, and 92% had evidence of hepatocellular injury. CONCLUSIONS: Hemophagocytic lymphohistiocytosis continues to have high mortality with hemophagocytic lymphohistiocytosis-1994/2004 (dexamethasone/etoposide), the current standard of care for all children with hemophagocytic lymphohistiocytosis. Hemophagocytic lymphohistiocytosis patients who developed disseminated intravascular coagulation, hepatobiliary dysfunction, or both had higher risk of death with mortalities of 60%, 77%, and 77%, respectively. Phenotypic classifications are urgently needed to guide individualized treatment strategies to improve outcomes for children with hemophagocytic lymphohistiocytosis.

Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis.

The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

Rolipram Improves Outcome in a Rat Model of Infant Sepsis-Induced Cardiorenal Syndrome.

While the mortality rate associated with sepsis in children has fallen over the years, it still remains unacceptably high. The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 cardiorenal syndrome (CRS) and is poorly understood in infants. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced CRS in rat pups then evaluated the therapeutic potential of the phosphodiesterase (PDE) 4 inhibitor, rolipram. Rat pups at 17-18-days old were subjected to cecal ligation and puncture (CLP) to induce fecal polymicrobial sepsis. Uptake of Evans Blue dye was used to assess renal microvascular leakage. Intravital videomicroscopy was used to assess renal microvascular perfusion and oxidant generation. Glomerular filtration rate (GFR) was used to assess renal function. Left ventricular (LV) catheterization and echocardiography were used to assess cardiac function. Impairment of both cardiac and renal function developed rapidly following CLP, indicating type 5 CRS. Most notable were the rapid decline in LV diastolic function, the decline in cardiac output, renal microvascular failure, and the decline in GFR. A dose-response study with rolipram determined 0.1 mg/kg, ip as the lowest most efficacious dose to protect the renal microcirculation. Rolipram was then evaluated using a clinically relevant delayed dosing paradigm (a single dose at 6 h post-CLP). With delayed dosing, rolipram restored the renal microcirculation and reduced microvascular leakage but did not reduce oxidant generation in the kidney nor restore GFR. In contrast, delayed dosing with rolipram restored cardiac function. Rolipram also improved 4-days survival. In summary, CLP in the rat pup produces a clinically relevant pediatric model of sepsis-induced CRS. The PDE4 inhibitor rolipram was effective in improving renal microvascular function and cardiac function, which improved mortality. These findings suggest that rolipram should be evaluated further as adjunctive therapy for the septic infant with CRS.

American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock.

OBJECTIVES: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine "Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock." DESIGN: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006-2014). The PubMed/Medline/Embase literature (2006-14) was searched by the Society of Critical Care Medicine librarian using the keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, extracorporeal membrane oxygenation, and American College of Critical Care Medicine guidelines in the newborn and pediatric age groups. MEASUREMENTS AND MAIN RESULTS: The 2002 and 2007 guidelines were widely disseminated, translated into Spanish and Portuguese, and incorporated into Society of Critical Care Medicine and American Heart Association/Pediatric Advanced Life Support sanctioned recommendations. The review of new literature highlights two tertiary pediatric centers that implemented quality improvement initiatives to improve early septic shock recognition and first-hour compliance to these guidelines. Improved compliance reduced hospital mortality from 4% to 2%. Analysis of Global Sepsis Initiative data in resource rich developed and developing nations further showed improved hospital mortality with compliance to first-hour and stabilization guideline recommendations. CONCLUSIONS: The major new recommendation in the 2014 update is consideration of institution-specific use of 1) a "recognition bundle" containing a trigger tool for rapid identification of patients with septic shock, 2) a "resuscitation and stabilization bundle" to help adherence to best practice principles, and 3) a "performance bundle" to identify and overcome perceived barriers to the pursuit of best practice principles.

Three Hypothetical Inflammation Pathobiology Phenotypes and Pediatric Sepsis-Induced Multiple Organ Failure Outcome.

OBJECTIVES: We hypothesize that three inflammation pathobiology phenotypes are associated with increased inflammation, proclivity to develop features of macrophage activation syndrome, and multiple organ failure-related death in pediatric severe sepsis. DESIGN: Prospective cohort study comparing children with severe sepsis and any of three phenotypes: 1) immunoparalysis-associated multiple organ failure (whole blood ex vivo tumor necrosis factor response to endotoxin < 200 pg/mL), 2) thrombocytopenia-associated multiple organ failure (new onset thrombocytopenia with acute kidney injury and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity < 57%), and/or 3) sequential multiple organ failure with hepatobiliary dysfunction (respiratory distress followed by liver dysfunction with soluble Fas ligand > 200 pg/mL), to those without any of these phenotypes. SETTING: Tertiary children's hospital PICU. PATIENTS: One hundred consecutive severe sepsis admissions. INTERVENTIONS: Clinical data were recorded daily, and blood was collected twice weekly. MEASUREMENTS AND MAIN RESULTS: Multiple organ failure developed in 75 cases and eight died. Multiple organ failure cases with any of the three inflammation phenotypes (n = 37) had higher inflammation (C-reactive protein, p = 0.009 and ferritin, p < 0.001) than multiple organ failure cases without any of these phenotypes (n = 38) or cases with only single organ failure (n = 25). Development of features of macrophage activation syndrome and death were more common among multiple organ failure cases with any of the phenotypes (macrophage activation syndrome: 10/37, 27%; death: 8/37, 22%) compared to multiple organ failure cases without any phenotype (macrophage activation syndrome: 1/38, 3%; p = 0.003 and death: 0/38, 0%; p = 0.002). CONCLUSIONS: Our approach to phenotype categorization remains hypothetical, and the phenotypes identified need to be confirmed in multicenter studies of pediatric multiple organ dysfunction syndrome.