Hyperferritinemic sepsis, macrophage activation syndrome, and mortality in a pediatric research network: A causal inference analysis

BACKGROUND: One of five global deaths are attributable to sepsis. Hyperferritinemic sepsis (\u3e 500 ng/mL) is associated with increased mortality in single-center studies. Our pediatric research network\u27s objective was to obtain rationale for designing anti-inflammatory clinical trials targeting hyperferritinemic sepsis. METHODS: We assessed differences in 32 cytokines, immune depression (low whole blood ex vivo TNF response to endotoxin) and thrombotic microangiopathy (low ADAMTS13 activity) biomarkers, seven viral DNAemias, and macrophage activation syndrome (MAS) defined by combined hepatobiliary dysfunction and disseminated intravascular coagulation, and mortality in 117 children with hyperferritinemic sepsis (ferritin level \u3e 500 ng/mL) compared to 280 children with sepsis without hyperferritinemia. Causal inference analysis of these 41 variables, MAS, and mortality was performed. RESULTS: Mortality was increased in children with hyperferritinemic sepsis (27/117, 23% vs 16/280, 5.7%; Odds Ratio = 4.85, 95% CI [2.55-9.60]; z = 4.728; P-value \u3c 0.0001). Hyperferritinemic sepsis had higher C-reactive protein, sCD163, IL-22, IL-18, IL-18 binding protein, MIG/CXCL9, IL-1β, IL-6, IL-8, IL-10, IL-17a, IFN-γ, IP10/CXCL10, MCP-1/CCL2, MIP-1α, MIP-1β, TNF, MCP-3, IL-2RA (sCD25), IL-16, M-CSF, and SCF levels; lower ADAMTS13 activity, sFasL, whole blood ex vivo TNF response to endotoxin, and TRAIL levels; more Adenovirus, BK virus, and multiple virus DNAemias; and more MAS (P-value \u3c 0.05). Among these variables, only MCP-1/CCL2 (the monocyte chemoattractant protein), MAS, and ferritin levels were directly causally associated with mortality. MCP-1/CCL2 and hyperferritinemia showed direct causal association with depressed ex vivo whole blood TNF response to endotoxin. MCP-1/CCL2 was a mediator of MAS. MCP-1/CCL2 and MAS were mediators of hyperferritinemia. CONCLUSIONS: These findings establish hyperferritinemic sepsis as a high-risk condition characterized by increased cytokinemia, viral DNAemia, thrombotic microangiopathy, immune depression, macrophage activation syndrome, and death. The causal analysis provides rationale for designing anti-inflammatory trials that reduce macrophage activation to improve survival and enhance infection clearance in pediatric hyperferritinemic sepsis

Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials

BACKGROUND: Thrombotic microangiopathy-induced thrombocytopenia-associated multiple organ failure and hyperinflammatory macrophage activation syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. The National Institutes of General Medical Science sepsis research working group recommendations call for application of new research approaches in extant clinical data sets to improve efficiency of early trials of new sepsis therapies. Our objective is to apply machine learning approaches to derive computable 24-h sepsis phenotypes to facilitate personalized enrollment in early anti-inflammatory trials targeting these conditions. METHODS: We applied consensus, k-means clustering analysis to our extant PHENOtyping sepsis-induced Multiple organ failure Study (PHENOMS) dataset of 404 children. 24-hour computable phenotypes are derived using 25 available bedside variables including C-reactive protein and ferritin. RESULTS: Four computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to all other phenotypes, PedSep-A patients (n = 135; 2% mortality) were younger and previously healthy, with the lowest C-reactive protein and ferritin levels, the highest lymphocyte and platelet counts, highest heart rate, and lowest creatinine (p \u3c 0.05); PedSep-B patients (n = 102; 12% mortality) were most likely to be intubated and had the lowest Glasgow Coma Scale Score (p \u3c 0.05); PedSep-C patients (n = 110; mortality 10%) had the highest temperature and Glasgow Coma Scale Score, least pulmonary failure, and lowest lymphocyte counts (p \u3c 0.05); and PedSep-D patients (n = 56, 34% mortality) had the highest creatinine and number of organ failures, including renal, hepatic, and hematologic organ failure, with the lowest platelet counts (p \u3c 0.05). PedSep-D had the highest likelihood of developing thrombocytopenia-associated multiple organ failure (Adj OR 47.51 95% CI [18.83-136.83], p \u3c 0.0001) and macrophage activation syndrome (Adj OR 38.63 95% CI [13.26-137.75], p \u3c 0.0001). CONCLUSIONS: Four computable phenotypes are derived, with PedSep-D being optimal for enrollment in early personalized anti-inflammatory trials targeting thrombocytopenia-associated multiple organ failure and macrophage activation syndrome in pediatric sepsis. A computer tool for identification of individual patient membership ( www.pedsepsis.pitt.edu ) is provided. Reproducibility will be assessed at completion of two ongoing pediatric sepsis studies

Application of systems dynamics and group model building to identify barriers and facilitators to acute care delivery in a resource limited setting

BACKGROUND: Group model building (GMB) is a method to facilitate shared understanding of structures and relationships that determine system behaviors. This project aimed to determine the feasibility of GMB in a resource-limited setting and to use GMB to describe key barriers and facilitators to effective acute care delivery at a tertiary care hospital in Malawi. METHODS: Over 1 week, trained facilitators led three GMB sessions with two groups of healthcare providers to facilitate shared understanding of structures and relationships that determine system behaviors. One group aimed to identify factors that impact patient flow in the paediatric special care ward. The other aimed to identify factors impacting delivery of high-quality care in the paediatric accident and emergency room. Synthesized causal maps of factors influencing patient care were generated, revised, and qualitatively analyzed. RESULTS: Causal maps identified patient condition as the central modifier of acute care delivery. Severe illness and high volume of patients were identified as creating system strain in several domains: (1) physical space, (2) resource needs and utilization, (3) staff capabilities and (4) quality improvement. Stress in these domains results in worsening patient condition and perpetuating negative reinforcing feedback loops. Balancing factors inherent to the current system included (1) parental engagement, (2) provider resilience, (3) ease of communication and (4) patient death. Perceived strengths of the GMB process were representation of diverse stakeholder viewpoints and complex system synthesis in a visual causal pathway, the process inclusivity, development of shared understanding, new idea generation and momentum building. Challenges identified included time required for completion and potential for participant selection bias. CONCLUSIONS: GMB facilitated creation of a shared mental model, as a first step in optimizing acute care delivery in a paediatric facility in this resource-limited setting

Blood conservation : cultural change in pediatric intensive care nursing

While monitoring of pediatric intensive care unit (PICU) patients requires repeated blood sampling, excessive sampling can lead to anemia. Upon PICU admission, 33% of patients are anemic and 41% develop anemia. Anemia increases the PICU length of stay and days of mechanical ventilation. Anemia is often treated with red blood cell (RBC) transfusion, but RBC transfusion is associated with increased healthcare costs and morbidity. Blood conservation strategies are needed in the PICU; these changes in turn require changes in PICU practice and culture to reduce the amount of blood overdraw

Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 2

To describe a number of conditions and therapies associated with multiple organ dysfunction syndrome (MODS) presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development MODS Workshop (March 26–27, 2015). In addition, the relationship between burn injuries and MODS is also included although it was not discussed at the Workshop

Pediatric Critical Care Transfusion and Anemia Expertise Initiative

Introduction/Hypothesis: Despite evidence that a lower hemoglobin threshold is safe in hemodynamically stable children, studies have shown that transfusion thresholds in practice are higher, exposing these children to the morbidity and mortality associated with RBC transfusion. Therefore, there is increased need for evidence-based blood management strategies for clinicians caring for critically ill children. Methods: The Pediatric Critical Care Transfusion and Anemia Expertise Initiative has brought together a group of 49 international experts in pediatric transfusion/critical care in collaboration with the Pediatric Critical Care Blood Research Network (BloodNet), and the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI), to conduct a consensus conference series on pediatric critical care blood management. The methodology is modeled after that used in the Pediatric Acute Lung Injury and Consensus Conference and will create consensus statements via a structured process outlining existing data in RBC transfusion. Novel features include engagement with implementation science experts to enable consensus uptake. Results: Two of the three expert meetings have been successfully conducted. Ten topics were identified and include recommendations on indications for RBC transfusion in critically ill children 1) based on hemoglobin triggers in the general population, 2) based on physiological triggers in the general population, 3) traumatic brain injury, 4) congenital heart disease, 5) hematologic/oncologic disease, 6) respiratory failure, 7) shock, 8) bleeding, 9) extracorporeal support, and 10) alternative processing. The systematic review was performed. The short text recommendations were generated, discussed at the second meeting and will undergo voting using the RAND UCLA Appropriateness Method to achieve consensus. Conclusions: The TAXI consensus series is the first consensus series to convene international and multidisciplinary experts to create consensus statements on transfusion practices to improve outcomes and safety for critically ill children at risk for, or who require, RBC transfusions