Inhibition of the JAK/STAT pathway with baricitinib reduces the multiple organ dysfunction caused by hemorrhagic shock in rats

Objective: The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB and NLRP3 caused by HS. Background: Post-traumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown. Methods: An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB and NLRP3 pathways were analyzed by western blotting in the kidney and liver. Results: We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB and NLRP3 pathways caused by HS in the rat. Conclusions: Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.

Predictive Value of Glycemia and Free Fatty Acid Levels upon Admission of Children with Scorpionism in Egypt

Scorpion envenomation is a life-threatening emergency and causes serious health problems in tropical and subtropical regions. The aim of this study was to correlate the serum levels of biochemical parameters at admission in children with scorpion envenomation with subsequent morbidity and mortality. It was a prospective, observational, and descriptive study conducted for scorpion-envenomed children who presented to emergency and intensive care units between April 2019 and September 2019. Demographic, clinical, and laboratory findings of patients were recorded and tabulated. Routine investigations were done for all patients in addition to blood levels of lactate, free fatty acids (FFA), and insulin. All patients were compared according to outcome as survivors and nonsurvivors and according to glucose level as normoglycemic and hyperglycemic groups. There were 62 scorpion sting cases; their mean age was 8.6 ± 3.2 years. Patients aged more than 6 years (74.2%), and males (66.1%) were more affected than others. As regards severity, 25.8% were suffering organ dysfunction, 40.3% suffered systemic manifestations without organ dysfunction, and (33.9%) with only local manifestations. Serum glucose and FFA were significantly higher in nonsurvivors compared with survivors. Shock, convulsion, coma, heart failure, and pulmonary edema were significantly more common in hyperglycemic than normoglycemic group. Hyperglycemia, and raised FFA were associated with severe scorpion envenomation. Raised FFA was well correlated with presence of heart failure, leucocytosis, and hyperglycemia. Adding serum glucose and FFA to monitoring parameters of scorpionism severity can help the prediction of high-risk patients.

Towards definitions of critical illness and critical care using concept analysis

Objective As critical illness and critical care lack consensus definitions, this study aims to explore how the concepts are used, describe their defining attributes and propose potential definitions. Design We used the Walker and Avant stepwise approach to concept analysis. The uses and definitions of the concepts were identified through a scoping review of the literature and an online survey of 114 global clinical experts. Through content analysis of the data we extracted codes, categories and themes to determine the concepts defining attributes and we proposed potential definitions. To assist understanding, we present model, related and contrary cases concerning the concepts, we identified antecedents and consequences to the concepts, and defined empirical referents. Results The defining attributes of critical illness were a high risk of imminent death; vital organ dysfunction; requirement for care to avoid death; and potential reversibility. The defining attributes of critical care were the identification, monitoring and treatment of critical illness; vital organ support; initial and sustained care; any care of critical illness; and specialized human and physical resources. Our proposed definition of critical illness is, a state of ill health with vital organ dysfunction, a high risk of imminent death if care is not provided and the potential for reversibility. Our proposed definition of critical care is, the identification, monitoring and treatment of patients with critical illness through the initial and sustained support of vital organ functions. Conclusion The concepts critical illness and critical care lack consensus definitions and have varied uses. Through concept analysis of uses and definitions in the literature and among experts we have identified the defining attributes of the concepts and propose definitions that could aid clinical practice, research, and policy making.

Cytokine Hemoadsorption as Rescue Therapy for Critically Ill Patients With SARS-CoV-2 Pneumonia With Severe Respiratory Failure and Hypercytokinemia

Introduction: A dysregulated inflammatory response, known as “cytokine storm”, plays an important role in the pathophysiology of coronavirus 2019 disease (COVID-19). Identifying patients with a dysregulated inflammatory response and at high risk for severe respiratory failure, organ dysfunction, and death is clinically relevant, as they could benefit from the specific therapies, such as cytokine removal by hemoadsorption. This study aimed to evaluate cytokine hemoadsorption as rescue therapy in critically ill patients with SARS-CoV-2 pneumonia, severe respiratory failure refractory to prone positioning, and hypercytokinemia.Methods: In this single center, observational and retrospective study, critically ill patients with SARS-CoV-2 pneumonia, severe acute respiratory failure, and hypercytokinemia were analyzed. All the patients underwent cytokine hemoadsorption using CytoSorb® (Cytosorbents Europe, Berlin, Germany). The indication for treatment was acute respiratory failure, inadequate clinical response to the prone position, and hypercytokinemia.Results: Among a total of 343 patients who were admitted to the intensive care unit (ICU) due to SARS-CoV-2 infection between March 3, 2020 and June 22, 2020, six patients received rescue therapy with cytokine hemoadsorption. All the patients needed invasive mechanical ventilation and prone positioning. A significant difference was found in the pre- and post-treatment D-dimer (17,868 mcg/ml [4,196–45,287] vs. 4,488 mcg/ml [3,166–17,076], p = 0.046), C-reactive protein (12.9 mg/dl [10.6] vs. 3.5 mg/dl [2.8], p = 0.028), ferritin (1,539 mcg/L [764–27,414] vs. 1,197 ng/ml [524–3,857], p = 0.04) and interleukin-6 (17,367 pg/ml [4,539–22,532] vs. 2,403 pg/ml [917–3,724], p = 0.043) levels. No significant differences in the pre- and post-treatment interleukin-10 levels (22.3 pg/ml [19.2–191] vs. 5.6 pg/ml [5.2–36.6], p = 0.068) were observed. Improvements in oxygenation (prehemoadsorption PaO2/FIO2 ratio 103 [18.4] vs. posthemoadsorption PaO2/FIO2 ratio 222 [20.9], p = 0.029) and in the organ dysfunction (prehemoadsorption SOFA score 9 [4.75] vs. posthemoadsorption SOFA score 7.7 [5.4], p = 0.046) were observed. ICU and in-hospital mortality was 33.7%.Conclusions: In this case series, critically ill patients with COVID-19 with severe acute respiratory failure refractory to prone positioning and hypercytokinemia who received adjuvant treatment with cytokine hemoadsorption showed a significant reduction in IL-6 plasma levels and other inflammatory biomarkers. Improvements in oxygenation and SOFA score were also observed.

Biomarkers for sepsis: more than just fever and leukocytosis—a narrative review

A biomarker describes a measurable indicator of a patient's clinical condition that can be measured accurately and reproducibly. Biomarkers offer utility for diagnosis, prognosis, early disease recognition, risk stratification, appropriate treatment (theranostics), and trial enrichment for patients with sepsis or suspected sepsis. In this narrative review, we aim to answer the question, "Do biomarkers in patients with sepsis or septic shock predict mortality, multiple organ dysfunction syndrome (MODS), or organ dysfunction?" We also discuss the role of pro- and anti-inflammatory biomarkers and biomarkers associated with intestinal permeability, endothelial injury, organ dysfunction, blood–brain barrier (BBB) breakdown, brain injury, and short and long-term mortality. For sepsis, a range of biomarkers is identified, including fluid phase pattern recognition molecules (PRMs), complement system, cytokines, chemokines, damage-associated molecular patterns (DAMPs), non-coding RNAs, miRNAs, cell membrane receptors, cell proteins, metabolites, and soluble receptors. We also provide an overview of immune response biomarkers that can help identify or differentiate between systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and sepsis-associated encephalopathy. However, significant work is needed to identify the optimal combinations of biomarkers that can augment diagnosis, treatment, and good patient outcomes.

Correlation of SOFA Score and Hormone Value for Predicting 28-days Mortality for Septic Patients

Introduction. Sepsis is a group of symptoms of organ dysfunction that can be life-threatening because of dysregulation of body response toward ongoing infection. Organ dysfunction in sepsis can be measured by Sequential Organ Failure Assessment (SOFA) and T3 hormone. The study was aimed to identify the correlation of T3 in predicting mortality of 28 days patients in Intensive Care Unit RSMH Palembang. Method. This study design is cohort prospective. The inclusion criteria consist of a patient diagnosed with sepsis and septic shock in the Intensive Care Unit, 18-64 years old. Patients with a history of thyroid disease, pregnant or post-pregnancy, the patient admitted in referral from other hospitals, and patients with a history of psychiatry medication and thyroid medication were excluded. Data collected is the patient whose stay in Intensive Care Unit RSMH followed in 28 days from January 2021 until the sample was fulfilled (39 samples). Analyzing data was SPSS version 23 with chi-square analysis and Fisher's Exact to identify the relationship. Pearson correlation to identify correlation coefficient, and Medical application to measure AUC, cutoff value, sensitivity, and specificity. Result. The result showed that age (p=0,445). gender (p=1,00), need of ICU (p=0,228), isolation-nonisolation ward (p=0,437) didn't have any significant relationship toward mortality. SOFA score correlate statistically with positive correlation and medium strength (0,633) toward mortality of sepsis patient (p=0,000). T3 hormon correlate positively with medium strength (0,514) toward mortality of sepsis patient (p=0,001). T3 hormone toward SOFA correlate negatively (-0,365) with significant correlation (p=0,22). T3 hormone has AUC 0,291 with sensitivity 3,3% and specificity 67,7%. Conclusion. T3 hormone has a significant negative correlation to mortality in sepsis patients but cannot be used to predict mortality with a low AUC value (0,291).

Pediatric Organ Dysfunction Information Update Mandate (PODIUM) Contemporary Organ Dysfunction Criteria: Executive Summary

Prior criteria for organ dysfunction in critically ill children were based mainly on expert opinion. We convened the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) expert panel to summarize data characterizing single and multiple organ dysfunction and to derive contemporary criteria for pediatric organ dysfunction. The panel was composed of 88 members representing 47 institutions and 7 countries. We conducted systematic reviews of the literature to derive evidence-based criteria for single organ dysfunction for neurologic, cardiovascular, respiratory, gastrointestinal, acute liver, renal, hematologic, coagulation, endocrine, endothelial, and immune system dysfunction. We searched PubMed and Embase from January 1992 to January 2020. Study identification was accomplished using a combination of medical subject headings terms and keywords related to concepts of pediatric organ dysfunction. Electronic searches were performed by medical librarians. Studies were eligible for inclusion if the authors reported original data collected in critically ill children; evaluated performance characteristics of scoring tools or clinical assessments for organ dysfunction; and assessed a patient-centered, clinically meaningful outcome. Data were abstracted from each included study into an electronic data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. Consensus was achieved for a final set of 43 criteria for pediatric organ dysfunction through iterative voting and discussion. Although the PODIUM criteria for organ dysfunction were limited by available evidence and will require validation, they provide a contemporary foundation for researchers to identify and study single and multiple organ dysfunction in critically ill children.

Patterns of Organ Dysfunction in Critically Ill Children Based on PODIUM Criteria

OBJECTIVES The goal of this study was to determine the incidence, prognostic performance, and generalizability of the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) organ dysfunction criteria using electronic health record (EHR) data. Additionally, we sought to compare the performance of the PODIUM criteria with the organ dysfunction criteria proposed by the 2005 International Pediatric Sepsis Consensus Conference (IPSCC). METHODS Retrospective observational cohort study of critically ill children at 2 medical centers in the United States between 2010 and 2018. We assessed prevalence of organ dysfunction based on the PODIUM and IPSCC criteria for each 24-hour period from admission to 28 days. We studied the prognostic performance of the criteria to discriminate in-hospital mortality. RESULTS Overall, 22 427 PICU admissions met inclusion criteria, and in-hospital mortality was 2.3%. The cumulative incidence of each PODIUM organ dysfunction ranged from 15% to 30%, with an in-hospital mortality of 6% to 10% for most organ systems. The number of concurrent PODIUM organ dysfunctions demonstrated good-to-excellent discrimination for in-hospital mortality (area under the curve 0.87–0.93 for day 1 through 28) and compared favorably to the IPSCC criteria (area under the curve 0.84–0.92, P < .001 to P = .06). CONCLUSIONS We present the first evaluation of the PODIUM organ dysfunction criteria in 2 EHR databases. The use of the PODIUM organ dysfunction criteria appears promising for epidemiologic and clinical research studies using EHR data. More studies are needed to evaluate the PODIUM criteria that are not routinely collected in structured format in EHR databases.

Refining the Pediatric Multiple Organ Dysfunction Syndrome

Since its introduction into the medical literature in the 1970s, the term multiple organ dysfunction syndrome (or some variant) has been applied broadly to any patient with >1 concurrent organ dysfunction. However, the epidemiology, mechanisms, time course, and outcomes among children with multiple organ dysfunction vary substantially. We posit that the term pediatric multiple organ dysfunction syndrome (or MODS) should be reserved for patients with a systemic pathologic state resulting from a common mechanism (or mechanisms) that affects numerous organ systems simultaneously. In contrast, children in whom organ injuries are attributable to distinct mechanisms should be considered to have additive organ system dysfunctions but not the syndrome of MODS. Although such differentiation may not always be possible with current scientific knowledge, we make the case for how attempts to differentiate multiple organ dysfunction from other states of additive organ dysfunctions can help to evolve clinical and research priorities in diagnosis, monitoring, and therapy from largely organ-specific to more holistic strategies.