The effect of myocardial dysfunction on mortality in children with septic shock: a prospective observational study.

Pediatric septic shock is defined as progressive multi-organ dysfunction and cardiovascular dysfunction accompanying sepsis. Studies showing myocardial dysfunction associated with pediatric septic shock are very limited. The aim of this study was to evaluate the relationship between myocardial functions calculated by echocardiography, disease severity, and clinical outcomes in children with septic shock. This observational prospective study was conducted in a pediatric intensive care at a university-affiliated tertiary hospital. The patients diagnosed with septic shock between January 2021 and February 2022 were included in the study. The study was conducted with 56 patients. The rate of myocardial dysfunction (systolic and/or diastolic dysfunction) was 50%. Of these, 39.3% (n = 22) had systolic dysfunction, 17.9% (n = 10) had diastolic dysfunction, and 8.9% (n = 5) had both systolic and diastolic dysfunction. PRISM III score (p = 0.004), VIS (p < 0.001), lactate (p = 0.002), CK-MB (p = 0.023), troponin (p = 0.038), EF (p = 0.004) EF z-score (p = 0.003), MAPSE z-score (p = 0.049), TAPSE (p = 0.010), TAPSE z-score (p = 0.003), and mitral valve E/e ´z-score (p = 0.028) were statistically significant difference with mortality. No significant difference was found for mortality with MAPSE (p = 0.090), mitral valve E/A (p = 0.624), and mitral valve E/A z-score (p = 0.327). EF z-score was found to be associated with 30-day mortality (OR = 0,681, 95% CI 0,480 to 0.991, p = 0,045). We found the TAPSE z-score to be the most significant parameter with 30-day mortality (OR = 0,690, 95% CI 0,489 to 0.998, p = 0,032).  Conclusion: We found left ventricular dysfunction associated factor with mortality. TAPSE showing right ventricular dysfunction was found to be the independent risk factor most associated with mortality. What is Known: • Studies showing myocardial dysfunction associated with pediatric septic shock are limited. • Little is known about the use of echocardiography in pediatric septic shock, and there are no specific guidelines for treatment and follow-up in pediatric patients. What is New: • Characteristics, echocardiographic measurements, and outcomes were comprehensively assessed in children with septic shock. • As a result of our analysis, we found that TAPSE, which is easily measured at the bedside, is the most critical parameter in relation to mortality. • We offer recommendations for its use in the follow-up of children with septic shock.

Accuracy of Pancreatic Stone Protein for diagnosis of sepsis in children admitted to pediatric intensive care or high-dependency care: a pilot study.

BACKGROUND: Pancreatic Stone Protein (PSP) is one of the most promising diagnostic and prognostic markers. The aim of the study was to assess the accuracy of PSP, compared to C-Reactive Protein (CRP), and Procalcitonin (PCT) for sepsis diagnosis in pediatric patients. Furthermore, we explored the correlation of PSP levels with sepsis severity and organ failure measured with PELOD-2 score. METHODS: Forty pediatric patients were enrolled following admission to pediatric intensive care, high dependency care or pediatric ward. PSP blood levels were measured in Emergency Department (nanofluidic point-of-care immunoassay; abioSCOPE, Abionic SA, Switzerland) on day 1, 2, 3, 5 and 7 from the onset of the clinical signs and symptoms of sepsis or SIRS. Inclusion criteria were: 1) patient age (1 month to 18 years old), 2) signs and symptoms of SIRS, irrespective of association with organ dysfunction. Exclusion criteria were: 1) hemato-oncological diseases and/or immunodeficiencies, 2) pancreatic diseases. RESULTS: Septic patients showed higher PSP levels than those with non-infectious systemic inflammation. The optimal cut-off in diagnosis of sepsis for PSP at day 1 was 167 ng/ml resulted in a sensitivity of 59% (95% IC 36%-79%) and a specificity of 83% (95% IC 58%-96%) with an AUC of 0.636 for PSP in comparison to AUC of 0.722 for PCT and 0.503 for C-RP. ROC analysis for outcome (survival versus no survival) has showed AUC 0.814 for PSP; AUC 0.814 for PCT; AUC of 0.657 for C-RP. CONCLUSIONS: PSP could distinguish sepsis from non-infectious systemic inflammation; however, our results need to be confirmed in larger pediatric population.

Molecular subtypes based on N6-methyladenosine RNA methylation demonstrate the heterogeneity of immune and biological functions in pediatric septic shock.

Introduction: Septic shock in children is a highly heterogeneous syndrome involving different immune states and biological processes. We used a bioinformatics approach to explore the relationship between N6-methyladenosine (m6A) methylation and septic shock in children. Methods: A gene expression dataset including information on 98 children with septic shock was selected. To construct and evaluate a risk prediction model, machine learning was used to screen marker m6A regulators. Based on differentially expressed m6A regulators, molecular subtypes for paediatric septic shock were constructed. Subsequently, the differences in the m6Ascore, heterogeneity of immune cell infiltration, and heterogeneity of biological functions between the different subtypes were analyzed. Finally, real-time quantitative PCR (RT-qPCR) was performed to validate the expression of the marker m6A regulators. Results: Fifteen differentially expressed m6A regulators were identified. Six marker m6A regulators, including LRPPRC, ELAVL1, RBM15, CBLL1, FTO, and RBM15B, were screened using the random forest method. The risk prediction model for paediatric septic shock constructed using m6A markers had strong consistency and high clinical practicability. Two subtypes of paediatric septic shock have been identified based on the differential expression pattern of m6A regulators. Significant differences were observed in RNA epigenetics, immune statuses, and biological processes between the two m6A subtypes. Differentially expressed genes between the two subtypes were enriched in cell number homeostasis, redox responses, and innate immune system responses. Finally, the six marker m6A regulators were verified in additional samples. Conclusions: Based on the heterogeneity of m6A methylation-regulated genes, two different subtypes of septic shock in children with different RNA epigenetics, immune statuses, and biological processes were identified, revealing the heterogeneity of the disease largely attributable to differential m6A methylation. The findings will help explore and establish appropriate individualized treatments.

The Correlations of Human Atrial Natriuretic Peptide on Cardiac Function and Hemodynamics in Pediatric Septic Shock.

Purpose: We aimed to determine the correlations of human Atrial Natriuretic Peptide (ANP) on cardiac function and hemodynamics in pediatric septic shock. Patients and Methods: We conducted an observational and prospective study on 30 children with septic shock. Measurement of the level of human atrial natriuretic peptide was determined in the serum of patients. Cardiac power (CP) is a cardiac function parameter measured with cardiac output (cardiovascular flow) and mean arterial (intravascular) pressure. Cardiac output and mean arterial pressure were monitored using pressure recording analytical methods (PRAM). Hemodynamic status was represented by a vasoactive inotropic score. Results: Thirty pediatric septic shock patients fulfilled the eligibility criteria. The human ANP level was not significantly different in pediatric septic shock on three days of examination. Cardiac power was significantly different in pediatric septic shock on three days of examination. There was a correlation between human ANP and cardiac power on day 3 and human ANP and VIS on day 2. Conclusion: There was a significant correlation between human ANP level and cardiac power on day 3 and ANP level and VIS on day 2. The cardiac power on day 3 and VIS on 48 hours can be alternatives to evaluate the hemodynamic status and cardiac function concerning human ANP in pediatric septic shock.

Cutoff Values of Hemodynamic Parameters in Pediatric Refractory Septic Shock.

Background: Refractory septic shock can cause severe morbidities and mortalities in children. Resuscitation based on hemodynamics is important in children with critical illness. Thus, this study aimed to identify the hemodynamics of refractory septic shock associated with poor prognosis at an early stage to allow for timely interventions. Methods: We evaluated children with refractory septic shock admitted to a pediatric intensive care unit (PICU) and monitored their hemodynamics using a pulse index continuous cardiac output (PiCCO) system. The serial cardiac index (CI), systemic vascular resistance index (SVRI), and vasoactive−inotropic score (VIS) were recorded during the first 72 h after PICU admission. Results: Thirty-three children with refractory septic shock were enrolled. The SVRI and VIS were both associated with fatality from septic shock. The non-survivors had lower serial SVRI and higher VIS (both p < 0.05). Based on the area under the ROC curve, the SVRI was the predictor during the early resuscitative stage (first 36 h) in pediatric refractory septic shock. Conclusions: Both SVRI and VIS are predictors of mortality in children with refractory septic shock, and the SVRI is the powerful predictor of mortality in the early resuscitative stage. A low serial SVRI may allow for the early awareness of disease severity and strategies for adjusting vasoactive−inotropic agents to increase the SVRI.

A six­gene support vector machine classifier contributes to the diagnosis of pediatric septic shock.

Septic shock is induced by an uncontrolled inflammatory immune response to pathogens and the survival rate of patients with pediatric septic shock (PSS) is particularly low, with a mortality rate of 25­50%. The present study explored the mechanisms of PSS using four microarray datasets (GSE26378, GSE26440, GSE13904 and GSE4607) that were obtained from the Gene Expression Omnibus database. Based on the MetaDE package, the consistently differentially expressed genes (DEGs) in the four datasets were screened. Using the WGCNA package, the disease­associated modules and genes were identified. Subsequently, the optimal feature genes were further selected using the caret package. Finally, a support vector machine (SVM) classifier based on the optimal feature genes was built using the e1071 package. Initially, there were 2,699 consistent DEGs across the four datasets. From the 10 significantly stable modules across the datasets, four stable modules (including the magenta, purple, turquoise and yellow modules), in which the consistent DEGs were significantly enriched (P<0.05), were further screened. Subsequently, six optimal feature genes (including cysteine rich transmembrane module containing 1, S100 calcium binding protein A9, solute carrier family 2 member 14, stomatin, uridine phosphorylase 1 and utrophin) were selected from the genes in the four stable modules. Additionally, an effective SVM classifier was constructed based on the six optimal genes. The SVM classifier based on the six optimal genes has the potential to be applied for PSS diagnosis. This may improve the accuracy of early PSS diagnosis and suggest possible molecular targets for interventions.

The efficacy of dopamine versus epinephrine for pediatric or neonatal septic shock: a meta-analysis of randomized controlled studies.

INTRODUCTION: The efficacy of dopamine versus epinephrine for pediatric or neonatal septic shock remains controversial. We conduct a meta-analysis to explore the influence of dopamine versus epinephrine on shock reversal for pediatric or neonatal septic shock. METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through July 2019 for randomized controlled trials (RCTs) assessing the efficacy and safety of dopamine versus epinephrine for pediatric or neonatal septic shock. RESULTS: Three RCTs are included in the meta-analysis. Overall for pediatric or neonatal septic shock, dopamine and epinephrine reveal comparable shock reversal within 1 h (risk ratios (RR) = 0.61; 95% CI = 0.16 to 2.31; P = 0.47), mortality (RR = 1.16; 95% CI = 0.87 to 1.55; P = 0.30), heart rate (standard mean differences (SMD) = 0.03; 95% CI = -0.28 to 0.34; P = 0.85), systolic blood pressure (SMD = -0.18; 95% CI = -0.69 to 0.33; P = 0.49), mean arterial pressure (SMD = -0.15; 95% CI = -1.64 to 1.34; P = 0.84) and adverse events (RR = 1.00; 95% CI = 0.94 to 1.07; P = 0.91). CONCLUSIONS: Dopamine and epinephrine show the comparable efficacy for the treatment of pediatric or neonatal septic shock.

Characterization of Myocardial Dysfunction in Fluid- and Catecholamine-Refractory Pediatric Septic Shock and Its Clinical Significance.

PURPOSE:: Myocardial dysfunction is a known complication in patients with pediatric septic shock (PSS); however, its clinical significance remains unclear. The purpose of this study was to characterize left ventricular (LV) and right ventricular (RV) dysfunction and their prevalence in patients with PSS using echocardiography (echo) and to investigate their associations with the severity of illness and clinical outcomes. METHODS:: Retrospective chart review between 2010 and 2015 from 2 tertiary care pediatric intensive care units. Study included 78 patients (mean age 9.3 ± 7 years) from birth up to 21 years who fulfilled criteria for fluid- and catecholamine-refractory septic shock. Echocardiographic parameters of systolic, diastolic, and global function were measured offline. They were correlated with admission Pediatric Risk of Mortality III (PRISM III) and Pediatric Logistic Organ Dysfunction scores, vasoactive-inotrope score (VIS), ß-type natriuretic peptide (BNP), lactate, type of shock, duration of mechanical ventilation (MV), intensive care unit and hospital length of stay, and mortality. RESULTS:: Overall, 28-day mortality was 26%, and 88% patients required MV. Prevalence of LV dysfunction was 72% and RV dysfunction was 63%. LV systolic dysfunction (fractional shortening z score <-2) was significantly associated with PRISM III, VIS, and BNP. RV systolic dysfunction (tricuspid annular plane systolic excursion z score <-2) was significantly associated with cold shock. LV and RV diastolic dysfunction did not have any significant clinical associations. No echocardiographic measures were associated with mortality. CONCLUSION:: Myocardial dysfunction is highly prevalent in PSS but is not associated with mortality. LV systolic dysfunction is associated with a higher severity of illness, use of vasoactives, and BNP, whereas RV systolic dysfunction is associated with cold shock. Further studies are needed to determine the utility of echo in the bedside management of patients with PSS.

Identification of key genes and pathways using bioinformatics analysis in septic shock children.

BACKGROUND AND HYPOTHESIS: Sepsis is still one of the reasons for serious infectious diseases in pediatric intensive care unit patients despite the use of anti-infective therapy and organ support therapy. As it is well-known, the effect of single gene or pathway does not play a role in sepsis. We want to explore the interaction of two more genes or pathways in sepsis patients for future works. We hypothesize that the discovery from the available gene expression data of pediatric sepsis patients could know the process or improve the situation. METHODS AND RESULTS: The gene expression profile dataset GSE26440 of 98 septic shock samples and 32 normal samples using whole blood-derived RNA samples were generated. A total of 1,108 upregulated and 142 downregulated differentially expressed genes (DEGs) were identified in septic shock children using R software packages. The Gene Ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were analyzed using DAVID software; Gene Set Enrichment Analysis method was also used for enrichment analysis of the DEGs. The protein-protein interaction (PPI) network and the top 10 hub genes construction of the DEGs were constructed via plug-in Molecular Complex Detection and cytoHubba of Cytoscape software. From the PPI network, the top 10 hub genes, which are all upregulated DEGs in the septic shock children, were identified as GAPDH, TNF, EGF, MAPK3, IL-10, TLR4, MAPK14, IL-1ß, PIK3CB, and TLR2. Some of them were involved in one or more significant inflammatory pathways, such as the enrichment of tumor necrosis factor (TNF) pathway in the activation of mitogen-activated protein kinase activity, toll-like receptor signaling pathway, nuclear factor-κB signaling pathway, PI3K-Akt signaling pathway, and TNF signaling pathway. These findings support future studies on pediatric septic shock.

Role of echocardiography in reducing shock reversal time in pediatric septic shock: a randomized controlled trial / Papel da ecocardiografia na redução do tempo de reversão do choque no choque séptico pediátrico: ensaio controlado randomizado

Abstract Objective: To evaluate the role of echocardiography in reducing shock reversal time in pediatric septic shock. Methods: A prospective study conducted in the pediatric intensive care unit of a tertiary care teaching hospital from September 2013 to May 2016. Ninety septic shock patients were randomized in a 1:1 ratio for comparing the serial echocardiography-guided therapy in the study group with the standard therapy in the control group regarding clinical course, timely treatment, and outcomes. Results: Shock reversal was significantly higher in the study group (89% vs. 67%), with significantly reduced shock reversal time (3.3 vs. 4.5 days). Pediatric intensive care unit stay in the study group was significantly shorter (8 ± 3 vs. 14 ± 10 days). Mortality due to unresolved shock was significantly lower in the study group. Fluid overload was significantly lower in the study group (11% vs. 44%). In the study group, inotropes were used more frequently (89% vs. 67%) and initiated earlier (12[0.5-24] vs. 24[6-72] h) with lower maximum vasopressor inotrope score (120[30-325] vs. 170[80-395]), revealing predominant use of milrinone (62% vs. 22%). Conclusion: Serial echocardiography provided crucial data for early recognition of septic myocardial dysfunction and hypovolemia that was not apparent on clinical assessment, allowing a timely management and resulting in shock reversal time reduction among children with septic shock.

Resumo Objetivo: Avaliar o papel da ecocardiografia na redução do tempo de reversão do choque no choque séptico pediátrico. Métodos: Estudo prospectivo conduzido em uma UTIP de um hospital universitário de cuidados terciários de setembro de 2013 a maio de 2016. Foram randomizados 90 pacientes com choque séptico na proporção 1:1 para comparar a terapia guiada por ecocardiografia em série com a terapia padrão no grupo de controle com relação ao curso clínico, tratamento oportuno e resultados. Resultados: A reversão do choque foi significativamente maior no grupo de estudo (89% em comparação com 67%) com redução significativa do tempo de reversão do choque (3,3 em comparação com 4,5 dias). A permanência na UTIP no grupo de estudo foi significativamente mais curta (8 ± 3 em comparação com 14 ± 10 dias). A mortalidade devido ao choque não resolvido foi significativamente menor no grupo de estudo. A sobrecarga de fluidos foi significativamente menor no grupo de estudo (11% em comparação com 44%). No grupo de estudo, os inotrópicos foram usados com mais frequência (89% em comparação com 67%) e foram administrados antecipadamente (12 [0,5-24] em comparação com 24 [6-72] horas) e o menor escore inotrópico máximo dos vasopressores (120 [30-325] em comparação com 170 [80-395]) revela o uso predominante de milrinona (62% em comparação com 22%). Conclusão: A ecocardiografia em série forneceu dados fundamentais para o reconhecimento precoce da disfunção miocárdica séptica e hipovolemia não evidente na avaliação clínica, possibilitou o manejo tempestivamente adequado e resultou na redução do tempo de reversão do choque entre crianças com choque séptico.

Role of echocardiography in reducing shock reversal time in pediatric septic shock: a randomized controlled trial.

OBJECTIVE: To evaluate the role of echocardiography in reducing shock reversal time in pediatric septic shock. METHODS: A prospective study conducted in the pediatric intensive care unit of a tertiary care teaching hospital from September 2013 to May 2016. Ninety septic shock patients were randomized in a 1:1 ratio for comparing the serial echocardiography-guided therapy in the study group with the standard therapy in the control group regarding clinical course, timely treatment, and outcomes. RESULTS: Shock reversal was significantly higher in the study group (89% vs. 67%), with significantly reduced shock reversal time (3.3 vs. 4.5 days). Pediatric intensive care unit stay in the study group was significantly shorter (8±3 vs. 14±10 days). Mortality due to unresolved shock was significantly lower in the study group. Fluid overload was significantly lower in the study group (11% vs. 44%). In the study group, inotropes were used more frequently (89% vs. 67%) and initiated earlier (12[0.5-24] vs. 24[6-72]h) with lower maximum vasopressor inotrope score (120[30-325] vs. 170[80-395]), revealing predominant use of milrinone (62% vs. 22%). CONCLUSION: Serial echocardiography provided crucial data for early recognition of septic myocardial dysfunction and hypovolemia that was not apparent on clinical assessment, allowing a timely management and resulting in shock reversal time reduction among children with septic shock.

Relative Adrenal Insufficiency in Pediatric Septic Shock.

Sepsis and septic shock represent important causes of morbidity and mortality in children, and adrenal dysfunction may play a role in the cardiovascular and immunological response. According to existing reports, the incidence of adrenal dysfunction in critically ill children varies significantly between 4 and 52% of patients. This article reviews the concept of adrenal insufficiency and the role it may play in a pediatric septic shock. Also discussed are the diagnosis, prognosis, and treatment of adrenal insufficiency in septic shock in adults and children. Finally, the latest recommendations about steroid use in pediatric septic shock are summarized.