In-hospital pediatric sepsis mortality has decreased substantially, but long-term mortality and morbidity among children initially surviving sepsis, is unknown. Accordingly, the Life After Pediatric ...Sepsis Evaluation investigation was conducted to describe the trajectory of mortality and health-related quality of life morbidity for children encountering community-acquired septic shock.
Prospective, cohort-outcome study, conducted 2013-2017.
Twelve academic PICUs in the United States.
Critically ill children, 1 month to 18 years, with community-acquired septic shock requiring vasoactive-inotropic support.
Demographic, infection, illness severity, organ dysfunction, and resource utilization data were collected daily during PICU admission. Serial parent proxy-report health-related quality of life assessments were obtained at baseline, 7 days, and 1, 3, 6, and 12 months following PICU admission utilizing the Pediatric Quality of Life Inventory or Stein-Jessop Functional Status Scale.
Among 389 children enrolled, mean age was 7.4 ± 5.8 years; 46% were female; 18% were immunocompromised; and 51% demonstrated chronic comorbidities. Baseline Pediatric Overall Performance Category was normal in 38%. Median (Q1-Q3) Pediatric Risk of Mortality and Pediatric Logistic Organ Dysfunction scores at PICU admission were 11.0 (6.0-17.0) and 9.0 (6.0-11.0); durations of vasoactive-inotropic and mechanical ventilation support were 3.0 days (2.0-6.0 d) and 8.0 days (5.0-14.0 d); and durations of PICU and hospital stay were 9.4 days (5.6-15.4 d) and 15.7 days (9.2-26.0 d). At 1, 3, 6, and 12 months following PICU admission for the septic shock event, 8%, 11%, 12%, and 13% of patients had died, while 50%, 37%, 30%, and 35% of surviving patients had not regained their baseline health-related quality of life.
This investigation provides the first longitudinal description of long-term mortality and clinically relevant, health-related quality of life morbidity among children encountering community-acquired septic shock. Although in-hospital mortality was 9%, 35% of survivors demonstrated significant, health-related quality of life deterioration from baseline that persisted at least 1 year following hospitalization for septic shock.
Purpose
Immunoparalysis defined by prolonged monocyte human leukocyte antigen DR depression is associated with adverse outcomes in adult severe sepsis and can be reversed with granulocyte macrophage ...colony-stimulating factor (GM-CSF). We hypothesized that immunoparalysis defined by whole-blood ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha (TNFα) response <200 pg/mL beyond day 3 of multiple organ dysfunction syndrome (MODS) is similarly associated with nosocomial infection in children and can be reversed with GM-CSF.
Methods
In study period 1, we performed a multicenter cohort trial of transplant and nontransplant multiple organ dysfunction syndrome (MODS) patients (≥2 organ failure). In study period 2, we performed an open-label randomized trial of GM-CSF therapy for nonneutropenic, nontransplant, severe MODS patients (≥3 organ failure) with TNFα response <160 pg/mL.
Results
Immunoparalysis was observed in 34% of MODS patients (
n
= 70) and was associated with increased nosocomial infection (relative risk RR 3.3, 95% confidence interval 1.8–6.0
p
< 0.05) and mortality (RR 5.8 2.1–16
p
< 0.05). TNFα response <200 pg/mL throughout 7 days after positive culture was associated with persistent nosocomial infection, whereas recovery above 200 pg/mL was associated with resolution of infection (
p
< 0.05). In study period 2, GM-CSF therapy facilitated rapid recovery of TNFα response to >200 pg/mL by 7 days (
p
< 0.05) and prevented nosocomial infection (no infections in seven patients versus eight infections in seven patients) (
p
< 0.05).
Conclusions
Similar to in adults, immunoparalysis is a potentially reversible risk factor for development of nosocomial infection in pediatric MODS. Whole-blood ex vivo TNFα response is a promising biomarker for monitoring this condition.
Multiple scores exist to characterize organ dysfunction in children.
To review the literature on multiple organ dysfunction (MOD) scoring systems to estimate severity of illness and to characterize ...the performance characteristics of currently used scoring tools and clinical assessments for organ dysfunction in critically ill children.
Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020.
Studies were included if they evaluated critically ill children with MOD, evaluated the performance characteristics of scoring tools for MOD, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes.
Data were abstracted into a standard data extraction form by a task force member.
Of 1152 unique abstracts screened, 156 full text studies were assessed including a total of 54 eligible studies. The most commonly reported scores were the Pediatric Logistic Organ Dysfunction Score (PELOD), pediatric Sequential Organ Failure Assessment score (pSOFA), Pediatric Index of Mortality (PIM), PRISM, and counts of organ dysfunction using the International Pediatric Sepsis Definition Consensus Conference. Cut-offs for specific organ dysfunction criteria, diagnostic elements included, and use of counts versus weighting varied substantially.
While scores demonstrated an increase in mortality associated with the severity and number of organ dysfunctions, the performance ranged widely.
The multitude of scores on organ dysfunction to assess severity of illness indicates a need for unified and data-driven organ dysfunction criteria, derived and validated in large, heterogenous international databases of critically ill children.
Despite intense interest in the links between the microbiome and human health, little has been written about dysbiosis among ICU patients. We characterized microbial diversity in samples from 37 ...children in a pediatric ICU (PICU). Standard measures of alpha and beta diversity were calculated, and results were compared with data from adult and pediatric reference datasets.
Bacterial 16S rRNA gene sequences were analyzed from 71 total tongue swabs, 50 skin swabs, and 77 stool samples or rectal swabs. The mean age of the PICU patients was 2.9 years (range 1-9 years), and many were chronically ill children that had previously been hospitalized in the PICU. Relative to healthy adults and children, alpha diversity was decreased in PICU GI and tongue but not skin samples. Measures of beta diversity indicated differences in community membership at each body site between PICU, adult, and pediatric groups. Taxonomic alterations in the PICU included enrichment of gut pathogens such as Enterococcus and Staphylococcus at multiple body sites and depletion of commensals such as Faecalibacterium and Ruminococcus from GI samples. Alpha and beta diversity were unstable over time in patients followed longitudinally. We observed the frequent presence of "dominant" pathogens in PICU samples at relative abundance >50%. PICU samples were characterized by loss of site specificity, with individual taxa commonly present simultaneously at three sample sites on a single individual. Some pathogens identified by culture of tracheal aspirates were commonly observed in skin samples from the same patient.
We conclude that the microbiota in critically ill children differs sharply from the microbiota of healthy children and adults. Acknowledgement of dysbiosis associated with critical illness could provide opportunities to modulate the microbiota with precision and thereby improve patient outcomes.
Objective
To provide a narrative review of the latest concepts and understanding of the pathophysiology of critical illness-related corticosteroid insufficiency (CIRCI).
Participants
A multispecialty ...task force of international experts in critical care medicine and endocrinology and members of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).
Data sources
Medline, Database of Abstracts of Reviews of Effects (DARE), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews.
Results
Three major pathophysiologic events were considered to constitute CIRCI: dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, altered cortisol metabolism, and tissue resistance to glucocorticoids. The dysregulation of the HPA axis is complex, involving multidirectional crosstalk between the CRH/ACTH pathways, autonomic nervous system, vasopressinergic system, and immune system. Recent studies have demonstrated that plasma clearance of cortisol is markedly reduced during critical illness, explained by suppressed expression and activity of the primary cortisol-metabolizing enzymes in the liver and kidney. Despite the elevated cortisol levels during critical illness, tissue resistance to glucocorticoids is believed to occur due to insufficient glucocorticoid alpha-mediated anti-inflammatory activity.
Conclusions
Novel insights into the pathophysiology of CIRCI add to the limitations of the current diagnostic tools to identify at-risk patients and may also impact how corticosteroids are used in patients with CIRCI.
To review the past year's literature, and selected prior literature relevant to these most recent findings, regarding intravenous fluid choices in the management of critically ill children.
...Twenty-eight publications were identified using the keywords pediatrics and intravenous fluid in the PubMed database. The subjects identified included intravenous fluid choices related to perioperative maintenance fluid management, rehydration for dehydration related to diarrhea losses, rehydration in diabetic ketoacidosis, intravenous fluid needs during mechanical ventilation, use of intravenous fluids as hyperosmolar agents in traumatic brain injury, isotonic fluid bolus resuscitation for sepsis-related capillary leak syndrome-induced hypovolemic shock, maintenance intravenous fluid and blood transfusion for malaria-associated euvolemic severe anemia shock, isotonic fluid and blood boluses for trauma-induced hemorrhagic shock, and isotonic fluid boluses and generous maintenance infusion for burn resuscitation.
Because intravenous fluid can be helpful or harmful, it can only be safely done in critically ill children when using state-of-the-art monitoring of patient volume, electrolyte, osmolarity, pH, and glucose status.
We tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis.
Prospective cohort study.
Tertiary ...PICU.
Children with 100 separate admission episodes of severe sepsis were enrolled.
Blood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2 × 2 contingency table using C-reactive protein and ferritin thresholds was developed.
A C-reactive protein of 4.08 mg/dL and a ferritin of 1,980 ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL category (6/13 46.15%) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin less than 1,980 ng/mL or C-reactive protein less than 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL categories (2/43 4.65%), and the "low-risk" C-reactive protein less than 4.08 mg/dL and ferritin less than 1,980 ng/mL category (0/44 0%) (odds ratio, 36.43 95% CI, 6.16-215.21). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 95% CI, 1.34-14.96) and macrophage activation syndrome (odds ratio, 24.20 95% CI, 5.50-106.54). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 35%; p < 0.05).
A C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08 mg/dL and ferritin of 1,980 ng/mL appeared to be a desired response in children with severe sepsis.
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The ...small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein–protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I–converting enzyme 2 (ACE2)–solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.
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