Hyperferritinemia and inflammation Kernan, Kate F; Carcillo, Joseph A
International immunology,
11/2017, Letnik:
29, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or ...secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an 'innocent bystander' biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.
To determine the efficacy of anakinra (recombinant interleukin-1 receptor antagonist) in improving 28-day survival in sepsis patients with features of macrophage activation syndrome. Despite ...equivocal results in sepsis trials, anakinra is effective in treating macrophage activation syndrome, a similar entity with fever, disseminated intravascular coagulation, hepatobiliary dysfunction, cytopenias, and hyperferritinemia. Hence, sepsis patients with macrophage activation syndrome features may benefit from interleukin-1 receptor blockade.
Reanalysis of deidentified data from the phase III randomized interleukin-1 receptor antagonist trial in severe sepsis.
Multicenter study recruiting through 91 centers from 11 countries in Europe and North America.
Sepsis patients with multiorgan dysfunction syndrome and/or shock (original study) were regrouped based on the presence or the absence of concurrent hepatobiliary dysfunction and disseminated intravascular coagulation as features of macrophage activation syndrome. The non-hepatobiliary dysfunction/disseminated intravascular coagulation group included patients with only hepatobiliary dysfunction, only disseminated intravascular coagulation, or neither.
Treatment with anakinra or placebo.
Main outcome was 28-day mortality. Descriptive and comparative statistics were performed. Data were available for 763 adults from the original study cohort, randomized to receive either anakinra or placebo. Concurrent hepatobiliary dysfunction/disseminated intravascular coagulation was noted in 43 patients (5.6% of total; 18-75 years old; 47% women). The 28-day survival was similar in both anakinra and placebo-treated non-hepatobiliary dysfunction/disseminated intravascular coagulation patients (71.4% vs 70.8%; p = 0.88). Treatment with anakinra was associated with significant improvement in the 28-day survival rate in hepatobiliary dysfunction/disseminated intravascular coagulation patients (65.4% anakinra vs 35.3% placebo), with hazard ratio for death 0.28 (0.11-0.71; p = 0.0071) for the treatment group in Cox regression.
In this subgroup analysis, interleukin-1 receptor blockade was associated with significant improvement in survival of patients with sepsis and concurrent hepatobiliary dysfunction/disseminated intravascular coagulation. A prospective randomized trial using features of macrophage activation syndrome for mortality risk stratification should be undertaken to confirm the role of interleukin-1 blockage.
Objective: To investigate whether pediatric sepsis phenotypes are stable in time. Methods: Retrospective cohort study examining children with suspected sepsis admitted to a Pediatric Intensive Care ...Unit at a large freestanding children's hospital during two distinct periods: 2010-2014 (early cohort) and 2018-2020 (late cohort). K-means consensus clustering was used to derive types separately in the cohorts. Variables included ensured representation of all organ systems. Results: One thousand ninety-one subjects were in the early cohort and 737 subjects in the late cohort. Clustering analysis yielded four phenotypes in the early cohort and five in the late cohort. Four types were in both: type A (34% of early cohort, 25% of late cohort), mild sepsis, with minimal organ dysfunction and low mortality; type B (25%, 22%), primary respiratory failure; type C (25%, 18%), liver dysfunction, coagulopathy, and higher measures of systemic inflammation; type D (16%, 17%), severe multiorgan dysfunction, with high degrees of cardiorespiratory support, renal dysfunction, and highest mortality. Type E was only detected in the late cohort (19%) and was notable for respiratory failure less severe than B or D, mild hypothermia, and high proportion of diagnoses and technological dependence associated with medical complexity. Despite low mortality, this type had the longest PICU length of stay. Conclusions: This single center study identified four pediatric sepsis phenotypes in an earlier epoch but five in a later epoch, with the new type having a large proportion of characteristics associated with medical complexity, particularly technology dependence. Personalized sepsis therapies need to account for this expanding patient population.
Immune system dysfunction is poorly represented in pediatric organ dysfunction definitions.
To evaluate evidence for criteria that define immune system dysfunction in critically ill children and ...associations with adverse outcomes and develop consensus criteria for the diagnosis of immune system dysfunction in critically ill children.
We conducted electronic searches of PubMed and Embase from January 1992 to January 2020, using medical subject heading terms and text words to define immune system dysfunction and outcomes of interest.
Studies of critically ill children with an abnormality in leukocyte numbers or function that is currently measurable in the clinical laboratory in which researchers assessed patient-centered outcomes were included. Studies of adults or premature infants, animal studies, reviews and commentaries, case series (≤10 subjects), and studies not published in English with inability to determine eligibility criteria were excluded.
Data were abstracted from eligible studies into a standard data extraction form along with risk of bias assessment by a task force member.
We identified the following criteria for immune system dysfunction: (1) peripheral absolute neutrophil count <500 cells/μL, (2) peripheral absolute lymphocyte count <1000 cells/μL, (3) reduction in CD4+ lymphocyte count or percentage of total lymphocytes below age-specific thresholds, (4) monocyte HLA-DR expression <30%, or (5) reduction in ex vivo whole blood lipopolysaccharide-induced TNFα production capacity below manufacturer-provided thresholds.
Many measures of immune system function are currently limited to the research environment.
We present consensus criteria for the diagnosis of immune system dysfunction in critically ill children.
Sepsis is a significant cause of morbidity and mortality. Children with sepsis often have alterations in microcirculation and vascular permeability. Our objective is current evidence regarding the ...role of the endothelial glycocalyx as a determinant of capillary leakage in these patients.
We reviewed PubMed, EMBASE, and Google scholar using MeSH terms "glycocalyx", "fluids", "syndecan", "endothelium", "vascular permeability", "edema", "sepsis", "septic shock", "children".
Articles in all languages were included. We include all studies in animals and humans related to glycocalyx and vascular permeability.
Studies in children and adults, as well as animal studies, were included.
One of the fundamental components of the endothelial barrier structure is the glycocalyx. It is a variable thickness layer distributed throughout the whole body, which fulfills a very important function for life: the regulation of blood vessel permeability to water and solutes, favoring vascular protection, modulation, and hemostasis. In the last few years, there has been a special interest in glycocalyx disorders and their relationship to increased vascular permeability, especially in patients with sepsis in whom the alterations that occur in the glycocalyx are unknown when they are subjected to different water resuscitation strategies, vasopressors, etc. This review describes the structural and functional characteristics of the glycocalyx, alterations in patients with sepsis, with regard to its importance in vascular permeability conservation and the possible impact of strategies to prevent and/or treat the injury of this fundamental structure.
The endothelial glycocalyx is a fundamental component of the endothelium and an important determinant of the mechanotransduction and vascular permeability in patients with sepsis. Studies are needed to evaluate the role of the different types of solutions used in fluid bolus, vasoactive support, and other interventions described in pediatric sepsis on microcirculation, particularly on endothelial integrity and the glycocalyx.
Objective
To update the 2008 consensus statements for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in adult and pediatric patients.
Participants
A ...multispecialty task force of 16 international experts in Critical Care Medicine, endocrinology, and guideline methods, all of them members of the Society of Critical Care Medicine and/or the European Society of Intensive Care Medicine.
Design/methods
The recommendations were based on the summarized evidence from the 2008 document in addition to more recent findings from an updated systematic review of relevant studies from 2008 to 2017 and were formulated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The strength of each recommendation was classified as strong or conditional, and the quality of evidence was rated from high to very low based on factors including the individual study design, the risk of bias, the consistency of the results, and the directness and precision of the evidence. Recommendation approval required the agreement of at least 80% of the task force members.
Results
The task force was unable to reach agreement on a single test that can reliably diagnose CIRCI, although delta cortisol (change in baseline cortisol at 60 min of <9 µg/dl) after cosyntropin (250 µg) administration and a random plasma cortisol of <10 µg/dl may be used by clinicians. We suggest against using plasma free cortisol or salivary cortisol level over plasma total cortisol (conditional, very low quality of evidence). For treatment of specific conditions, we suggest using intravenous (IV) hydrocortisone <400 mg/day for ≥3 days at full dose in patients with septic shock that is not responsive to fluid and moderate- to high-dose vasopressor therapy (conditional, low quality of evidence). We suggest not using corticosteroids in adult patients with sepsis without shock (conditional recommendation, moderate quality of evidence). We suggest the use of IV methylprednisolone 1 mg/kg/day in patients with early moderate to severe acute respiratory distress syndrome (PaO
2
/FiO
2
< 200 and within 14 days of onset) (conditional, moderate quality of evidence). Corticosteroids are not suggested for patients with major trauma (conditional, low quality of evidence).
Conclusions
Evidence-based recommendations for the use of corticosteroids in critically ill patients with sepsis and septic shock, acute respiratory distress syndrome, and major trauma have been developed by a multispecialty task force.
In response to the landmark 1999 report by the Institute of Medicine and safety initiatives promoted by the Leapfrog Group, our institution implemented a commercially sold computerized physician ...order entry (CPOE) system in an effort to reduce medical errors and mortality. We sought to test the hypothesis that CPOE implementation results in reduced mortality among children who are transported for specialized care.
Demographic, clinical, and mortality data were collected of all children who were admitted via interfacility transport to our regional, academic, tertiary-care level children's hospital during an 18-month period. A commercially sold CPOE program that operated within the framework of a general, medical-surgical clinical application platform was rapidly implemented hospital-wide over 6 days during this period. Retrospective analyses of pre-CPOE and post-CPOE implementation time periods (13 months before and 5 months after CPOE implementation) were subsequently performed.
Among 1942 children who were referred and admitted for specialized care during the study period, 75 died, accounting for an overall mortality rate of 3.86%. Univariate analysis revealed that mortality rate significantly increased from 2.80% (39 of 1394) before CPOE implementation to 6.57% (36 of 548) after CPOE implementation. Multivariate analysis revealed that CPOE remained independently associated with increased odds of mortality (odds ratio: 3.28; 95% confidence interval: 1.94-5.55) after adjustment for other mortality covariables.
We have observed an unexpected increase in mortality coincident with CPOE implementation. Although CPOE technology holds great promise as a tool to reduce human error during health care delivery, our unanticipated finding suggests that when implementing CPOE systems, institutions should continue to evaluate mortality effects, in addition to medication error rates, for children who are dependent on time-sensitive therapies.
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.
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.
Tertiary children's hospital PICU.
One hundred consecutive severe sepsis admissions.
Clinical data were recorded daily, and blood was collected twice weekly.
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).
Our approach to phenotype categorization remains hypothetical, and the phenotypes identified need to be confirmed in multicenter studies of pediatric multiple organ dysfunction syndrome.
More children are surviving critical illness but are at risk of residual or new health conditions. An evidence-informed and stakeholder-recommended core outcome set is lacking for pediatric critical ...care outcomes. Our objective was to create a multinational, multistakeholder-recommended pediatric critical care core outcome set for inclusion in clinical and research programs.
A two-round modified Delphi electronic survey was conducted with 333 invited research, clinical, and family/advocate stakeholders. Stakeholders completing the first round were invited to participate in the second. Outcomes scoring greater than 69% "critical" and less than 15% "not important" advanced to round 2 with write-in outcomes considered. The Steering Committee held a virtual consensus conference to determine the final components.
Multinational survey.
Stakeholder participants from six continents representing clinicians, researchers, and family/advocates.
Overall response rates were 75% and 82% for each round. Participants voted on seven Global Domains and 45 Specific Outcomes in round 1, and six Global Domains and 30 Specific Outcomes in round 2. Using overall (three stakeholder groups combined) results, consensus was defined as outcomes scoring greater than 90% "critical" and less than 15% "not important" and were included in the final PICU core outcome set: four Global Domains (Cognitive, Emotional, Physical, and Overall Health) and four Specific Outcomes (Child Health-Related Quality of Life, Pain, Survival, and Communication). Families (n = 21) suggested additional critically important outcomes that did not meet consensus, which were included in the PICU core outcome set-extended.
The PICU core outcome set and PICU core outcome set-extended are multistakeholder-recommended resources for clinical and research programs that seek to improve outcomes for children with critical illness and their families.
The Institute of Medicine has called for the development of clinical guidelines and practice parameters to develop "best practice" and potentially improve patient outcome.
To provide American College ...of Critical Care Medicine clinical guidelines for hemodynamic support of neonates and children with septic shock.
Individual members of the Society of Critical Care Medicine with special interest in neonatal and pediatric septic shock were identified from literature review and general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (1998-2001).
The MEDLINE literature database was searched with the following age-specific keywords: sepsis, septicemia, septic shock, endotoxemia, persistent pulmonary hypertension, nitric oxide, and extracorporeal membrane oxygenation. More than 30 experts graded literature and drafted specific recommendations by using a modified Delphi method. More than 30 more experts then reviewed the compiled recommendations. The task-force chairman modified the document until <10% of experts disagreed with the recommendations.
Only four randomized controlled trials in children with septic shock could be identified. None of these randomized trials led to a change in practice. Clinical practice has been based, for the most part, on physiologic experiments, case series, and cohort studies. Despite relatively low American College of Critical Care Medicine-graded evidence in the pediatric literature, outcomes in children have improved from 97% mortality in the 1960s to 60% in the 1980s and 9% mortality in 1999. U.S. hospital survival was three-fold better in children compared with adults (9% vs. 27% mortality) in 1999. Shock pathophysiology and response to therapies is age specific. For example, cardiac failure is a predominant cause of death in neonates and children, but vascular failure is a predominant cause of death in adults. Inotropes, vasodilators (children), inhaled nitric oxide (neonates), and extracorporeal membrane oxygenation can be more important contributors to survival in the pediatric populations, whereas vasopressors can be more important contributors to adult survival.
American College of Critical Care Medicine adult guidelines for hemodynamic support of septic shock have little application to the management of pediatric or neonatal septic shock. Studies are required to determine whether American College of Critical Care Medicine guidelines for hemodynamic support of pediatric and neonatal septic shock will be implemented and associated with improved outcome.
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