How to ENHANCE our knowledge of activated protein C during pediatric sepsis trials: pediatric versus adult trials.
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Adult↗
Biomedical subjects
Jan A Hazelzet
Publications and source records attributed to Jan A Hazelzet.
CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity.
INTRODUCTION: Chemokines are a superfamily of small peptides involved in leukocyte chemotaxis and in the induction of cytokines in a wide range of infectious diseases. Little is known about their role in meningococcal sepsis in children and their relationship with disease severity and outcome. METHODS: Monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP) 1alpha, growth-related gene product (GRO)-alpha and interleukin (IL)-8 were measured in 58 children with meningococcal sepsis or septic shock on admission and 24 hours thereafter. Nine patients died. Serum chemokine levels of survivors and nonsurvivors were compared, and the chemokine levels were correlated with prognostic disease severity scores and various laboratory parameters. RESULTS: Extremely high levels of all chemokines were measured in the children's acute-phase sera. These levels were significantly higher in nonsurvivors compared with survivors and in patients with septic shock compared with patients with sepsis (P < 0.0001). The cutoff values of 65,407 pg/ml, 85,427 pg/ml and 460 pg/ml for monocyte chemoattractant protein, for IL-8 and for macrophage inflammatory protein 1alpha, respectively, all had 100% sensitivity and 94-98% specificity for nonsurvival. Chemokine levels correlated better with disease outcome and severity than tumor necrosis factor (TNF)-alpha and correlated similarly to interleukin (IL)-6. In available samples 24 hours after admission, a dramatic decrease of chemokine levels was seen. CONCLUSION: Initial-phase serum levels of chemokines in patients with meningococcal sepsis can predict mortality and can correlate strongly with disease severity. Chemokines may play a key role in the pathophysiology of meningococcal disease and are potentially new targets for therapeutic approaches.
Adolescent↗
Levels of protein C and activated protein C: what do they mean?
Acute pancreatitis is a local inflammatory process that leads to a systemic inflammatory response in the majority of cases, and sometimes leads to multiple organ failure. It is obvious that coagulation and especially the protein C system are involved in this disease. The present commentary is related to a study in patients with pancreatitis with and without multiple organ failure in which protein C and activated protein C levels were studied. The protein C system and other studies analyzing (activated) protein C levels are discussed.
Humans↗
Plasminogen activator inhibitor type 1 gene polymorphism and sepsis.
Plasminogen activator inhibitor type 1 (PAI-1) is a 50-kilodalton glycoprotein of the serine protease inhibitor family. The primary role of PAI-1 in vivo is the inhibition of both tissue- and urokinase-type plasminogen activators. In addition to this function, PAI-1 acts as an acute-phase protein during acute inflammation. PAI-1 is a pivotal player in the pathogenesis of sepsis, a complex clinical syndrome that results from a systemic inflammatory response. In patients with sepsis, the levels of PAI-1 are positively related to poor outcome, increased severity of disease, and increased levels of various cytokines, acute-phase proteins, and coagulation parameters. The 4G/5G insertion/deletion promoter polymorphism, which leads to differences in PAI-1 production, has been demonstrated to affect the risk of developing severe complications and dying from sepsis during meningococcal infection and multiple trauma.
Clinical Trials as Topic↗
Euthyroid sick syndrome in meningococcal sepsis: the impact of peripheral thyroid hormone metabolism and binding proteins.
CONTEXT AND OBJECTIVES: The objective of this study was to elucidate the influence of disease severity, deiodination, sulfation, thyroid hormone binding, and dopamine use on thyroid function in euthyroid sick syndrome. SETTING: The study was performed at a university-affiliated pediatric intensive care unit (PICU). DESIGN: This was an observational cohort study. PATIENTS: Sixty-nine children with meningococcal sepsis were studied. MAIN OUTCOME MEASURES: Differences in thyroid function among nonsurvivors, shock survivors, and sepsis survivors on PICU admission were the main outcome measures. RESULTS: The main study group consisted of 45 non-dopamine-treated children. All children had decreased total T3 (TT3)/rT3 ratios without elevated TSH. T4 sulfate levels were decreased in 88%. Nonsurvivors had paradoxically higher TT3/rT3 ratios than shock survivors (0.71 vs. 0.30); this ratio also correlated with shorter duration of disease (r = -0.43). TT4 and T4-binding globulin (TBG) levels declined with increasing disease severity. TBG levels correlated inversely with elastase levels (r = -0.46). Only TSH levels were significantly lower in 24 dopamine-treated children compared with non-dopamine-treated children (0.65 vs. 0.84), whereas other thyroid hormones did not significantly differ. Both higher TT3/rT3 ratios and lower TT4 levels were predictive for mortality, but this disappeared when IL-6 was entered into the regression model. CONCLUSIONS: All children with meningococcal sepsis showed signs of euthyroid sick syndrome. Alterations in peripheral thyroid hormone metabolism related inversely to the duration of disease and seemed to be enacted by profound induction of type 3 deiodinase rather than by down-regulation of type 1. Lower TT4 levels were related to increased turnover of TBG by elastase. Dopamine was found to suppress only TSH secretion, not other thyroid hormone levels, on PICU admission. Both the TT3/rT3 ratio and TT4 levels were predictive for mortality, but were not superior to IL-6.
Cardiotonic Agents↗
Adrenal insufficiency in meningococcal sepsis: bioavailable cortisol levels and impact of interleukin-6 levels and intubation with etomidate on adrenal function and mortality.
CONTEXT: Adequate adrenal function is pivotal to survive meningococcal sepsis. OBJECTIVES: The objective of the study was to evaluate adrenocortical function in meningococcal disease. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a university-affiliated pediatric intensive care unit. PATIENTS: Sixty children with meningococcal sepsis or septic shock participated in the study. MAIN OUTCOME MEASURES: The differences in adrenal function between nonsurvivors (n = 8), shock survivors (n = 43), and sepsis survivors (n = 9) on pediatric intensive care unit admission were measured. RESULTS: Nonsurvivors had significantly lower median cortisol to ACTH ratio than shock survivors and sepsis survivors. Because cortisol binding globulin and albumin levels did not significantly differ among the groups, bioavailable cortisol levels were also significantly lower in nonsurvivors than sepsis survivors. Nonsurvivors had significantly lower cortisol to 11-deoxycortisol ratios but not lower 11-deoxycortisol to 17-hydroxyprogesterone ratios than survivors. Using multiple regression analysis, decreased cortisol to ACTH ratio was significantly related to higher IL-6 levels and intubation with etomidate (one single bolus), whereas decreased cortisol to 11-deoxycortisol ratio was significantly related only to intubation with etomidate. Aldosterone levels tended to be higher in nonsurvivors than shock survivors, whereas plasma renin activity did not significantly differ. CONCLUSIONS: Our study shows that the most severely ill children with septic shock had signs of adrenal insufficiency. Bioavailable cortisol levels were not more informative on adrenal function than total cortisol levels. Besides disease severity, one single bolus of etomidate during intubation was related to decreased adrenal function and 11beta-hydroxylase activity. Decreased adrenal function was not related to decreased 21-hydroxylase activity. Based on our results, it seems of vital importance to take considerable caution using etomidate and consider combining its administration with glucocorticoids during intubation of children with septic shock.
17-alpha-Hydroxyprogesterone↗
Thyroid function and outcome in children who survived meningococcal septic shock.
OBJECTIVE: To investigate the time course of thyroid function, factors that affect it, and its relationship to outcome in children surviving meningococcal septic shock. DESIGN AND SETTING: Observational cohort study in a university-affiliated pediatric intensive care unit (PICU). PATIENTS AND PARTICIPANTS: We divided the 44 children admitted to the PICU who survived meningococcal septic shock into those with short-stay (<7 days, n=33) or long-stay (>or=7 days, n=11). MEASUREMENTS AND RESULTS: Serum thyroid hormone concentrations were determined on PICU admission and after 24 and 48 h. The Pediatric Risk of Mortality score and selected laboratory parameters were used to assess disease severity. On admission all children showed signs of euthyroid sick syndrome: low total triiodothyronine (TT3) and high reverse triiodothyronine (rT3) without compensatory elevated thyrotropin (TSH). Admission rT3 levels and the TT3/rT3 ratio were correlated with C-reactive protein levels and with time from first petechia to admission. Short-stay children only had higher TT3 and lower interleukin 6 levels at admission than long-stay children; after 48 h they showed higher total thyroxin, free thyroxin, TT3, and TSH and lower rT3 than long-stay children. All changes in thyroid parameters within the first 24 h were related to length of PICU stay. In children receiving dopamine TSH levels and TT3/rT3 ratios remained unchanged, whereas both values increased in those who did not receive dopamine or in whom dopamine was discontinued. CONCLUSIONS: All children surviving meningococcal septic shock showed signs of euthyroid sick syndrome on admission. Thyroid hormone level changes in the first 24 h were prognostic for length of PICU stay.
Adolescent↗
Serum lipids and disease severity in children with severe meningococcal sepsis.
OBJECTIVE: To evaluate the role of cholesterol and lipoproteins in children with severe meningococcal sepsis. DESIGN: Retrospective observational study. SETTING: A university-affiliated pediatric intensive care unit. PATIENTS: Fifty-seven patients admitted to the pediatric intensive care unit with meningococcal sepsis or septic shock. INTERVENTIONS: Total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) concentrations were measured in serum samples drawn within 6 hrs after admission to the pediatric intensive care unit and 12, 24, 48, 72 hrs, 7 days, and 1-3 months afterward. Standard deviation scores of these variables (sd scores) were calculated to correct for age-related differences. To assess disease severity, the Pediatric Risk of Mortality (PRISM) score, the Sepsis-related Organ Failure Assessment (SOFA) score, and the Disseminated Intravascular Coagulation (DIC) score were determined as well as selected laboratory variables. MEASUREMENTS AND MAIN RESULTS: Ten patients died. Total serum cholesterol on admission was very low in all patients. This hypocholesterolemia was caused by low HDL concentrations but in particular by low LDL cholesterol levels. Eight patients had undetectable LDL levels on admission. Total cholesterol levels were significantly lower in nonsurvivors than in survivors (0.97 vs. 1.60, p = .013), whereas levels of LDL and HDL did not significantly differ between both groups. Total cholesterol sd scores were similar between survivors and nonsurvivors. Within survivors, cholesterol sd score was significantly lower in patients with shock compared with those with sepsis. The total cholesterol, HDL, and LDL levels correlated with clinical variables of disease severity and with levels of cytokines. Total cholesterol, HDL, and LDL levels normalized rapidly in survivors and were completely normal 1-3 months after admission. CONCLUSIONS: Extremely low levels of total serum cholesterol, HDL, and LDL are found in the initial phase of children with severe meningococcal disease. Total cholesterol levels are significantly lower in nonsurvivors than in survivors, but not the sd score. Total cholesterol, HDL, and LDL levels on admission are inversely associated with disease severity. Hypocholesterolism is associated with hypocortisolism. The concentrations of total cholesterol and lipoproteins steadily increase after 24 hrs in survivors and are normalized 1-3 months after pediatric intensive care unit admission.
Adolescent↗
Diagnosing meningococcemia as a cause of sepsis.
OBJECTIVE: In 2004, a consensus meeting of critical care and infectious disease experts was organized to review and make recommendations on current definitions of infections, sepsis, and organ failure for neonates and children and for the predisposing conditions leading to these diseases. Among the infections leading to sepsis, meningococcemia is so distinguishable that a separate article on its diagnosis and management was thought to be warranted. DESIGN AND METHODS: The process included a modified Delphi method, a consensus conference, subsequent smaller meetings of subgroups and key individuals, and electronic-based discussion among subgroups. A systematic review of the literature was undertaken. CONCLUSIONS: Early recognition and treatment of likely meningococcal sepsis has led to decreased mortality. Since the start of vaccination against serogroup C, the prevalence of this disease has decreased. Not only the possible presence of a meningococcal sepsis is important, but also the assessment of the shock state and the severity of disease and the possible presence of meningoencephalitis. There are also a number of genetic predispositions determining the severity of disease. The only three randomized trials in this disease have led to the conclusion that mortality is not a stable end point. Improvement in organ function, morbidity (including amputations), and functional outcome are better outcome measures.
Bacteremia↗
Parent satisfaction in pediatric intensive care: a critical appraisal of the literature.
OBJECTIVE: To assess the content and characteristics of satisfaction surveys for the development of a parent satisfaction questionnaire to improve clinical practice in pediatric intensive care. DESIGN: A structured literature review process. The databases PubMed and CINAHL were searched, via identified search terms, for relevant articles published between May 1994 and May 2004. Assessment and analysis of the material was related to development, content, reliability and validity, scales for scoring, and distribution of the satisfaction questionnaires. MAIN RESULTS: Twelve original studies were identified using ten different satisfaction surveys in pediatric, neonatal, or adult intensive care units or in general pediatric wards. All surveys counted a total of 248 questions or statements. Six satisfaction questionnaires categorized the questions or statements in 21 different formulated domains. Most questionnaires showed sufficient results on reliability and validity. Except for one satisfaction instrument, Likert-type scales were used for rating. One study described the distribution of the questionnaire after discharge from the hospital, whereas other questionnaires were distributed during hospital admission. CONCLUSION: The use of parent satisfaction surveys in pediatric intensive care is not well documented. Family-centered care has become widely accepted as an important issue in quality of care, and satisfaction surveys are a valuable resource for measuring and improving clinical practice. Parent satisfaction surveys need to be developed based on the needs and experiences of parents, and emphasis should be put on methodologic issues to have the results accepted as valid and effective for possible changes in clinical practice.
Adult↗
Clinical information systems: CareSuite from Picis.
In this article, we discuss the implementation of the CareSuite system (Picis, Wakefield, MA) in 5 intensive care units of the Erasmus Medical Center, Rotterdam, the Netherlands. We give a description of the implementation process, and the system as it is currently being used. We also confront the lessons learned during the implementation of this clinical information systems with insights from the research field of implementation, and thereby show the value of a socio-technical approach to clinical information systems implementation.
Computer Communication Networks↗
Pediatric considerations.
OBJECTIVE: In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for other supportive therapies in sepsis that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and to improve outcome in severe sepsis. DESIGN AND METHODS: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee. Pediatric representatives attended the various section meetings and workshops to contrast adult and pediatric management. These are published here as pediatric considerations. CONCLUSION: Pediatric considerations included a more likely need for intubation due to low functional residual capacity, more difficult intravenous access, fluid resuscitation based on weight with 40-60 mL kg or higher needed, decreased cardiac output and increased systemic vascular resistance as the most common hemodynamic profile, greater use of physical examination therapeutic endpoints, the unsettled issue of high-dose steroids for therapy of septic shock, and greater risk of hypoglycemia with aggressive glucose control.
Cardiotonic Agents↗
Activation of protein C following infusion of protein C concentrate in children with severe meningococcal sepsis and purpura fulminans: a randomized, double-blinded, placebo-controlled, dose-finding study.
BACKGROUND: Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial. METHODS: Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products. RESULTS: Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes. CONCLUSIONS: Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.
Anticoagulants↗
Low serum cortisol in combination with high adrenocorticotrophic hormone concentrations are associated with poor outcome in children with severe meningococcal disease.
OBJECTIVES: To study the correlation between serum concentrations of adrenocorticotrophic hormone (ACTH) and cortisol in relation to severity of disease in children with meningococcal sepsis. METHODS: Subjects were children with meningococcal sepsis, admitted to the pediatric intensive care unit. Clinical data, laboratory values and blood samples were selected. Arterial cortisol, ACTH, interleukin 6 and tumor necrosis factor alpha concentrations were measured on admission and studied for their relation to severity of disease (sepsis, septic shock/survivors, septic shock/nonsurvivors). RESULTS: Seventy-two patients fulfilled the criteria for meningococcal sepsis. Sixty-two of these children with positive blood cultures of Neisseria meningitidis, who were not treated with corticosteroids before admission, were included. Fifty of the 62 patients had septic shock. Twelve of those children (24%) died. The median age of the subjects was 2.6 years (range, 0.3 to 16.1 years). Cortisol values were significantly lower in non-survivors (median, 654 nmol/l) than in survivors (median, 2184 nmol/l) (P < 0.01). ACTH values were significantly higher in children who died (median, 1271 ng/l) than in survivors (85 ng/l) (P < 0.01). The median cortisol:ACTH ratio decreased significantly depending on the disease severity categories. CONCLUSIONS: Low serum cortisol concentrations in combination with high ACTH concentrations are associated with poor outcome in children with severe meningococcal disease.
Adolescent↗
Bench-to-bedside review: genetic influences on meningococcal disease.
This review discusses the possible involvement of a variety of genetic polymorphisms on the course of meningococcal disease. It has been shown that several common genetic polymorphisms can either influence the susceptibility to meningococcal disease or can account for a higher mortality rate in patients. Gene polymorphisms concerning antibody receptors, lipopolysaccharide (LPS) binding receptors or proteins, innate complement proteins as well as cytokines and hemostatic proteins are described. The study of genetic polymorphisms might provide important insights in the pathogenesis of meningococcal disease and could make it possible to identify individuals who are at risk of either contracting or dying from meningococcal disease.
Adolescent↗