Rationale and design of the pediatric critical illness stress-induced immune suppression (CRISIS) prevention trial.
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SUBMITTER: Carcillo J
PROVIDER: S-EPMC2918276 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesNosocomial infection/sepsis occurs in up to 40% of children requiring long-term intensive care. Zinc, selenium, glutamine, metoclopramide (a prolactin secretalogue), and/or whey protein supplementation have been effective in reducing infection and sepsis in other populations. We evaluated whether daily nutriceutical supplementation with zinc, selenium, glutamine, and metoclopramide, compared to whey protein, would reduce the occurrence of nosocomial infection/sepsis in this at-risk population.DesignRandomized, double-blinded, comparative effectiveness trial.SettingEight pediatric intensive care units in the National Institutes of Child Health and Human Development Collaborative Pediatric Critical Care Research Network.PatientsTwo hundred ninety-three long-term intensive care patients (age 1-17 yrs) expected to require >72 hrs of invasive care.InterventionsPatients were stratified according to immunocompromised status and center and then were randomly assigned to receive daily enteral zinc, selenium, glutamine, and intravenous metoclopramide (n = 149), or daily enteral whey protein (n = 144) and intravenous saline for up to 28 days of intensive care unit stay. The primary end point was time to development of nosocomial sepsis/infection. The analysis was intention to treat.Measurements and main resultsThere were no differences by assigned treatment in the overall population with respect to time until the first episode of nosocomial infection/sepsis (median whey protein 13.2 days vs. zinc, selenium, glutamine, and intravenous metoclopramide 12.1 days; p = .29 by log-rank test) or the rate of nosocomial infection/sepsis (4.83/100 days whey protein vs. 4.99/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .81). Only 9% of the 293 subjects were immunocompromised and there was a reduction in rate of nosocomial infection/sepsis with zinc, selenium, glutamine, and intravenous metoclopramide in this immunocompromised group (6.09/100 days whey protein vs. 1.57/100 days zinc, selenium, glutamine, and intravenous metoclopramide; p = .011).ConclusionCompared with whey protein supplementation, zinc, selenium, glutamine, and intravenous metoclopramide conferred no advantage in the immune-competent population. Further evaluation of zinc, selenium, glutamine, and intravenous metoclopramide supplementation is warranted in the immunocompromised long-term pediatric intensive care unit patient.
| S-EPMC3302948 | biostudies-literature
Project description:BackgroundCritical illness is a major ongoing health care burden worldwide and is associated with high mortality rates. Sodium-glucose cotransporter-2 inhibitors have consistently shown benefits in cardiovascular and renal outcomes. The effects of sodium-glucose cotransporter-2 inhibitors in acute illness have not been properly investigated.MethodsDEFENDER is an investigator-initiated, multicenter, randomized, open-label trial designed to evaluate the efficacy and safety of dapagliflozin in 500 adult participants with acute organ dysfunction who are hospitalized in the intensive care unit. Eligible participants will be randomized 1:1 to receive dapagliflozin 10mg plus standard of care for up to 14 days or standard of care alone. The primary outcome is a hierarchical composite of hospital mortality, initiation of kidney replacement therapy, and intensive care unit length of stay, up to 28 days. Safety will be strictly monitored throughout the study.ConclusionDEFENDER is the first study designed to investigate the use of a sodium-glucose cotransporter-2 inhibitor in general intensive care unit patients with acute organ dysfunction. It will provide relevant information on the use of drugs of this promising class in critically ill patients.Clinicaltrials.gov registryNCT05558098.
| S-EPMC10734800 | biostudies-literature
Project description:Stress hyperglycemia (SH) commonly occurs during critical illness in children. The historical view that SH is beneficial has been questioned in light of evidence that demonstrates the association of SH with worse outcomes. In addition to intrinsic changes in glucose metabolism and development of insulin resistance, specific intensive care unit (ICU) practices may influence the development of SH during critical illness. Mechanical ventilation, vasoactive infusions, renal replacement therapies, cardiopulmonary bypass and extracorporeal life support, therapeutic hypothermia, prolonged immobility, nutrition support practices, and the use of medications are all known to mediate development of SH in critical illness. Tight glucose control (TGC) to manage SH has emerged as a promising therapy to improve outcomes in critically ill adults, but results have been inconclusive. Large variations in ICU practices across studies likely resulted in inconsistent results. Future studies of TGC need to take into account the impact of commonly used ICU practices and, ideally, standardize protocols in an attempt to improve the accuracy of conclusions from such studies.
| S-EPMC3320820 | biostudies-other
Project description:Critical illness hyperglycemia (CIH) is common in pediatric and adult intensive care units (ICUs). Children undergoing surgical repair or palliation of congenital cardiac defects are particularly at risk for CIH and its occurrence has been associated with increased morbidity and mortality in this population. Strict glycemic control through the use of intensive insulin therapy (IIT) has been shown to improve outcomes in some adult and pediatric studies, yet these findings have sparked controversy. The practice of strict glycemic control has been slow in extending to pediatric ICUs because of the documented increase in the incidence of hypoglycemia in patients treated with IIT. Protocol driven approaches with more liberal glycemic targets have been successfully validated in general and cardiac critical care pediatric patients with low rates of hypoglycemia. It is unknown whether a therapeutic benefit is obtained by keeping patients in this more liberal glycemic control target. Definitive randomized controlled trials of IIT utilizing these targets in critically ill children are ongoing.
| S-EPMC3320819 | biostudies-other
Project description:BACKGROUND:Many sepsis survivors develop chronic critical illness (CCI) and are assumed to be immunosuppressed, but there is limited clinical evidence to support this. We sought to determine whether the incidence of secondary infections and immunosuppressive biomarker profiles of patients with CCI differ from those with rapid recovery (RAP) after sepsis. METHODS:This prospective observational study evaluated 88 critically ill patients with sepsis and 20 healthy controls. Cohorts were defined based on clinical trajectory (early death, RAP, or CCI), whereas immunosuppression was clinically determined by the presence of a postsepsis secondary infection. Serial blood samples were collected for absolute lymphocyte counts (ALCs), monocytic human leukocyte antigen-DR (mHLA-DR) expression, and plasma-soluble programmed death-ligand 1 (sPD-L1) concentrations. RESULTS:Of the 88 patients with sepsis, 3 (3%) died within 14 days of sepsis onset, 50 (57%) experienced RAP, and 35 (40%) developed CCI. Compared with RAP patients, CCI patients exhibited a higher incidence and overall number of infections adjusted for hospital length of stay. ALC and mHLA-DR levels were dramatically reduced at the time of sepsis diagnosis when compared with healthy controls, whereas sPD-L1 concentrations were significantly elevated. There were no differences between RAP and CCI patients in ALC, sPD-L1, or mHLA-DR at the time of diagnosis or within 24?h after sepsis diagnosis. However, in contrast to the RAP group, CCI patients failed to exhibit any trend toward restoration of normal values of ALC, HLA-DR, and sPD-L1. CONCLUSIONS:Septic patients demonstrate clinical and biological evidence to suggest they are immunosuppressed at the time of sepsis diagnosis. Those who develop CCI have a greater incidence of secondary infections and persistently aberrant markers of impaired host immunity, although measurements at the time of sepsis onset did not distinguish between subjects with RAP and CCI.
| S-EPMC5809297 | biostudies-literature
Project description:Annual seasonal influenza epidemics of variable severity result in significant morbidity and mortality in the United States (U.S.) and worldwide. In temperate climate countries, including the U.S., influenza activity peaks during the winter months. Annual influenza vaccination is recommended for all persons in the U.S. aged 6 months and older, and among those at increased risk for influenza-related complications in other parts of the world (e.g. young children, elderly). Observational studies have reported effectiveness of influenza vaccination to reduce the risks of severe disease requiring hospitalization, intensive care unit admission, and death. A diagnosis of influenza should be considered in critically ill patients admitted with complications such as exacerbation of underlying chronic comorbidities, community-acquired pneumonia, and respiratory failure during influenza season. Molecular tests are recommended for influenza testing of respiratory specimens in hospitalized patients. Antigen detection assays are not recommended in critically ill patients because of lower sensitivity; negative results of these tests should not be used to make clinical decisions, and respiratory specimens should be tested for influenza by molecular assays. Because critically ill patients with lower respiratory tract disease may have cleared influenza virus in the upper respiratory tract, but have prolonged influenza viral replication in the lower respiratory tract, an endotracheal aspirate (preferentially) or bronchoalveolar lavage fluid specimen (if collected for other diagnostic purposes) should be tested by molecular assay for detection of influenza viruses.Observational studies have reported that antiviral treatment of critically ill adult influenza patients with a neuraminidase inhibitor is associated with survival benefit. Since earlier initiation of antiviral treatment is associated with the greatest clinical benefit, standard-dose oseltamivir (75 mg twice daily in adults) for enteric administration is recommended as soon as possible as it is well absorbed in critically ill patients. Based upon observational data that suggest harms, adjunctive corticosteroid treatment is currently not recommended for children or adults hospitalized with influenza, including critically ill patients, unless clinically indicated for another reason, such as treatment of asthma or COPD exacerbation, or septic shock. A number of pharmaceutical agents are in development for treatment of severe influenza.
| S-EPMC6563376 | biostudies-literature
Project description:This scoping review aimed to elucidate and summarize the predictive role of serum ferritin in critical pediatric illness. The Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was employed to conduct a scoping review of 5 databases (MEDLINE, CENTRAL, ProQuest, ScienceDirect, and Epistemonikos) from the date of inception through January 24, 2022. Primary research studies involving subjects aged <18 years and serum ferritin levels were screened and reviewed independently following an a priori defined protocol. Of the 1,580 retrieved studies, 66 were analyzed. Summary statistics of serum ferritin levels for overall and condition-specific studies were reported in 30 (45.4%) and 47 studies (71.2%), respectively. The normal range was defined in 16 studies (24.2%), whereas the threshold was determined in 43 studies (65.1%). A value of <500 ng/mL was most often the upper limit of the normal range. Serum ferritin as a numerical variable (78.9%) was usually significantly higher (80.8%) in the predicted condition than in controls, while as a categorical variable with preset thresholds, ferritin was a significant predictor in 84.6% of studies. A total of 22 predictive thresholds predicted mortality (12 of 46 [26.1%]), morbidity (18 of 46 [39.1%]), and specific (16 of 46 [34.8%]) outcomes in 15 unique conditions. Increased precision in serum ferritin measures followed by close attention to the threshold modeling strategy and reporting can accelerate the translation from evidence to clinical practice.
| S-EPMC9989723 | biostudies-literature
Project description:OBJECTIVE(S):Determine the associations between having participation-focused strategies and receiving rehabilitation services in the pediatric intensive care unit (PICU) with caregiver stress over 6 months post-PICU discharge. DESIGN:Substudy of a data from Wee-Cover, a prospective cohort study. SETTING:Two PICU sites. PARTICIPANTS:Caregivers (N=168) of children 1-17 years old admitted into a PICU for ?48 hours. MAIN OUTCOME MEASURES:Data were collected from caregivers at enrollment and 3 and 6 months post-PICU discharge. Caregiver stress was assessed using the Pediatric Inventory for Parents. Having strategies to support their child's participation in home-based activities was assessed using the Participation and Environment Measure (PEM). In PEM, caregivers report on strategies used to support their child's participation in home-based activities. Data were dichotomized (yes, no) to denote having participation-focused strategies and if their child received PICU rehabilitation services. Additional covariates were history of a preexisting condition, child age, length of PICU stay, and change in functional capacities at PICU discharge. RESULTS:History of a preexisting condition, time, and change in functional capacities significantly predicted caregiver stress frequency and difficulty. The interaction of having strategies-by-rehabilitation-by-time significantly predicted caregiver stress frequency and difficulty. CONCLUSION(S):Results highlight the role of early rehabilitation and the importance of working with caregivers to develop participation-focused strategies to support their child's functioning post-PICU. Families of children with a preexisting condition or those who experience a decrease in function during a PICU stay are susceptible to higher levels of stress and may be a priority population to target for rehabilitation services.
| S-EPMC6435394 | biostudies-literature
Project description:BackgroundBurst suppression in mechanically ventilated intensive care unit (ICU) patients is associated with increased mortality. However, the relative contributions of propofol use and critical illness itself to burst suppression; of burst suppression, propofol, and critical illness to mortality; and whether preventing burst suppression might reduce mortality, have not been quantified.MethodsThe dataset contains 471 adults from seven ICUs, after excluding anoxic encephalopathy due to cardiac arrest or intentional burst suppression for therapeutic reasons. We used multiple prediction and causal inference methods to estimate the effects connecting burst suppression, propofol, critical illness, and in-hospital mortality in an observational retrospective study. We also estimated the effects mediated by burst suppression. Sensitivity analysis was used to assess for unmeasured confounding.ResultsThe expected outcomes in a "counterfactual" randomized controlled trial (cRCT) that assigned patients to mild versus severe illness are expected to show a difference in burst suppression burden of 39%, 95% CI [8-66]%, and in mortality of 35% [29-41]%. Assigning patients to maximal (100%) burst suppression burden is expected to increase mortality by 12% [7-17]% compared to 0% burden. Burst suppression mediates 10% [2-21]% of the effect of critical illness on mortality. A high cumulative propofol dose (1316 mg/kg) is expected to increase burst suppression burden by 6% [0.8-12]% compared to a low dose (284 mg/kg). Propofol exposure has no significant direct effect on mortality; its effect is entirely mediated through burst suppression.ConclusionsOur analysis clarifies how important factors contribute to mortality in ICU patients. Burst suppression appears to contribute to mortality but is primarily an effect of critical illness rather than iatrogenic use of propofol.
| S-EPMC7483190 | biostudies-literature
Project description:Patients who survive initial burn injury are susceptible to nosocomial infections. Anemia of critical illness is a compounding factor in burn patients that necessitates repeated transfusions, which further increase their susceptibility to infections and sepsis. Robust host response is dependent on an adequate number and function of monocytes/macrophages and dendritic cells. In addition to impaired RBC production, burn patients are prone to depletion of dendritic cells and an increase in deactivated monocytes. In steady-state hematopoiesis, RBCs, macrophages, and dendritic cells are all generated from a common myeloid progenitor within the bone marrow. We hypothesized in a mouse model of burn injury that an increase in myeloid-specific transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homolog B at the common myeloid progenitor stage steers their lineage potential away from the megakaryocyte erythrocyte progenitor production and drives the terminal fate of common myeloid progenitors to form macrophages vs. dendritic cells, with the consequences being anemia, monocytosis, and dendritic cell deficits. Results indicate that, even though burn injury stimulated bone marrow hematopoiesis by increasing multipotential stem cell production (LinnegSca1poscKitpos), the bone marrow commitment is shifted away from the megakaryocyte erythrocyte progenitor and toward granulocyte monocyte progenitors with corresponding alterations in peripheral blood components, such as hemoglobin, hematocrit, RBCs, monocytes, and granulocytes. Furthermore, burn-induced V-maf musculoaponeurotic fibrosarcoma oncogene homolog B in common myeloid progenitors acts as a transcriptional activator of M-CSFR and a repressor of transferrin receptors, promoting macrophages and inhibiting erythroid differentiations while dictating a plasmacytoid dendritic cell phenotype. Results from small interfering RNA and gain-of-function (gfp-globin transcription factor 1 retrovirus) studies indicate that targeted interventions to restore V-maf musculoaponeurotic fibrosarcoma oncogene homolog B/globin transcription factor 1 balance can mitigate both immune imbalance and anemia of critical illness.
| S-EPMC6608024 | biostudies-literature