This is a prospective observational cohort study to enroll 400 children with severe sepsis to test the hypotheses that children with these phenotypes have; 1) increased mortality, 2) predisposing genotype and environmental risk factors, and 3) increased CRP and Ferritin levels that correlate with clinical outcome. If patients’ clinical outcomes are related to a spectrum of inflammation pathobiology and increased systemic inflammation biomarkers, then this will inform a paradigm shift supporting future study of the use of phenotype specific therapies, directed to normalizing CRP and Ferritin levels in children with severe sepsis induced MOF.
In GRACE-1 we will perform an open-label interventional trial to identify the optimal dose and route of delivery (IV vs SQ) for GM-CSF in children with sepsis-induced MODS, with reversal of immunoparalysis as the primary outcome variable. This will include the collection and analysis of unique pharmacokinetic data that will further inform future GM-CSF dosing strategies. We will also gather feasibility and effect magnitude and variation data that will be crucial for developing an accurate sample size calculation for a future RCT focusing on improving clinical outcomes. Lastly, we will gather preliminary data on the relationships between immune function, coagulation, and the microbiome in the setting of GM-CSF treatment. These data will be used to develop specific aims that will be part of the grant proposal that will fund the subsequent placebo-controlled RCT.
We anticipate that the GRACE program will represent a paradigm shift in the management of pediatric sepsis care in that it will demonstrate the role of patient-specific immunomodulation in promoting resolution of organ failure and reducing mortality from pediatric sepsis-induced MODS.
Bereavement I – Parents’ Perspective
Bereavement II – PICU Study
Bereavement III – Physician’s Perspective
The objective of this study was to describe physicians’ experience with and attitudes toward follow-up meetings after a child’s death. Semi-structured audio-recorded telephone interviews were conducted with PICU attending physicians and fellows from the CPCCRN affiliated children’s hospitals. Interviews were transcribed verbatim and analyzed using standard qualitative methods. Meeting content included discussing autopsy, hospital course, diagnosis, genetic risk, parent questions, family coping, and bereavement services; providing reassurance; expressing sympathy; and receiving feedback from parents. Barriers to follow-up meetings included time, scheduling, distance, transportation, language, cultural issues, physician willingness, and lack of systematic meeting initiation. Of the 70 physicians that were interviewed, 23 (33%) reported never having previously participated in a follow-up conference. Sixty-three (90%) of all physicians interviewed reported that follow-up meetings should be routinely offered. PICU physicians have a wide range of experience conducting follow-up meetings with bereaved parents. These data, along with parents’ perspectives described in prior research, provide a basis for developing a framework for follow-up conferences after a child’s death.
Bereavement IV: Pilot Study of Framework for Physician-Parent Follow-up Meetings
CPCCRN undertook several preliminary studies to gain knowledge to help us develop and test a framework for conducting physician-parent follow-up meetings after a child’s death in the PICU. We have used our research findings along with relevant literature on physician-parent communication to create a framework for physician-parent follow-up meetings after a child’s death in the PICU. We pilot tested this developed framework to refine its components and assess feasibility of implementation across CPCCRN sites.
The Parent Bereavement Study was a multicenter pilot study of video-recorded physician-parent follow-up meetings using the CPCCRN framework. Results of the pilot test were used to assess the feasibility of the framework and to refine the framework prior to conducting a randomized controlled trial of the effect of physician-parent follow-up meetings on parental bereavement outcomes. This study has been completed and the results have been published.
Cortisol Quantification Investigation (CQI)
Although the therapeutic use of corticosteroids has long existed there still remains a lack of consensus regarding the target population for corticosteroid replacement therapy. This is due, in large part, to the time consuming method of free cortisol assessment called equilibrium dialysis isolation. Cortisol Quantification Investigation (CQI) was a prospective, observational cohort study that assessed baseline total and free serum cortisol concentrations in a convenience sample of critically ill children exhibiting a spectrum of illness severity. The goal was to determine whether plasma ultrafiltration can be used in place of equilibrium dialysis by comparing the measured free cortisol following each fractionation method. If successful, this would make rapid (within hours) free cortisol measurements feasible in future CPCCRN studies.
This study was conducted on 165 critically ill children across the spectrum of illness severity. Analyses determined that centrifugal ultrafiltration fractionated free cortisol was fast and results correlated highly with equilibrium dialysis fractionated free cortisol. This study ascertains that real-time free cortisol quantification is feasible to potentially help guide future research to enhance clinical decision making for cortisol replacement therapy in the pediatric intensive care unit.
Functional Status Scale (FSS)
The purpose of the FSS (Functional Status Scale) study was to create a functional status outcome measure for large outcome studies that is well defined, quantitative, rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide range of ages and inpatient environments. This study was designed with the intention that, if successful, FSS would be used throughout the world of pediatric medicine as an assessment tool.
Functional Status Scale (FSS) domains of functioning included mental status, sensory functioning, communication, motor functioning, feeding, and respiratory status, categorized from normal (Score=1) to very severe dysfunction (score=5). The Adaptive Behavior Assessment System II (ABAS II) established construct validity and calibration within domains. Seven CPCCRN institutions provided PICU patients within 24 hours before or after PICU discharge, high-risk non-PICU patients within 24 hours after admission, and technology-dependent children. Primary care nurses completed the ABAS II.
A total of 836 children, with a mean FSS score of 10.3 (SD: 4.4), were studied. Eighteen percent had the minimal possible FSS score of 6, 44% had FSS scores of ≥ 10, 14% had FSS scores of ≥ 15, and 6% had FSS scores of ≥ 20. Each FSS domain was associated with mean ABAS II scores (P < .0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II scores (P < .001 for improvements). Discrimination was very good for moderate and severe dysfunction (ABAS II categories) and improved with FSS weighting. Intraclass correlations of original and weighted total FSS scores were 0.95 and 0.94, respectively.
The FSS study met all objectives and was determined to be well suited for large outcome studies.
Despite use of CDC recommended preventive strategies, nosocomial infection / sepsis occurs in up to 40% of children requiring long stay intensive care. Since lymphopenia and protein malnutrition are known risk factors, we evaluated whether directed nutraceutical supplements would reduce nosocomial infection / sepsis. A multicenter randomized double-blinded comparative trial was conducted to determine if enteral zinc, selenium, glutamine and IV metoclopramide (ZSGM) would reduce nosocomial infection / sepsis compared with enteral whey protein (WHEY) and IV placebo, when administered for up to 28 days of Pediatric Intensive Care Unit (PICU) stay. This study has been completed and the results have been published.
To reduce pain, anxiety, or agitation critically ill children routinely receive opioids for analgesia and sedation in the pediatric intensive care unit (PICU). Routine use of opioid therapy often leads to tolerance and dependence. The objective of this prospective, observational study was to estimate the incidence and risk factors for opioid tolerance in critically ill children and describe analgesic practices in the PICU. Significant variability in clinical practices related to opioid analgesia in PICUs makes it difficult to launch scientific efforts for reducing the complications of opioid therapy or testing key hypotheses in this area. This study has been completed and the results published.
Critical Asthma Mortality and Morbidity Planning Study
Status asthmaticus is the most common medical emergency in children today and is responsible for nearly half a million hospital admissions annually. Despite evidence that asthma hospitalizations are decreasing, asthma mortality is not.
In order to gain a better understanding of status asthmaticus, its treatment, and its overall outcomes, each PICU research team within the Collaborative Pediatric Critical Care Research Network (CPCCRN) examined its admissions records in detail for children ages 1 year to 18 years old, over 5 years for any instances of deaths resulting from a diagnosis of asthma (fatal asthma). Post-mortem data was reviewed where available. In addition, the medical records for children intubated and mechanically ventilated for asthma (near-fatal asthma) were analyzed.
This review and abstraction has enabled CPCCRN investigators to quantify the current variability of critical asthma treatment and has helped us to identify additional medical problems, such as organ failure and the relatively high intubation rate for African-American children that occurred during the patient’s near-fatal illness. Data from this study will inform development of prospective studies investigating the management of critical asthma.
Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in U.S. children, especially among young infants. Although pertussis is a well-known precipitant of critical illness, especially in infants, several gaps of knowledge about critical pertussis (pertussis associated with a PICU admission) exist. Understanding the morbidity and cost burden of severe pertussis, will inform national prevention strategies as adequate U.S. data do not exist, generate hypotheses, and help prioritize research.
Among children <18 years of age with pertussis who require hospitalization in the PICU, the aims of this multicenter study were to 1) characterize the acute course during the PICU admission; 2) assess reported health status and family impact following PICU discharge; 3) assess developmental sequelae and quality of life among infants who were less than 12 months of gestational age at time of PICU admission 12-months following PICU discharge; and 4) assess risk factors associated with developmental sequelae in infants.
A prospective cohort of children with critical pertussis was identified through the National Institute for Child Health and Human Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN) and other PICU sites utilizing existing national research infrastructure. With enhanced PICU surveillance, approximately 250 critical pertussis case-children were enrolled. Eligible pertussis cases were defined using study case definitions. Demographic and clinical information was collected through chart abstraction and parental interview. Six months after hospital discharge, health status was assessed through questionnaire administered by mail survey. Among infants <12 months of gestational age at the time of PICU admission, developmental sequelae survivor outcomes was evaluated with the validated Mullen Scales of Early Learning and potential risk factors for sequelae assessed through univariate and multivariable analyses.
Trichotomous Outcome Prediction in Critical Care
Critical care in general and pediatric critical care in particular, has developed excellent measures of severity of illness calibrated to mortality. However, severity may be reflected in subsequent morbidity as well as survival. A major challenge of critical care outcomes research is the development of methodologies that predict the full range of outcomes from normal through the range of morbidities as well as death. Critical care mortality prediction models are highly dependent on physiological system dysfunctions such as cardiovascular, neurological, respiratory, renal, metabolic, and hematological dysfunction. Yet the same dysfunction may result in intermediate and/or long-term functional status changes. ICU therapies such as steroid use and mechanical ventilation are associated with long-term sequelae including myopathy and chronic lung disease. It is logical to postulate that morbidity related to the progression of injury resulting from physiologic dysfunction such that, in the context of critical care, morbidity is an intermediate outcome between complete recovery and death.
TOPICC was a prospective observational cohort study where a probability sample of all patients under 18 years of age, who were admitted to all non-neonatal CPCCRN PICUs, were selected. The final sample size estimated in at 10,000 patients. The duration of the study was two years. During this time, the project looked to determine the optimal time window in which to collect data elements representing the initial medical and physiological condition of PICU patients at the time of admission to the PICU. Also, investigators aimed to derive and validate a predictor of three or more outcome states following pediatric intensive care; specifically death, survival with reduced functional status, and survival with normal or unchanged functional status. The ultimate goal of this study was to develop and validate a new predictive instrument to measure quality of care provided to children in PICUs across the country. This instrument will facilitate comparisons in quality of care and help inform the development of new interventions aimed at improving the quality of pediatric critical care.
Translating an Adult Ventilator Computer Protocol to Pediatric Critical Care
The purpose of this study was to evaluate a strategy for ventilator management (ventilator management protocol) that was developed in adult intensive care units for patients with Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS). The goal was to evaluate the extent to which this ventilator management protocol needs to be changed to make it acceptable for use in the pediatric ICU. We evaluated the size and scale (granularity) of the data input into the protocol and the granularity of recommendations for changes to ventilator settings. A ventilator management protocol that is scaled for pediatric use could support future research studies in the CPCCRN network and in other PICUs. The project was supported by Award Number R21HD061870 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development. This study was completed and the results are being prepared for publication.
Bleeding and Thrombosis During ECMO
Bleeding and thrombosis represent major adverse events during extracorporeal membrane oxygenation (ECMO). Complications resulting from these events can lead to death or need for long term rehabilitation support. Despite the increasing use of extracorporeal support and new technology which makes it simpler and potentially safer to apply, little scientific information regarding the predictors of bleeding or thrombosis exist.
This project sought to describe the incidence of bleeding and thrombosis in ECMO patients at CPCCRN sites, describe current anticoagulation monitoring practices and seek evidence of association between bleeding and thrombotic complications, laboratory coagulation measurements, patient characteristics, ECMO circuitry and adherence to center-specific ECMO management protocols. The ultimate goal of this research was to eliminate bleeding and thrombotic complications during ECMO and improve outcome for these patients.
This study, entitled “Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA),” evaluated whether regulating the body temperature would improve the outcome for children after cardiac arrest. There was a separate trial for children who arrested in the hospital (THAPCA-IH) and children who arrested out of the hospital (THAPCA-OH). The goal of these two randomized trials was to determine if therapeutic hypothermia improved survival with good neurobehavioral outcome in children who have had a cardiac arrest. Fever commonly occurs after cardiac arrest and is associated with worse outcome (death or brain damage). It is not known whether therapeutic hypothermia is superior to simply preventing elevated body temperature by keeping it in a normal range (normothermia). The trials were funded by the National Heart, Lung and Blood Institute (NHLBI) to enroll approximately 850 subjects at the CPCCRN centers and 27 additional sites throughout the United States and Canada. Enrollment began in September 2009. The trials are registered at ClinicalTrials.gov. For further information, visit the THAPCA website at www.thapca.org.
Extracorporeal membrane oxygenation (ECMO) provides partial or complete support for patients with severe cardiopulmonary failure, and can be used as a bridge to recovery from mechanical support/organ replacement. The impact of ECMO on the pharmacokinetics (PK) of commonly used intensive care drugs should be fully understood to ensure optimal drug therapy, minimal toxicity and improve patient outcomes.
In critically ill patients not receiving ECMO, numerous PK studies have demonstrated highly significant changes to drug exposure through interactions between the patient, pathology and the drug. The ECMO system introduces additional variables, which are inherent to the circuit itself, as well as the systemic inflammation that results from use of an extracorporeal circuit. Sequestration of drugs in the circuit, increased volume of distribution and decreased clearance are the major PK changes associated with ECMO, although the extent of such changes remains poorly characterized. The amount of variability in drug disposition and pharmacokinetics that is introduced by different circuit components is largely unknown. Therefore, the objective of Pediatric ECMO and Cefepime Study, or PEACE, was to gain preliminary data on the impact of ECMO on the pharmacokinetics of cefepime administered as standard of care to infants.
We hypothesized that the volume of distribution of cefepime would be increased, and the clearance reduced in patients receiving ECMO. Also, there would be variability in cefepime PK across different circuit types.
Cardiac arrests in children are a major public health problem. Thousands of children in the USA are treated in pediatric intensive care units (ICUs) with cardiopulmonary resuscitation (CPR) each year for sudden in-hospital cardiac arrest. Neurological outcomes following these in-hospital PICU CPR events are often abnormal. As children with neurological deficits following in-hospital CPR are a major burden for families and society, improving neurological outcomes through superior blood flow during CPR is an important clinical goal.
High-fidelity hemodynamic data was obtained during qualifying CPR Events in the ICU, and then analyzed by pediatric cardiopulmonary resuscitation field experts. This investigation’s aim was to obtain evidentiary support to associate hemodynamics (arterial diastolic pressure and end tidal carbon dioxide) during CPR with outcomes in those children who suffer an arrest within CPCCRN ICUs.
The purpose of this prospective observational study was to describe short and long-term outcomes among a moderate cohort of children surviving septic shock. In contrast to adult medicine, little is known about the long term outcomes following pediatric sepsis. For the first time LAPSE investigated the intensity and duration of sepsis-associated morbidity that persists in the weeks and months following the acute septic event. LAPSE has described the post sepsis illness trajectory through serial measurements of Health Related Quality of Life (HRQL) and subject functional status (FS). In addition LAPSE examined organ dysfunction, as well as individual and environmental characteristics that influenced these outcome measures.
We hypothesized that significant variation of HRQL and functional status would be observed following survival of severe sepsis, enabling development of suitable composite outcome measures for future interventional trials of pediatric sepsis. We further hypothesized that deterioration of HRQL and functional status following survival of severe sepsis would correlate with (1) the intensity and duration of specific organ failures that adversely affect systemic oxygen delivery and consumption during the acute illness; and (2) characteristics of the individual (chronic co-morbid conditions, personality traits) and environment (socioeconomic factors, family dynamics and parental stress).
Acute lung injury (ALI) occurs in approximately 9% of mechanically ventilated children with 80% progressing to ALI’s most severe form, acute respiratory distress syndrome (ARDS). Inhaled nitric oxide (iNO) is an important therapy for neonates with persistent pulmonary hypertension of the newborn, older children with pulmonary hypertension and patients with congenital heart disease. It has been hypothesized that iNO should benefit patients with ALI/ARDS by improving oxygenation and limiting ventilator and oxygen induced lung injury. Clinical trials, however, have not been able to prove this hypothesis. Despite lack of proof of efficacy, iNO continues to be frequently used in pediatric ALI/ARDS. The continued use of iNO may be based on bias towards intervention and the perceived lack of toxic effects of iNO. Inhaled nitric oxide is variably used among the sites within the CPCCRN. In the recently published TOPICC study, 285 (2.8%) of the 10,078 enrolled subjects received iNO during the PICU admission, which represents approximately 500 patients per year.
This study was a prospective observational cohort study.
This study used retrospective chart review of TOPICC (Trichotomous Outcome Prediction in Critical Care) database records to identify important pathophysiological processes resulting in morbidity and mortality, as well as needed therapeutic additions and advances including life support methodologies that could prevent or ameliorate morbidity and mortality, which if known could improve PICU clinical outcomes.
Mechanically ventilated children are at high risk for nosocomial infections, including ventilator-associated pneumonia (VAP). Limited understanding of the microbial and host factors associated with VAP pathogenesis has precluded development of truly effective prevention and treatment strategies. Recent evidence has revealed that the lungs, previously considered a sterile microenvironment, contain microbial populations. Study of the microbiome, the genomic content of the microbiota, is a novel approach to expand our understanding of the complexities of the airway microbiota. Interrogating the relationships between an intubated individual’s respiratory microbiota, the host’s immune response, and the disease process will provide important insights into the pathogenesis of VAP, help identify at-risk children early in the course of illness, and suggest new and more effective prevention and therapeutic strategies to improve outcomes and reduce resource utilization and costs. In this study, it was hypothesized that specific ecological patterns of the airway microbiome precede VAP and that the interaction of viral infection, bacterial populations, and the balance between immune activation and immune suppression play crucial roles in determining whether a given patient develops VAP.
This was a prospective longitudinal observational study of high risk mechanically ventilated children with systematic bacterial and viral analyses of the respiratory tract along with proteomic evaluation of the host response to determine whether specific taxa and patterns of bacterial microbiota contribute to VAP risk and whether bacterial communities are modulated by viral infection and host immune responses to increase risk of VAP.
The study was based around a multi-site longitudinal survey of parents 6 & 13 months after their child’s death in a CPCCRN-affiliated ICU. Parent characteristics and perceived therapeutic alliance were assessed at 6 months, while parent health outcomes were measured at 6 & 13 months. The study has determined the extent of therapeutic alliance bereaved parents perceived to have occurred between parents and their child’s physicians and other healthcare providers during the child’s PICU stay, as well as which therapeutic alliance is associated with parents’ health outcomes after their child’s death in a PICU.
Traumatic injury remains, by far, the leading cause of death for children outside the neonatal period in the United States. The incidence of nosocomial infection is extremely high in injured children who require ICU care and it represents an important source of morbidity and health care costs. Impairment of innate immune function is common following critical injury in adults and is characterized by a reduced capacity of whole blood to produce the pro-inflammatory cytokine tumor necrosis factor (TNF-α) upon ex vivo stimulation with bacterial lipopolysaccharide (LPS) and reduced monocyte HLA-DR expression.
We developed the capacity to perform highly standardized, generalizable, rapid functional immune monitoring in our laboratory and our preliminary data showed that children with an ex vivo LPS-induced TNF-α production capacity < 600 pg/mL were at particularly high risk for the development of nosocomial infection. Our pediatric preliminary data, along with several small adult studies, suggested that GM-CSF could reverse critical illness-induced immunosuppression. GM-CSF, FDA-approved for use in children, has a low side-effect profile, but has never been studied in critically injured children.
GIFT-1 was conducted as a dose finding study to determine the lowest tolerable dose of GM-CSF that will reverse trauma-induced immune suppression in high-risk, critically injured children. We performed multi-center dose-escalation studies in four cohorts of traumatized children, identified by presence or absence of severe traumatic brain injury (TBI) and Tanner stage (1 and >1).
CPCCRN Core Data Project (CCDP)
Touch assesses the relationship between injury region & severity with functional status at hospital discharge as well as the relationship between functional status at hospital discharge and outcomes. It includes functional status and Health Related Quality of Life (HRQoL), at 6 months after hospital discharge.
PICU Core Outcomes
This project developed a collaborative, stakeholder-informed Core Outcomes Set (COS) for pediatric critical care medicine (PCCM) research programs. A core outcome is defined as “a patient outcome, health-related condition, or aspects of health that relevant stakeholders agree are essential to assess in all clinical research studies evaluating outcomes”. The COS serves as a guideline resource for investigators to assure that outcomes most important to all stakeholders are considered in PCCM clinical research programs.
Acute Respiratory Distress Syndrome (ARDS) is a major cause of morbidity and mortality in both adult and pediatric patients, with an incidence of 200,000 patients per year in the United States. The reported mortality among pediatric patients with ARDS varies from 16% to 43%. Most clinical trials have been negative and the only therapy proven to reduce ARDS-related mortality is a lung-protective ventilator strategy. Utilizing markers of underlying biological pathophysiology, to inform treatment responsiveness, may allow targeted application of therapies and discovery of newer more elective treatments. Our preliminary data suggest that mediators in the inflammation and coagulation pathways such as sThrombomodulin (sTM) a biomarker for endothelial damage and loss of TM activity on endothelial cells, and Angiopioietin-2 (Ang-2) a mediator, of inflammation are associated with mortality among patients with ARDS.
This prospective longitudinal observational cohort study will validate the association between these biomarkers and mortality risk in children with ARDS and examine relationship of these markers with long-term morbidity and functional outcomes among survivors.