Pediatric critical care, or the effective and efficient care of children with critical or unstable conditions, is an important and growing subspecialty in pediatrics. The number of pediatric intensivists, pediatric intensive care units (PICUs), and pediatric intensive care beds in the United States has increased dramatically in recent years. Mortality in U.S. PICUs has fallen precipitously, yet survivors of childhood critical illness and injury remain at risk for morbidity and disability.
Much of the technology and many therapies in pediatric critical care have evolved without adequate study or have been adopted uncritically from adult, neonatal, or anesthetic practice. Because of this, the risks and benefits of much of intensive care practice remain largely unknown. Research is needed in order to make optimal decisions regarding effective critical care practices. Rigorous use of appropriate scientific methodology, deployed across a network structure, achieves the numbers of patients required to provide answers more rapidly than individual sites acting alone.
To meet this challenge, in April 2004 the NICHD put forth a request for applications (RFAs) to establish the Collaborative Pediatric Critical Care Research Network (CPCCRN). Clinical Sites and a Data Coordinating Center (DCC) were identified through a competitive application process. The Network was renewed by the same process in 2009 and 2014.
The Network is a major priority of the NICHD Pediatric Trauma and Critical Illness Branch (PTCIB) and is supported through the Cooperative Agreement mechanism (UG1 for clinical sites, and U01 for the DCC) in 5-year competitive cycles. For the 2014-2019 cycle, the CPCCRN includes seven clinical sites with large PICUs and a DCC.
The goal of the Network is to develop an infrastructure to pursue well-designed collaborative clinical trials and meaningful descriptive studies in pediatric critical care medicine. The Network seeks to reduce morbidity and mortality in pediatric critical illness and injury, and to provide a framework for the development of the scientific basis of pediatric critical care practice.
Data from CPCCRN studies constitute an important scientific resource, and public use datasets are available to qualified researchers. These data sets are administered by the Data Coordinating Center on behalf of the CPCCRN. Learn more about the CPCCRN Public Use Datasets .
The CPCCRN conducts controlled observations and objective evaluations of pediatric critical care practices, including new management and technology methodologies, in children with complex critical illnesses and injuries. The resulting data will help to balance prompt implementation of new technologies and treatments with effective evaluation of their safety, efficacy, cost/risk/benefit ratios, and effects on long-term outcomes for children and their families.
CPCCRN research priorities reflect the four topic areas described below.
Bereavement and Grief
Intensive Care Clinical Processes and Protocols
Infection and Sepsis
Bereavement and Grief
Following the death of a child in the PICU, all parents grieve. Guidance for communicating about and considering the family's grief, emotional burden, and difficult decision making remains largely anecdotal. Some bereaved parents are incapacitated for a prolonged period, a situation known as "complicated grief." CPCCRN investigators explore whether a follow-up meeting with the child's PICU physician after a child's death helps decrease complicated grief in these bereaved parents. Completed projects in this area include:
- Bereavement I. The Parents' Opinions on Physician Conference study assessed whether bereaved parents would be interested in a follow-up conference with the physician following the child's death and, if so, the desirable components and participants in the conference. This study indicated that the large majority of bereaved parents expressed an interest in such a conference and that there were consistent thematic suggestions for the potential content. Parents seek to gain information and emotional support, and to give feedback about their PICU experience.
- Pediatric Perspective Regarding a Physician-Parent Conference After Their Child's Death in the Pediatric Intensive Care Unit (Meert, et al.; 2007; PMC1993355)
- Parents' Perspectives on Physician-Parent Communication Near the Time of a Child's Death in the PICU (Meert, et al.; 2008; PMC3198033)
- Ethical and Logistical Considerations of Multicenter Parental Bereavement Research (Meert, et al.; 2008; PMC3279723)
- Accounting For Medical Communication: Parent's Perceptions of Communicative Roles and Responsibilities in the PICU (Gordon, et al.; 2009; PMC3277327)
- Bereavement II. The PICU Bereavement Study measured the incidence of complicated grief and associated risk factors in bereaved parents at 6 and 18 months, using five previously validated survey instruments. The study demonstrated that a significant number of parents exhibit complicated grief at 6 months, and a smaller but still large number of parents have complicated grief at 18 months. These results substantiate the importance of an effective intervention to prevent complicated grief.
- Complicated Grief and Associated Risk Factors Among Parents Following a Child's Death in the PICU (Meert, et al.; 2010; PMC3279721)
- Follow-Up Study of Complicated Grief Among Parents 18 Months After a Child's Death in the PICU (Meert, et al.; 2011; PMC3037801)
- Bereavement III. The Physicians' Perspectives on the Physician-Parent Follow-Up Conference study evaluated physicians' perspectives on the follow-up conference, revealing that the majority of physicians agree with the concept. In addition, physicians provided information to help guide the formulation of a content and structure for such meetings.
- Physician's Experiences and Perspectives Regarding Follow-Up Meetings with Parents After a Child's Death in the PICU (Meert, et al.; 2011; PMC3327296)
- Physicians' Conceptualization of "Closure" as a Benefit of Physician-Parent Follow-Up Meetings After a Child's Death in the PICU (Eggly, et al.; 2013; PMC3817557)
- Bereavement IV. Following the previous study of physicians, CPCCRN investigators developed a structured framework for these meetings in the Pilot Study of a Framework for Physician-Parent Follow-Up Meetings. The framework was intended to enable physicians, and perhaps other health care providers , to conduct the meetings in a predictable manner, with the ultimate goal being a randomized trial of the intervention. This pilot study evaluated the feasibility of using the framework that was developed.
- A Framework for Conducting Follow-Up Meetings with Parents After a Child's Death in the PICU (Meert, et al.; 2011; PMC3285236)
- Feasibility and Perceived Benefits of a Framework for Physician-Parent Follow-Up Meetings After a Child's Death in the PICU (Meert, et al.; 2014; PMC3867593)
Two continuing priorities of the CPCCRN Advisory Committee, especially the parents who serve on the Committee, are to improve processes of care and concentrate on functional outcomes of children requiring critical care. To provide a mechanism for measuring functional outcome, CPCCRN has undertaken the following studies.
- In the Development of a Quantitative Functional Status Scale (FSS) for Pediatric Patients study, CPCCRN investigators tested a new functional status scoring system that had been developed with 500 initial patients and validated with a test set of 250 additional patients. The FSS was compared with the Adaptive Behavior Assessment System II (ABAS II). The FSS study is complete and resulted in 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, making it well suited for large outcome studies (Pollack, et al.; 2009; PMC3191069).
- The Trichotomous Outcome Prediction in Critical Care (TOPICC) Study has enrolled more than 10,000 PICU patients and will attempt to predict the outcome of PICU admissions in a trichotomous manner, using the three outcomes of good survival, poor survival, and death. The FSS was used to assess the quality of survival. Subject accrual for this study is complete, and the data are being analyzed. If a predictive model is successfully developed, this model could be used in future studies to assess the quality of care in different intensive care units, and it may also be a useful outcome measure for interventional PICU trials.
- Ideal Time Interval for Critical Care Severity-of-Illness Assessment (Pollack, et al.; 2013; PMC3720693)
- Relationship Between the Functional Status Scale and the Pediatric Overall Performance Category and Pediatric Cerebral Performance Category Scales (Pollack, et al.; 2014; PMID 24862461)
- Pediatric Intensive Care Outcomes: Development of New Morbidities During Pediatric Critical Care (Pollack, et al.; 2014; PMID25226501)
Intensive Care Clinical Processes and Protocols
To improve the evidence base for pediatric critical care practices, CPCCRN investigators selected clinical processes that are either frequently used or very high risk and implemented the following studies.
- The Pediatric Intensive Care Quality of CPR (PICqCPR) Study is studying whether American Heart Association guidelines for proper performance of cardiopulmonary resuscitation (CPR) are utilized in the hospital setting, particularly within the PICU. This study is evaluating high-fidelity physiological data (arterial waveforms) in PICU patients during CPR. The goal is to identify areas for improving CPR performance in the PICU setting to improve diastolic coronary perfusion and enhance return of spontaneous circulation.
- Ration of PICU Versus Ward CPR Events Is Increasing (Berg, et al.; 2013; PMC3783604)
- The Bleeding and Thrombosis During ECMO (BATE) Study aims to quantify the incidence of bleeding and thrombosis adverse events in more than 500 pediatric patients requiring extracorporeal membrane oxygenation (ECMO) and to explore potential associations of complications with variations in anticoagulation protocols at different hospitals. 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 ultimate goal of this research is to eliminate bleeding and thrombotic complications during ECMO and to improve outcomes for these patients. Study recruitment is complete, and data analyses have begun.
- The Pediatric ECMO and Cefepime (PEACE) Study aims to enhance the knowledge base regarding the impact of ECMO on cefepime pharmacokinetics to help improve accurate dosing. These pharmacokinetic data will be important in ECMO patients because therapeutic drug monitoring is not available for this antibiotic, thus affecting the ability to ensure optimal drug therapy, minimal toxicity, and improve patient outcomes.
- The Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) Trials aim to determine whether therapeutic hypothermia, in which the body’s temperature is lowered and maintained several degrees below normal for a limited period of time, is as successful at treating children who experience cardiac arrest as it has been in treating adults. The THAPCA Trials were developed with input from investigators in CPCCRN and the Pediatric Emergency Care Applied Research Network (PECARN), which is funded by the Emergency Medical Services in Children program in the Maternal and Child Health Bureau at Health Resources Services Administration. The THAPCA Trials are funded by the National Heart, Lung, and Blood Institute with CPCCRN sites serving as Vanguard sites for the initial phase of the trial. The trials evaluate therapeutic hypothermia’s efficacy at increasing survival rates and reducing the risk of brain injury in infants and children who experience a cardiac arrest while out of the hospital (THAPCA-OH, ClinicalTrials.gov NCT00878644) or in the hospital (THAPCA-IH, ClinicalTrials.gov NCT00880087). Subject accrual is complete for THAPCA-OH, but continues for the in-hospital trial.
- Therapeutic Hypothermia After Pediatric Cardiac Arrest Trial: The Vanguard Phase Experience and Implications for Other Trials (Pemberton, et al.; 2013; PMC3540393)
- Rationale, Timeline, Study Design and Protocol Overview of the Therapeutic Hypothermia after Pediatric Cardiac Arrest (THAPCA) Trials (Moler, et al.; 2013; PMC3947631)
- Early Postresuscitation Hypotension Is Associated with Increased Mortality Following Pediatric Cardiac Arrest (Topjian, et al.; 2013; PMC4085105)
- Efficacy Outcome Selection in the Therapeutic Hypothermia After Pediatric Cardiac Arrest Trials (Holubkov, et al.; 2014; PMC – pending (E-pub ahead of print)
- The Measuring Opioid Tolerance Induced by Fentanyl (MOTIF) Study to examine the clinical factors associated with increased opioid analgesia dose among mechanically ventilated children in the PICU.
- Opioid Analgesia in Mechanically Ventilated Children: Results from the multicenter Measuring Opioid Tolerance Induced by Fentanyl Study (Anand, et al.; 2013; PMC3581608)
- Tolerance and Withdrawal from Prolonged Opioid Use in Critically Ill Children (Anand, et al.; 2010; PMC3275643)
- Status asthmaticus (critical asthma) 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. The Variations in Pediatric Severe Asthma Care study gathered information from the Pediatric Hospital Information System (PHIS) database for hospitals that participate in the CPCCRN and analyzed the data to evaluate variation of management of critical asthma. Large variations were found between sites within the Network, as well as between overall CPCCRN sites and the nation.
- Critical Care for Pediatric Asthma: Wide Care Variability and Challenges for Study (Bratton, et al.; 2012; PMC3298633)
- In the Critical Asthma Mortality and Morbidity Planning (CAMMP) Study,CPCCRN investigators followed up on the PHIS analysis and conducted a retrospective medical record review of all patients admitted to CPCCRN PICUs during a 5-year period. The results confirmed significant variability of asthma management between individual sites participating in CPCCRN. The results from this and the Variations in Pediatric Severe Asthma Care study indicate areas for further research concerning drug therapy and mechanical ventilation strategies for children with critical, near-fatal asthma.
- Fatal and Near-Fatal Asthma in Children: The Critical Care Perspective (Newth, et al.; 2012; PMC3402707)
- Variation of management of mechanical ventilation in pediatric patients was observed in the CAMMP study, but adult ventilator computer protocols have been successful in reducing such variation in adult critical care. In the R21-funded Translating an Adult Ventilator Computer Protocol to Pediatric Critical Care study, CPCCRN investigators have evaluated the acceptability of computer support decisions to PICU physicians and nurses.
- Weaning and Extubation Readiness in Pediatric Patients (Newth, et al.; 2009; PMC2849975)
- Variability in Usual Care Mechanical Ventilation for Pediatric Acute Lung Injury: The Potential Benefit of a Lung-Protective Computer Protocol (Khemani, et al.; 2011; PMC3589567)
- The CPCCRN Core Data Project (CCDP) obtains descriptive information about all PICU discharges from the Network Clinical Sites, based primarily on Clinical Site hospital administrative databases and provides a valuable resource to the CPCCRN by helping to stimulate new research protocols, identify potential need for non-network partners to access additional patient populations, and provide a descriptive understanding of the critically ill infants and children cared for within the network. This project provides pilot and descriptive data necessary for hypothesis generation, study design, preliminary power analyses, and recruitment projections for future studies.
- Traumatic Brain Injury (TBI) remains a leading cause of death and disability in children. Despite numerous studies to determine the best approaches for clinical management of pediatric TBI, evidence-based guidelines remain limited. The Approaches and Decisions in Acute Pediatric TBI (ADAPT) Trial is an international research study designed to evaluate the impact of interventions on the outcomes of children with severe traumatic brain injury. CPCCRN investigators are collaborating in the study, which is funded by the National Institute of Neurological Disorders and Stroke.
Infection and Sepsis
The Network concentrates on several major critical illness burdens including sepsis:
- Biomarker Phenotyping of Pediatric Sepsis and Multiple Organ Failure (PHENOMS) Study. Severe sepsis remains the leading cause of death in children worldwide. Most U.S. children dying from sepsis in the do so with multiple organ failure (MOF). Sepsis-induced MOF is a poorly understood syndrome for which treatment is directed to organ dysfunction rather than inflammation biomarker responses, such as occurs in the treatment of rheumatologic multiple system organ disease. This prospective observational cohort study aims to enroll 400 children with severe sepsis and will test the hypothesis that children with inflammation pathobiology phenotypes have: (1) increased mortality; (2) predisposing genotype and environmental risk factors; and (3) increased C-reactive protein (CRP) and ferritin levels that correlate with clinical outcomes. If patient's 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.
- Life After Pediatric Sepsis Evaluation (LAPSE) Study. Little is known about the long-term outcomes following pediatric sepsis. The purpose of this prospective observational study is to describe the post-sepsis illness trajectory through serial measurements of Health Related Quality of Life (HRQL), subject functional status, and examination of organ dysfunction, as well as individual and environmental characteristics that may influence these outcome measures.
- Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in U.S. children, especially among young infants. The Critical Pertussis Study, the largest prospective cohort ever assembled for scientific study of critical pertussis, is a project undertaken to characterize the acute course of critical pertussis in children. The project established trans-federal partnerships as well as partnerships with non-CPCCRN sites to conduct enhanced passive and active surveillance of 33,000 PICU admissions annually. Additionally, the study led to a translational partnership with a basic science laboratory funded by the National Institute of General Medical Sciences to improve understanding of the genomic and biological contributions to this persistent and often lethal disease for children. Study researchers collected detailed data on pertussis-related mortality, organ failure, level of support, disability, and family burden. The study seeks evidence of association between acute course characteristics, mortality, and long-term neurobehavioral outcomes for survivors and their families. The study is now closed to enrollment, and data analyses are currently underway.
- The CPCCRN Critical Pertussis Study: Collaborative Research in Pediatric Critical Care Medicine (Burr, et al.; 2011; PMC3439849)
- Critical Pertussis Illness in Children: A Multicenter Prospective Cohort Study (Berger, et al.; 2013; PMC3885763)
- Genome Sequences of 28 Bordatella Pertussis U.S. Outbreak Strains Dating from 2010 to 2012 (Harvill, et al.; 2013; PMC3868863)
- The Critical Illness Stress-induced Immune Suppression (CRISIS) Prevention Trial was intended to evaluate "prophylaxis" strategies used to prevent stress-induced nosocomial infection and sepsis. Nosocomial infection/sepsis occurs in up to 40% of children requiring prolonged care in the PICU. The study used a double-blind, randomized, controlled trial design to test the hypothesis that daily prophylaxis with metoclopramide, zinc, selenium, and glutamine would reduce nosocomial infection and sepsis in critically ill children. The study was terminated for futility after enrollment of 293 subjects.
- Rationale and Design of the Pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial (Carcillo, et al.; 2009; PMC2918276)
- Is "Rescue" Therapy Ethical in Randomized Controlled Trials? (Holubkov, et al.; 2009; PMC3259684)
- The Randomized Comparative Pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial (Carcillo, et al.; 2012; PMC3302948)
- The Role of the Data and Safety Monitoring Board in a Clinical Trial: The CRISIS Study (Holubkov, et al.; 2013; PMC3648617)
- Baseline Serum Concentrations of Zinc, Selenium, and Prolactin in Critically Ill Children (Heidemann, et al.; 2013; PMC3913275)
- The Cortisol Quantification Investigation (CQI) study addresses the task of studying adrenocortical function in children with sepsis and septic shock, commonly difficult to study because total cortisol measurements include protein-bound cortisol, which is not active. In the past, measurement of free cortisol has required 24-hour equilibrium dialysis. In this study, CPCCRN investigators developed and validated an ultracentrifugation method that enables free cortisol quantification within 2 hours. This study ascertains that real-time cortisol quantification is feasible to potentially help guide future research to enhance clinical decision making for cortisol replacement therapy in the PICU. An ancillary component of this study was to examine single nucleotide polymorphisms in candidate genes regulating cortisol synthesis, metabolism, and activity to determine if genetic differences were associated with variability in the cortisol response among critically ill children. The study found that the A allele at rs1941088 in the MC2R gene, which encodes the adrenocorticotropic hormone receptor, is associated with a low cortisol response in critically ill children.
- Real-Time Free Cortisol Quantification Among Critically Ill Children (Zimmerman, et al.; 2011; PMC3566572)
- A Single Nucleotide Polymorphism in the Corticotropin Receptor Gene Is Associated with a Blunted Cortisol Response During Pediatric Critical Illness (Jardine, et al.; 2014; PMID25055195)
- Benioff Children’s Hospital (University of California San Francisco)
- Children’s Hospital of Colorado (University of Colorado Denver)
- Children’s Hospital of Michigan (Wayne State University)
- Children’s Hospital of Philadelphia
- Children’s National Medical Center (Washington, D.C.)
- Nationwide Children’s Hospital (The Ohio State University)
- University of Pittsburgh Medical Center
- University of Utah Health Sciences Center (Data Coordinating Center)
In addition, previous sites within the Network include Arkansas Children's Hospital, Little Rock; Children’s Hospital Los Angeles and Mattel Children’s Hospital/University of California Los Angeles; Phoenix Children’s Hospital; University of Michigan, Ann Arbor; and Seattle Children's Hospital.