2002 Pediatric Grant Proposal

This was a proposed grant for 2002. I have not found any further information about such grant/s.

http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-02-026.html

CLINICAL TRIAL PLANNING GRANTS TO GUIDE AND IMPROVE TIMING, INTENSITY, DURATION AND OUTCOMES OF PEDIATRIC CRITICAL CARE AND REHABILITATION THERAPEUTIC INTERVENTIONS IN CHILDHOOD CARDIOPULMONARY ARREST

RELEASE DATE: July 26, 2002
RFA: HD-02-026
National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov)

LETTER OF INTENT RECEIPT DATE: October 31, 2002 APPLICATION RECEIPT DATE: November 25, 2002

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA

o Research Objectives

o Mechanism of Support

o Funds Available o Eligible Institutions

o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application

o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations

PURPOSE OF THIS RFA The purpose of the Clinical Trial Planning Grant is to provide support for the initial development and organization of an effective research team and the elements essential for conducting successful clinical trials. The National Center for Medical Rehabilitation Research (NCMRR) of the National Institute of Child Health and Human Development (NICHD) wishes to use its program in pediatric critical care and rehabilitation research (PCCR) to support clinical trials focused on evaluating the timing, intensity, duration and outcomes of pediatric critical care and rehabilitation interventions for childhood cardiopulmonary arrest.

RESEARCH OBJECTIVES

Background Outcomes after childhood cardiopulmonary arrest remain suboptimal, despite attempts to standardize rapid intervention and advanced pediatric life support. Neurodevelopmental devastation after restoration of cardiopulmonary function is too common. The effects on the family unit of caring for children after such an occurrence are well known to every pediatric intensivist, rehabilitation specialist and general pediatrician. Both profound neurodevelopmental change and persistent vegetative state are common, enduring, and expensive in terms of financial and social costs to the larger community, as well as to the family.

In the United States, 16,000 children are estimated to die of unexpected cardiopulmonary arrest (CPA) each year. Remarkably, overall incidence in children (survivors and non-survivors) remains somewhat difficult to assess, although one recent prospective study found an overall annual incidence of 19.7/100,000 children.

Although the data set created by the current literature remains somewhat ambiguous, the current figures assigned to survival to hospital discharge among children arriving at the hospital in both cardiac and pulmonary arrest is reported as two to eight percent. Of survivors of combined cardiac and respiratory arrest, neurological devastation is likely in a high proportion of children: some studies find poor functional outcomes in virtually all such survivors.

One study of children discharged from the hospital in a persistent vegetative state showed that death or only minimal awareness was the uniform outcome in subsequent years, and substantial costs (greater than $90,000 per year per patient) were sustained. The prognosis is better for children who experience a respiratory arrest alone. A collective review of available studies shows that there is a 75 percent survival to discharge rate among children arriving at the hospital apneic but with a palpable pulse. The same study showed a much higher percentage of children with a good neurologic outcome, as compared to those with both cardiac and pulmonary arrest.

In-hospital cardiopulmonary arrest is also known to carry a better prognosis, but there is considerable variability in reported outcomes. As the initiation and withdrawal of resuscitation, critical care and rehabilitative strategies in childhood cardiopulmonary arrest take place in the context of tragedy, decision making is exceptionally difficult, and the lack of substantial data and uniformity of practice standards adds to the agony for patients, families and practitioners.

The challenge for the health care system is to develop and universally adopt guidelines to avoid futile resuscitation and to improve the outcomes in survivors. The emerging discipline of pediatric rehabilitation is providing interventions for some special needs children that may be beneficial in promoting improvements in functional areas such as cognition, mobility, performance of self-care, community and school integration, and family/caregiver education and support.

Important questions, however, remain regarding the effectiveness of individual treatment strategies, as well as the organization and intensity of pediatric rehabilitation services that realistically can be offered. Similarly, innovative strategies to improve outcomes in the acute setting and minimize organ damage are needed. Hypothermia, institution of extracorporeal life support systems, and development of new therapies for the prevention and treatment of hypoxic-ischemic encephalopathy are a few of the newer therapeutic avenues under discussion in the literature.

The roles of excitotoxic amino acids, proteolytic enzymes, free radicals, nitric oxide and leukocyte biology are not precisely understood. The importance of reperfusion injury after anoxic-ischemic encephalopathy is emerging in the critical care literature. As injury and cellular repair mechanisms, especially neuronal apoptosis and necrosis and neuronal stem cell biology, are better understood, potential avenues for therapeutic interventions are developed. Such therapeutic strategies may be of different value in immature vs. mature animals and humans.

The increasing presence of comorbidities in childhood cardiopulmonary arrest parallels the increased numbers of children with special needs in our communities. The increasing numbers of children with impaired pulmonary function, immunologic disability, post-surgical cardiac conduction and functional limitations, and impaired cognition and mobility, impose additional complexity. In planning for clinical research addressing improvement for childhood victims of cardiopulmonary arrest, investigators should take into account the differences in appropriate strategies for special needs children, and how comorbidities may influence therapeutic outcome.

Treatments delivered by rehabilitation specialists can dramatically increase the quality of life and functional independence for individuals following devastating illnesses. There is presently inadequate evidence in the pediatric and rehabilitation literature to substantiate the use of rehabilitation treatment as effective for minimizing disability in survivors of cardiopulmonary arrest. These factors underscore the need to determine efficacious rehabilitation strategies for these disorders. Such evidence is urgently needed as the population of childhood cardiopulmonary arrest survivors increases.

Central to rehabilitation is the primary goal of functional independence and return to pre-injury or pre-surgical status. Where such goals are unrealistic, or adequate data to support realistic goal- setting is lacking, the choice, timing, intensity and duration of therapeutic interventions must be subjective, and the influence of socioeconomic disparities maximal. Although these issues underlie medical rehabilitation practice, few studies have demonstrated the most appropriate treatment course to help guide clinical practice in cohorts of cardiopulmonary arrest survivors.

Similarly, there is a lack of adequate evidence to demonstrate which components in the resuscitation continuum are most critical in preventing neurological devastation in childhood arrests. It might be hypothesized that oxygenation must be restored to pre-arrest levels, but is this to be prioritized over restoration of circulation or metabolic manipulation (hypothermia, substrate)? Is enhanced oxygen delivery of benefit in the child in cardiopulmonary arrest? Some studies suggest that increased oxygen concentration in the injured brain may exacerbate reperfusion injury via oxygen radical formation and lipid peroxidation.

In a few animal models, neurologic outcome was less favorable in subjects resuscitated with higher inspired oxygen concentrations. Inadequate data exist regarding the timing, intensity, and duration of resuscitation treatment interventions and outcomes after childhood cardiopulmonary arrest. For the community of clinical rehabilitation practitioners, the techniques and therapies to maximize functional ability in cohorts of childhood cardiopulmonary arrest survivors have not been demonstrated empirically.

Additionally, the data substantiating the time frame of rehabilitation interventions to maximize outcome is vital to planning for such services. Due, in part, to the diversity of the needs and goals of the post-arrest population, there is little agreement among professionals as to treatment strategies, the efficacy of rehabilitation, or desired or achievable outcomes.

What is the sequence by which different areas of function recover following arrest, and how can this information be used to design/guide intervention? Should rehabilitation begin in the pediatric intensive care unit (PICU)? If so, which interventions can or should be implemented in the intensive care unit? If rehabilitation intervention is initiated in the PICU immediately after resuscitation, is outcome enhanced? Is there an optimum time for aggressive intervention? Is twice-a-day physical therapy more effective than once-a-day therapy? Is there a point in time when one or the other is more effective? The relationship between the choice, timing, intensity and duration of treatment and subsequent follow up is an issue that pervades all pediatric critical care and rehabilitation practice. The importance and timeliness of this topic was highlighted at the NICHD Patient Learning During Medical Rehabilitation Conference (1998), the NICHD Neonatal Follow-up Conference (June, 2002), and the NICHD Pediatric Critical Care Research Planning Conference (May, 2002).

The purpose of this initiative is to encourage studies that evaluate models of providing pediatric critical care and rehabilitation that consider choice, timing, intensity and duration of treatment. In addition, current practice has evolved in response to reimbursement guidelines, rather than clinical evidence.

This RFA builds on the recommendations of these workshops, and encourages clinical research studies that will establish optimal delivery schedules and the kinds and amounts of pediatric critical care and rehabilitation services for patients in different diagnosis groups or categories. Research Scope Current constraints on clinical researchers make the complex and time- consuming process of planning Phase III clinical trials problematic, especially in the fields of pediatric critical care and rehabilitation where there is not a well-established clinical research infrastructure.

These planning grants will provide a mechanism for early peer review of the rationale and design of the potential clinical trial, and provide successful applicants resources to assist them in the development of detailed clinical trial study plans and collaborations. It is hoped that these Planning Grants will help to facilitate the development of clinical trial projects in the NCMRR pediatric critical care and rehabilitation research (PCCR) program.

The range of activities that may be supported by this Clinical Trial Planning Grant includes:

1. Development of a detailed experimental design, including: translation of the clinical question into a statistical hypothesis; determination of the sample size and duration of the trial; selection of endpoint(s) and data to be collected; creation of inclusion/exclusion criteria.

2. Development of specific protocols, including: patient selection and informed consent procedures; randomization and masking procedures; data collection techniques; treatment administration and dose/quantity measurements; follow-up and quality control procedures.

3. Development of detailed plans for patient recruitment and retention, including women and minority individuals, and plans for recruitment outreach.

4. Identification of other personnel necessary to perform the proposed research, including statisticians, data managers, and study coordinators.

5. Identification of the physical resources necessary to perform the proposed research, including clinical space and equipment that is accessible to subjects and researchers with disabilities.

6. Selection of specific methods of data analysis.

7. Evaluation of models of the pediatric critical care and rehabilitation treatment processes, including: involvement of various professional disciplines, team approaches and treatment settings, coordination of health care systems and resources.