NIH Roundtable on Emergency Trauma Research

NIH EMERGENCY MEDICINE RESEARCH ROUNDTABLES/SPECIAL CONTRIBUTION

NIH Roundtable on Emergency Trauma Research Charles B. Cairns, MD, Ronald V. Maier, MD, Opeolu Adeoye, MD, Darryl Baptiste, PhD, William G. Barsan, MD, Lorne Blackbourne, MD, Randall Burd, MD, PhD, Christopher Carpenter, MD, MSc, David Chang, PhD, William Cioffi, MD, Edward Cornwell, MD, J. Michael Dean, MD, MBA, Carmel Dyer, MD, David Jaffe, MD, Geoff Manley, MD, PhD, William J. Meurer, MD, MS, Robert Neumar, MD, PhD, Robert Silbergleit, MD, Molly Stevens, MD, MSCE, Michael Wang, MD, Debra Weiner, MD, PhD, David Wright, MD Roundtable External Participants and Roundtable Steering Committee and Federal Participants*

Study objective: The National Institutes of Health (NIH) formed an NIH Task Force on Research in Emergency Medicine to enhance NIH support for emergency care research. The NIH Trauma Research Roundtable was convened on June 22 to 23, 2009. The objectives of the roundtable are to identify key research questions essential to advancing the scientific underpinnings of emergency trauma care and to discuss the barriers and best means to advance research by exploring the role of trauma research networks and collaboration between NIH and the emergency trauma care community. Methods: Before the roundtable, the emergency care domains to be discussed were selected and experts in each of the fields were invited to participate in the roundtable. Domain experts were asked to identify research priorities and challenges and separate them into mechanistic, translational, and clinical categories. During and after the conference, the lists were circulated among the participants and revised to reach a consensus. Results: Emergency trauma care research is characterized by focus on the timing, sequence, and time sensitivity of disease processes and treatment effects. Rapidly identifying the phenotype of patients on the time spectrum of acuity and severity after injury and the mechanistic reasons for heterogeneity in outcome are important challenges in emergency trauma research. Other research priorities include the need to elucidate the timing, sequence, and duration of causal molecular and cellular events involved in time-critical injuries, and the development of treatments capable of halting or reversing them; the need for novel experimental models of acute injury; the need to assess the effect of development and aging on the postinjury response; and the need to understand why there are regional differences in outcomes after injury. Important barriers to emergency care research include a limited number of trained investigators and experienced mentors, limited research infrastructure and support, and regulatory hurdles. Conclusion: The science of emergency trauma care may be advanced by facilitating the following: (1) development of an acute injury template for clinical research; (2) developing emergency trauma clinical research networks; (3) integrating emergency trauma research into Clinical and Translational Science Awards; (4) developing emergency care–specific initiatives within the existing structure of NIH institutes and centers; (5) involving acute trauma and emergency specialists in grant review and research advisory processes; (6) supporting learn-phase or small, clinical trials; (7) performing research to address ethical and regulatory issues; and (8) training emergency care investigators with research training programs. [Ann Emerg Med. 2010;56:538-550.] 0196-0644/$-see front matter Copyright © 2010 by the American College of Emergency Physicians. doi:10.1016/j.annemergmed.2010.05.029

*All participants are listed in the Appendix.

SEE RELATED ARTICLES AND EDITORIALS, P. 522, 551, 565, 568. INTRODUCTION The National Institutes of Health (NIH) Roundtable on Emergency Medicine Research on Trauma, cosponsored by the National Institute of General Medical Sciences and the National Institute for Neurological and Stroke Disorders (NINDS), was 538 Annals of Emergency Medicine

held on June 22 and 23, 2009. The overall goal of the roundtable was to engage basic, translational, and clinical researchers in a discussion to assist the NIH in prioritizing support for research in acute injury conditions, with an emphasis on time-sensitive diseases requiring rapid evaluation and treatment. Emergency trauma research includes discovery and characterization of the mechanisms and response to injury, translational research, and applied clinical research.1-3 Volume , .  : November 

Cairns et al The primary challenge of emergency trauma care involves efficient management of undifferentiated patients with acute injury that have the potential for significant morbidity and mortality, and in whom the effectiveness of therapy is time critical in the range of minutes to hours.3 Mechanistic research that delineates the timing, sequence, and duration of causal molecular and physiologic events in acute injury is essential to developing optimized diagnostic and therapeutic strategies. Clinical research that improves the accuracy, speed, safety, and cost-effectiveness of diagnosis and treatment in the emergency care setting has the potential to both improve outcomes and reduce resource use.1,3,4 Real-time bedside strategies that guide diagnostic and therapeutic approaches and monitor response to therapy will facilitate personalized optimization of care interventions. Finally, research into diagnostic and therapeutic strategies that take into account the characteristics of the emergency care environment (eg, patient populations defined by broad clinical presentations and out-ofhospital settings) is most likely to have lasting and broad influence. Unique aspects of emergency trauma clinical research because of the time sensitivity of disease and critical condition of patients include consent and enrollment issues, conduct of research in the out-of-hospital setting, a wide range of patient ages, and the effect of environmental factors on the host response to injury.1-4 The effect of emergency trauma research on society could be profound because injury remains the leading cause of productive years lost in the United States.1,5

MATERIALS AND METHODS Goals of the Roundtable In preparation for the roundtable, the NIH released a request for information in June 2008 to solicit input on needs and challenges in the field of emergency medicine research.6 Respondents to the request for information individually identified with a large group of professional organizations spanning the adult and pediatric fields of emergency medicine, trauma, and critical care, along with nursing and emergency medical services (EMS) providers. The largest group of diseaseoriented responses to the request for information was classified under the topics of general trauma and neurologic injuries, including traumatic brain injury and spinal cord injury. Other injury areas identified included burn injury, out-of-hospital environments, and special populations such as children and geriatric patients. Within these injury domains, the non-diseaserelated responses were largely related to diagnosis/monitoring, therapeutic interventions, out-of-hospital care, and epidemiology. There have been few rigorous scientific evaluations of important questions in these areas. Of even more importance is the fundamental lack of a process to perform programmatic research in out-of-hospital (EMS) environments and to translate injury-related research from adults to children (and potentially vice versa). Volume , .  : November 

NIH Roundtable on Emergency Trauma Research Other fundamental issues identified included challenges in consent, the time-sensitive interactive pathobiology among multiple organ systems, and use of undifferentiated signs and symptoms involved in emergency trauma research. This research inherently crosses the missions of multiple individual NIH institutes and centers. The structure and orientation of the NIH and its institutes and centers as a cluster of silos was perceived as a barrier to emergency medicine research. The overall goal of this roundtable was to have an open discussion about emergency trauma research and to highlight the gaps that should be of high priority for research support. The primary intended audience for this report will be the office of the Director of the NIH, along with leadership of the NIH institutes and centers, the recently developed Emergency Care Coordination Center, the US Department of Health and Human Services, and researchers in acute illness and injury.

RESEARCH AGENDA: PROPOSALS AND CHALLENGES Clinical Trials in Emergency Trauma Injury remains the leading cause of productive years of life lost in the United States.1 Furthermore, rapid diagnosis and early treatment in patients with acute injury have been shown to improve patient outcomes, prevent long-term disability, and decrease health resource use.3 The intersection of the timing and severity of injury and its importance to defining the “acute injury phenotype” is an area in which greater discovery will be important to the design of future clinical research. Understanding the timing and sequence of events on the patient level leading to the progression of injury is fundamental to the conduct of successful studies and generation of high-quality data. The emergency department (ED) and out-of-hospital settings represent unique potential laboratories for injury research because of their all inclusive populations, including groups frequently underrepresented in medical research (minorities, economically disadvantaged, lower level of education, lacking in health insurance, all ages).3,4 In addition, these settings allow for collaboration and integration between multiple specialties and disciplines.1,2 These settings are also unique because of the scope and severity of clinically important conditions.7 For example, multiple organ system trauma is important and common in clinical practice, yet it is uncommonly incorporated into experimental research models. This discordance results in an important void of prospective human clinical trials in favor of retrospective studies based on observational data sets, often with limited data. The clinical complexity of trauma will require collaboration between basic, translational, and clinical scientists for experimental modeling of bench-to-bedside research addressing mechanisms, diagnosis, treatment, and prevention of traumatic injury. Emergency trauma research will require a better understanding of events and interventions early in the postinjury period. Little is known about traumatic events in the out-of-hospital setting.8 Thus, research into these events will Annals of Emergency Medicine 539

NIH Roundtable on Emergency Trauma Research require research across multiple settings, including the out-ofhospital (EMS), ED, and inhospital locations. The response to injury across the developmental spectrum from infancy through geriatric age needs further definition. A fundamental question in postinjury deterioration in geriatric patients is whether it is the result of differences caused by aging or the result of preexisting comorbid disease. Conversely, in infants and children, an understanding of the effect of early development will be required to further characterize the injury response. Incorporation of an acute care phenotype may require different research approaches and alternative trial designs. These approaches could include a therapy individually optimized to each individual in the trial (similar to early goal-directed therapy in sepsis). This would tailor the phenotyping of the acute injury state to the treatment goals and study outcomes. Timedependent surrogate outcomes for injury interventions are also needed. This need for individualization and time-dependent surrogates has not been addressed well by contemporary clinical trial designs. There are challenges in the consent and enrollment process that are unique to emergency research.1-4 The time-sensitive nature and severity of the disease frequently preclude the possibility of standard consent processes. Although there are provisions to allow for studies with waiver or exception from informed consent for emergency research, these consent options are difficult to implement and uncommonly used.3 Challenges to the use of expedited or waived consent provisions include varying comfort of local institutional review boards in the interpretation of “common rule” provisions, challenges and costs of community consultation, and lack of standardization in public disclosure.3 Because of these challenges, there is the potential for bias against acute care research because of a lack of standardized approaches or lack of content expertise in acute conditions. Finally, adoption of the “common rule” is not even universal throughout the federal system. Because of these issues, a centralized process for acute illness and trauma research would be useful. There is the precedent of the National Cancer Institute, which developed a central institutional review board to standardize study processes, develop consent approaches, and provide support for local institutional review boards. A centralized institutional review board, potentially at the NIH, with domain expertise in acute illness and injury and the difficulties inherent in emergency research could be very beneficial. The development of a common consent template for an institutional review board review that explained issues in the context of acute research would be valuable. These consent templates could discuss approaches that are sensitive to the needs of acute care research. These consent approaches include verbal, short form, waived, and exception approaches.4 Many current grant review panels and NIH study sections lack content expertise on consent and enrollment issues in acute illness and trauma research. For example, there is no guidance to 540 Annals of Emergency Medicine

Cairns et al study sections on how to review human subjects protection in acute care research. With the potential for a lack of content expertise in acute care research, there is the potential for systematic bias against acute care on study sections. A solution could be the development of a transinstitute review body for acute care research, which could provide guidance to study sections on the suitability of consent and enrollment plans for proposed clinical research. Given the variation in the timing and care settings of acute care research, larger study populations may be required to adequately test interventions. Many currently used research protocols greatly limit the number of eligible patients, can be complicated to implement, and are relatively insensitive to the timing of interventions. One practical solution would be the implementation of large simple trials. These pragmatic trials could capture a large patient population and be designed for quickly implemented interventions using streamlined protocols and broader inclusion criteria. Larger sample sizes will be required because of diagnostic uncertainty as interventions are targeted earlier after injury. Understanding of the longitudinal course of injury progression (from seconds to minutes to hours) is extremely limited for acute injury. Thus, earlier patient phenotyping based on the mechanism of disease as the basis for the intervention will be required. In addition to traditional approaches of mechanism of injury, organ system level, and physiologic characterizations, the phenotyping approach will probably require molecular characterization of genomic, proteomic, and metabolomic elements. Statistical approaches that address misclassification may also be important because trials that enroll or observe patients earlier and earlier will have more uncertainty about the accuracy of the diagnosis. These challenges exist particularly in out-of-hospital settings, especially in rural areas. Interventional studies in these settings and other austere environments may be particularly relevant to combat and remote locations. Most current studies, including analyses of administrative databases, prospective observational studies, and clinical trials, do not have a good mechanism to link to what happens to patients either before or after they leave the hospital. Integration of out-of-hospital data to ED and hospital data is needed to better address the full time spectrum of emergency and trauma research. Federal privacy rules seriously impede the ability to link EMS and hospital data. Therefore, the ability to follow individual patients through the key units of service during an episode of care postinjury is limited.3 A potential solution would be the development of a universal unique patient identifier to link information from the National Highway Traffic Safety Administration and other (National Emergency Medical Services Information System, National Emergency Department Sample, National Inpatient Sample) databases. Template for Acute Injury Clinical Research A standardized approach would be valuable to the appropriate design, review, and conduct of acute injury research. A proposed template is presented in Table 1. This template Volume , .  : November 

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Table 1. Template for clinical research in acute trauma. Component Patient identification Consent and enrollment

Aspects

Solutions

Characterization of injury acuity over time Characterization of severity of injury over time Rapid strategies for enrollment Time-sensitive consent approaches All-inclusive populations

Acute injury phenotype

Rapid, definitive diagnostic strategies Time-dependent acuity of injury Bedside monitoring of disease and effect of therapies

Specialized settings

Incorporate out-of-hospital, ED, operating room, ICU, and rehabilitation clinical settings Interdisciplinary and specialty collaboration All-inclusive populations, including underserved and underrepresented groups Pediatrics and geriatric populations

Special populations

Comorbidities

Study design considerations

General system injury Central nervous system injury Combined general system and central nervous system injury Preexisting and associated conditions Inclusion population broader than targeted population Adaptive trial designs Heightened need for preliminary studies Appropriate follow-up evaluations

Development of rapid diagnostics Characterization and definition of acute injury phenotype NIH help on HIPAA consent and databases Central institutional review board for NIH emergency and trauma research (transinstitute) Transfederal agency central institutional review board Federal support of institutional review board reciprocity Clinical Translational Science Institutes support of emergency trauma consent and enrollment initiatives Development of EFIC, waiver, verbal, short-form consent approaches NIH specialized qualified reviewers to CSR and institute Need to rapidly phenotype injury Diagnostic approaches consistent with injury mechanisms Timing and severity markers of injury and host response Biomarkers (genomic, proteomic, and metabalomic) Develop meaningful surrogates for therapeutic outcomes Theragnostics EMS system integration and standardization Must assure specialty integration Specialized geriatric settings Recognize aging vs disease vs trauma effects Pediatric settings Account for ontogeny and aging effects Recognize complexities in predictive modeling Recognize premorbid function

Standardization of care Protocolized care Harmonization Outcomes database linkage Request for information better acute injury trial design NIH requires acute injury study template Acute researcher input into review for directed programs Clinical Translational Science Institutes wiki for social networking

EFIC, Exception from informed consent; CSR, Center for Scientific Review.

would address key issues in patient identification, consent and enrollment, disease characterization, specialized care settings, special populations, comorbidities, and study methodology, including the following: ● Acute injury patients need to have a firm characterization of the timing and severity of the injury. This will require rapid diagnostic strategies. In addition, this characterization needs to be monitored over time, with bedside monitoring of disease and effect of therapies. ● Enrollment strategies must be rapid; thus, consent approaches need to be time sensitive and apply to broad populations. ● Study protocols need to incorporate all appropriate care settings, including EMS, ED, operating room, ICU, and rehabilitation facilities, thus requiring interdisciplinary and specialty collaboration. Volume , .  : November 

●

Study protocols need to incorporate the needs of and injury impact on special patient populations, including pediatric and geriatric patients. ● Study protocols need to account for comorbidities, including concomitant general system trauma, central nervous system injury, intoxication, substance abuse, and preexisting conditions. ● Studies will need to incorporate optimal study designs, including enhanced inclusion strategies, adaptive trial designs, individualized treatment regimens, and appropriate follow-up and outcome evaluations. Coordination of acute injury clinical research could facilitate the review of research proposals, as well as integrate efforts across multiple institutes and medical disciplines. A specific centralized source listing currently funded projects in acute injury, investigators with acute care expertise, and guidance on Annals of Emergency Medicine 541

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Table 2. Integrating clinical research approaches: example of postinjury hemorrhagic shock. Approach Mechanistic

Translational

Clinical

Immediate Opportunity

Long-Term Objective

What is the time course and sequence of events that lead to acute and delayed organ failure during and after hemorrhagic shock? How can we characterize the level of severity of the injury response over time? What is the effect of sex and developmental status on the injury response? What causal mechanisms are best therapeutic targets? What are the optimal methods for maintaining tissue oxygen delivery during life-threatening hemorrhage? What bedside diagnostic and monitoring tools can be developed or used to guide better goal-directed resuscitation? What novel, time-sensitive therapies or combination of therapies improves both acute and long-term outcomes in patients with life-threatening hemorrhage? What novel, bedside diagnostic and monitoring techniques can guide the selection, dosing, and duration of therapies to improve outcome in life-threatening hemorrhage?

Create animal models of hemorrhagic shock that incorporate these time and severity relationships to better reflect human clinical phenotypes, including very young, older, and those with comorbid conditions. Develop molecular patterns of the injury response specific to the severity and duration of the injury.

the conduct of acute injury clinical trials could serve as a valuable resource for investigators, reviewers, and administrators. This NIH source could complement the efforts of the Emergency Care Coordination Center to develop a search engine for emergency-related grant opportunities across multiple agencies. As mentioned, many current grant review panels and NIH study sections lack content expertise on issues of acute illness and injury research. The further development of special emphasis panels would ensure that sufficient acute illness/injury content expertise is brought to the review of acute injury research. The Clinical Translational Science Institutes (awarded through the Clinical Translational Science Institutes program) may be another mechanism to facilitate the conduct of acute illness and injury research.9 Traditional NIH-funded institutional clinical research programs such as General Clinical Research Programs have focused on protocols in relatively stable patients in a set research location within the hospital. Research in acute injury and illness will require specialized protocols in different hospital settings, including the ED, ICU, and operating rooms. Thus, acute phase research has been historically underrepresented at the General Clinical Research Center and even Clinical Translational Science Institutes level. Further guidance and support from NIH will be required to enable acute injury research across the Clinical Translational Science Institutes.9 Specific Example Conditions: Post-Injury Hemorrhagic Shock and Central Nervous System Injury General and central nervous system trauma is a leading cause of morbidity and mortality, yet successful clinical interventional trials remain elusive.10 Yet there is evidence that therapeutic interventions are beneficial. For example, the wide variations in acute central nervous system injury outcomes (mortality from 542 Annals of Emergency Medicine

Move the tools that achieve immediate opportunities to the bedside—must be usable in initial clinical care, minutes to hours deployable.

Create new national standards and guidelines to ease consent and enrollment for those participating in injury research, recognizing that current waiver/exemption criteria do not fully address the demands and needs. Train the future science leaders for these efforts.

traumatic brain injury varies from 18% to 65% by center) suggest that there are therapeutic approaches that are beneficial and, conversely, those that are potentially detrimental. There remain fundamental challenges to the design and conduct of clinical trials in acute injury. There is a lack of adequate characterization of premorbid (preinjury) health status. Thus, the outcomes of injury trials should be designed in a way that is individualized. As an example, a head-injured 30year-old may need to return to work to achieve an excellent outcome; however, a head-injured 90-year-old may need to be able feed himself to achieve an excellent outcome. In addition, further characterization of the severity of injury may be required. For example, frontal contusions represent a specific disease within central nervous system injury in which the current research does not provide adequate information to phenotype. Additional measures such as cognitive testing may be needed to better define both disease severity and outcome of interventions. It is also important to tailor acute phenotypes to mechanisms of the injury response, which will require the integration of mechanistic translational and clinical approaches for both general trauma (Table 2) and central nervous system injury (Table 3). This will require more attention to clinical correlates in experimental studies. For example, animal models that involve pretreatment with an agent inherently do not translate well to human trials with a 12- to 24-hour treatment window. Use of an integrated generalized template for trial design (Table 1) in both general trauma and central nervous system injury could help in the evaluation and design of trials. This integrated approach could assess for clarity in entry criteria and also emphasize need for a mechanistic approach to phenotyping and the response to interventions. Specific requests for proposals for better acute injury/illness trial designs would facilitate the evolution and incorporation of this template. Such proposals Volume , .  : November 

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Table 3. Integrating clinical research approaches: example of central nervous system injury. Approach

Immediate Opportunity

Solutions

Mechanistic

What are the time course and sequence of molecular events that cause neuronal dysfunction and death after central nervous system trauma? How do these change according to injury severity, developmental status, sex, comorbid conditions, and polytrauma? What causal mechanisms are best therapeutic targets?

Translational

What therapies improve neurologic outcome after traumatic brain and spinal cord injury, and what are the optimal timing, dose, and duration of these therapies, either applied individually or in combination? What bedside diagnostic and monitoring tools can be developed or used to guide better guide therapy?

Clinical

What novel, time-sensitive therapies or combinations of therapies improve outcome in patients with traumatic brain or spinal cord injury? What novel, bedside diagnostic and monitoring techniques can guide the selection, dosing, and duration of therapies to improve outcome in central nervous system injury?

Create methods and technology (ie, bioassay, biomarker, imaging) to serially measure the time course and sequence of causal molecular events in animal models of central nervous system injury. Compare the time course and sequence of causal molecular events in different age groups and sexes, and in models with comorbid conditions, including polytrauma. Recruit grant reviewers with understanding the timing and sequence of emergency and acute injury. Develop SEP to focus on time course, sequence, and measurement of mechanisms in acute injury Requests for applications to address need for biomarker for time course and sequence of injury mechanisms Move the tools that achieve immediate opportunities to the bedside— usable in initial clinical care and deployable within minutes to hours. Marker for injury mechanism, timing, and severity. Marker for interventional effect (response to therapy) Develop “-omic” approaches to phenotyping over time. Facilitate collaborations with other fields (engineering, analytic sciences) Collaborative Activities to Promote Translational Research (NINDS) supplemental grants for collaborations Development of a preclinical network consortium Need to identify mechanism of injury (or surrogate). Need to monitor mechanistic proxy of intervention. Create new national standards and guidelines to ease consent and enrollment for those participating in injury research, recognizing that current waiver/exemption criteria do not fully address the demands and needs. Encourage T2 research Community partner engagement in Clinical Translational Science Institutes Multidisciplinary teamwork approach to clinical research Effective clinical research training and mentor programs

SEP, Special Emphasis Panel.

could explore new clinical trial simulation testing and the incorporation of Bayesian methods in which a learning phase is followed by a confirmatory phase. Furthermore, the NIH should advocate for a team approach to acute central nervous system injury clinical research in which emergency medicine, trauma surgery, neurosurgery, critical care, and neurologic rehabilitation are all involved. Observational Patient-Oriented Research Because clinical trials generally have strict inclusion criteria and consent requirements, they do not yield unbiased populations of patients with diseases of interest. Thus, important advances of knowledge in the field have come from observational studies of broad databases. For example, the Traumatic Coma Databank, which has data that are more than 30 years old, has provided most of the humanlevel data about the degree to which hypoxia and hypotension cause secondary injury and degrade clinical outcomes in traumatic brain injury.11 In addition, guideline Volume , .  : November 

adherence and implementation research are other areas that benefit from observational research approaches. Furthermore, there is a need to update the epidemiology and progression of acute injury conditions. This observational approach to acute injury phenotyping could also complement efforts for prospective acute injury trials. Outcome measures for acute injury are needed that capitalize on common data elements available in observational databases. Registries targeted to critical research questions in acute injury could be helpful. In addition, federally funded clinical trials in injury should be encouraged to collect common data elements in usable form. Incorporation of standardized common data elements would allow for pseudoexperimental designs and prospective cohort studies to address important questions not answerable by clinical trials. Such studies may be able to provide meaningful information based on the differences in outcomes across care centers. There is need for the development of a formal traumatic research infrastructure. This infrastructure could be similar to Annals of Emergency Medicine 543

NIH Roundtable on Emergency Trauma Research the one built through National Cancer Institute for the “war on cancer.” This would allow for a “war on trauma,” with attendant emphasis on advancing discovery and improving health. A template for this infrastructure could be the Resuscitation Outcomes Consortium epistry, which required substantial training and standardization across study sites. Analysis of standardized data enabled the discovery of 100% magnitude differences in resuscitation survival among Resuscitation Outcomes Consortium study sites.11 Although the epistry project has been a highly useful aspect of the Resuscitation Outcomes Consortium, it was not initially funded through conventional NIH means. Linkage of patient-oriented outcomes to mechanisms of injury progression would be integral to better understanding the timing and sequences of the injury response. National Cancer Institute expertise in database development would be beneficial to the development of an acute injury data set. In addition, it may be useful to try to match common data elements across NIH and other federal agencies. It would also be important for EMS to standardize and integrate data elements into this larger data set. The development of a standardized acute injury outcomes database could lead to better population-based perspective on injury. Embedding more detailed data on injury conditions of interest (head trauma) within the design of a nationally representative survey such as the National Hospital Ambulatory Medical Care Survey would have substantial appeal. Also it may be helpful to intersect with national efforts to standardize electronic medical records and clinical billing. Finally, data sharing and the production of publicly available data sets is currently just a check box in scientific review of clinical trials, rather than a condition for award. The NIH is in a unique position to advance the cause of collecting standardized, time-stamped information in clinical injury research. The goals for the development, design, and analysis for observational studies in acute injury are summarized in Figure 1. Basic and Translational Research in Emergency Trauma Fundamental questions about the timing and sequence of events after acute injury research remain, such as, When does a neuron die? The limitations of past human clinical trials in central nervous system injury and ischemia are rooted not only in the methods that have been used in the trials themselves but also in the basic science research questions that contributed to their design. Developing a timeline of events after injury at the organ, cellular, genomic, and proteomic levels would lead to more targeted treatments to improve human outcomes. Even current animal data are limited with respect to these questions because most measurements are cross-sectional (ie, animal is killed at a given time and histologic studies are then performed). This approach fundamentally limits the ability to understand the timing and sequence of events after injury and thus translate understanding to the dynamic processes that occur in human injury. Translational research should be bidirectional between animal and clinical studies. Both successful and failed clinical 544 Annals of Emergency Medicine

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Figure 1. Observational research priorities in emergency trauma.

trials should lead to more experimental studies. Conversely, experimental studies should pay more attention to optimal dosing, duration of treatment, and the opportunity window for treatments with convincing signals of efficacy. As an example, thrombolytic trials in stroke were effective in animal models but failed in early studies in humans until the correct time window and dosing were more clearly defined. Thus, the identification of appropriate surrogate markers for trauma outcomes should be pursued. Ideally, a treatment must be effective in modifying a specific surrogate marker before a definitive clinical trial is performed. Adaptive trial designs should be used to identify the optimal timing and dosing of interventions after acute injury. It will be important to better understand the timing and sequence of events in neuronal ischemia, reperfusion, and death. New biomarkers including laboratory tests, imaging, and the like need to be developed; ideally, these would measure not only cellular death but also cells at risk of or in the process of dying. These newly identified biomarkers could be used to define acute injury phenotype over time and the response to interventions. A dedicated NIH review system, potentially study section or special emphasis panel, for experimental studies on the timing and sequence of events after injury trauma could support requests for applications for studies to better delineate the longitudinal mechanism of cellular injury during acute injury states in both experimental studies and clinical settings. Translational research that “results to everyday clinical practice and health decisionmaking” is of great importance to emergency medicine and acute injury care.12,13 As an analogy to injury, the field of sepsis has advanced by using genomic, proteomic, and metabolomic methods in the acute phase. Examining temporal changes in these parameters, with multiple changes over time, can be an analytical challenge. Bringing Volume , .  : November 

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Clearinghouse of Training Opportunities Central repository of training opportunities in acute injury Centralized access to acute injury resources at the Emergency Care Coordination Center, NIH, National Center for Research Resources Expansion of Stage-Specific Training Models Debt forgiveness programs K-12 national (transinstitute) R25 (NINDS model) Training Supplements Clinical Translational Science Institutes supplemental training support for acute injury investigators Emergency and acute injury network support for training Investigator Development Mentorship development (K24 model) Clinical trialist (boot camp) Figure 3. Training priorities for emergency trauma research.

TRAINING TO ADDRESS CRITICAL NEEDS IN EMERGENCY TRAUMA RESEARCH Figure 2. Strategies for better translational research in emergency trauma.

together scientists from different disciplines could help accelerate research in the field. The NIH has formal programs, such as the NINDS Collaborative Activities to Promote Translational Research program or the National Institute of General Medical Sciences Large Scale Collaborative Research Consortia (Glue Grants), that encourage collaboration between scientists from the preclinical and clinical realms. The extension of such translational research programs with an emphasis on building collaborations with emergency medicine, trauma, and acute injury researchers could create more important connections within and between institutions to accelerate discovery in acute injury. To facilitate these translational research endeavors, methods for real time, noninvasive cellular injury monitoring (both in humans and animal models) are needed to better investigate the sequence, timing, and mechanism of injury and to evaluate whether treatments are leading to a cessation or reversal of cellular injury. These prioritized goals for translational research in emergency trauma are summarized in Figure 2. Volume , .  : November 

Training was identified as a key but surmountable obstacle to adequate emergency care research. The roundtable participants believed the NIH has an opportunity to advance emergency care research through targeted training programs for evolving emergency researchers, support of mentors, and systematic development of a pipeline of future investigators. The advancement of emergency care research would be facilitated by having an NIH clearinghouse of training opportunities and by expansion of stage-specific training models. The priorities for training initiatives for emergency trauma research are summarized in Figure 3. Given the structure of the NIH and the varied interests of the different federal funding agencies, emergency care and trauma researchers may straddle different institutes, centers, or agencies. The various agencies that participate in conduct and training of emergency care research may not be known to the individual investigator, which leads to investigators expending energy and resources with little yield because of “shopping around” for appropriate funding sources. This could serve as a deterrent to the pursuit of emergency care research. Currently, there is no single source from which interested emergency care investigators may gain information about training and research funding, making it difficult to identify opportunities for emergency care research. A central federal clearinghouse could provide information on training options Annals of Emergency Medicine 545

NIH Roundtable on Emergency Trauma Research and funding programs available to emergency care researchers across different agencies. This clearinghouse may provide muchneeded information about available training paths and funding mechanisms from different agencies, strengths and weaknesses of these paths, and access to national experts and mentors; ultimately, the clearinghouse may facilitate the improvement of emergency care services in the United States through research. In the meantime, the NIH may also coordinate intra- and interinstitute training of emergency care investigators. Specifically, the NIH may: ● improve transparency of training and funding opportunities for emergency care research across the various institutes and centers at the NIH; and ● provide an incentive for pursuit of emergency care research by expanding loan repayment programs and providing transparency in the process of loan repayment awards. There is no single dedicated source of information for NIH training and funding opportunities in emergency care research. Emergency care research traverses various institutes and centers at the NIH. This is a necessity of the multidisciplinary nature of injury and emergency care research. Thus, continued transinstitute funding and participation in emergency research is warranted. However, the individual investigator may have difficulties in finding the appropriate institute and mechanism for funding. Further, investigators may not be aware of funded and ongoing projects, given the current limitations of existing databases. Improved coordination across NIH institutes and centers would allow better access to information on training and funding opportunities at the NIH. Potentially, such an office could be set up in the Emergency Care Coordination Center or the National Center for Research Resources. According to the American Medical Association, the average educational debt of medical students graduating in 2007 was about $140,000. Medical education debt and medical school tuitions are outpacing inflation rates. Roundtable participants suggested that current debt levels at graduation may serve as a disincentive for pursuit of an academic career. Although the NIH does currently have a loan repayment program, its current structure could be improved in a manner that rewards young investigators who are committed to a research career. For example, no feedback is currently provided by the NIH after a candidate is not selected for a loan repayment program award. Although candidates are encouraged to reapply, the current lack of transparency likely discourages some applicants. Further, it was suggested that the period of eligibility for the loan repayment program could be extended such that a candidate who may not have appeared committed to a career in injury research but subsequently becomes a successful researcher could still seek loan repayment program funding. A shortage of emergency care researchers at every level of expertise was acknowledged at the roundtable. In contrast, a sizeable number of medical students pursue fields related to acute injuries and emergency care such as emergency medicine, trauma surgery, and critical care. A large proportion of these 546 Annals of Emergency Medicine

Cairns et al students and residents (⬎25%) are interested in academic careers.1 Recruitment of these potential academicians to research would address the relative shortage of emergency care researchers. To this end, it was recommended that the NIH target training models to the different levels of acute injury research expertise through the following realms: ● support for a national, transinstitute K12 ● program support for mentorship development ● network development/supplemental support Many impediments to successful attainment of a career development grant (K award) from the NIH were discussed. The 2- to 3-year period immediately after residency and fellowship training was identified as a critical period during which burgeoning investigators may become disillusioned with the process of sorting out where and how to receive funding for emergency care research from the NIH. There are successful examples of programs targeted to investigators during this crucial phase. The American Academy of Neurology offers annual career development awards that protects junior investigators for up to 2 years. The reported success rate in achieving NIH K awards from these investigators is up to 90%.14 Thus, if junior investigators with an interest in emergency care research are provided with protected time early in their career, this could translate into significant advances in the field of emergency care. Institutions with well-developed research programs are often able to offer the K12 grant to junior investigators. The K12 is an Institutional Research and Academic Career Development Award that is awarded to educational institutions or professional organizations to support career development experiences for clinicians leading to research independence. K12s are often funded for 2 to 3 years, with the expectation that awardees will seek career development awards from the NIH at the end of the K12 period. Junior researchers at non-K12 institutions do not have an opportunity for this level of support. The National Institute of Child Health and Human Development offers a national K12 program for pediatric critical care investigators. In the more than 4 years since its inception, this program has funded 16 pediatric critical care scholars throughout the United States. Funding is provided for 2 to 3 years, and scholars are expected to obtain NIH funding or continued support from their department in subsequent years. A national advisory committee of senior investigators participates in the selection and development of scholars. Although not a national K12 program, the National Heart, Lung, and Blood Institute is developing a program of K12 programs across the country, with a requirement for multidisciplinary proposals, which is often necessary in emergency care research. The Emergency Medicine Foundation issues annual career development awards but is only able to support 1 scholar per year. In 2009, 26 applications for the Emergency Medicine Foundation awards were received,15 which suggests that there is ample interest in academic careers among junior emergency care investigators. Thus, the NIH may foster Volume , .  : November 

Cairns et al this interest through provision of a dedicated national K12 award program and transparency of information about funding opportunities for emergency care researchers. The limited number of emergency care researchers who are qualified to serve as mentors for junior investigators was recognized by roundtable participants. In addition to developing a pipeline of future investigators, providing intermediate-stage investigators with the skills to become successful mentors was endorsed. The NIH may support this goal by targeting existing funding mechanisms for mentorship development toward emergency care researchers. For example, the K24 Mid-Career Investigator Award in Patient-Oriented Research is designed to provide support for clinicians and allow them protected time to devote to patient-oriented research and to act as mentors for beginning clinical investigators. The R25 grant award mechanism is another instrument through which the NIH may support the training of new emergency care researchers. The Research Education Grant (R25) is awarded to institutions/organizations that propose to support the development or implementation of programs that relate to education and training of clinical residents and fellows to foster careers as clinician-scientists. Eligible principal investigators would have a track record of successful mentoring and NIH research funding. Support for the principal investigator and other faculty participating in the research education project is not allowable under the R25, although there is no limit to the number of potential participants. The T32 and other mentored training grants also do not provide salary support for mentors. This puts potential mentors in a position whereby they are encouraged to assume much responsibility but are offered little in the way of tangible rewards in return. Given the financial constraints of academic departments and the pressure to balance patient care and academic productivity, it was recommended that the NIH consider rewarding mentors through salary support for the time they commit to mentoring. Finally, not all NIH institutes or centers currently offer the K24 and R25. In particular, no institute offers dedicated programs for emergency care researchers. These mentorship development awards are as such subject to the issues relating to transparency and lack of a central source of information described earlier. The development of a transinstitute, multidisciplinary network dedicated to emergency care research was proposed as an additional means by which the NIH may facilitate the training of emergency researchers. The Resuscitation Outcomes Consortium is an example of such a network funded by multiple federal agencies in the United States and Canada.16 The Resuscitation Outcomes Consortium is designed to provide infrastructure and project support for clinical trials and other outcome-oriented research in the areas of cardiopulmonary arrest and severe traumatic injury. Yet the Resuscitation Outcomes Consortium investigations are particularly geared toward EMS research in cardiac and trauma populations and as such do not fully capture the spectrum of emergency injury research. Supplemental support for the Resuscitation Outcomes Volume , .  : November 

NIH Roundtable on Emergency Trauma Research Consortium is provided by the funding agencies for junior investigators to receive training in clinical or fundamental research and to conduct clinical or bench research in resuscitation. Other evolving federally funded emergency care research networks that could be leveraged for the development of junior investigators in emergency trauma include the Pediatric Emergency Care Applied Research Network,17 the Neurological Emergency Treatment Trials program,18 and the US Critical Illness and Injury Trials Group.19

CONCLUSIONS Enhancing the research base supporting the care of trauma emergencies will require progress in specific mechanistic, translational, and clinical domains; effective collaboration of academic investigators across traditional clinical and scientific boundaries; federal support of research in high-priority areas; and overcoming limitations in available infrastructure, research training, and access to patient populations. Supervising editors: Donald M. Yealy, MD; Michael L. Callaham, MD Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. Funding for the Roundtable on Emergency Trauma Research was provided by the NIH. Publication dates: Received for publication February 17, 2010. Revision received May 8, 2010. Accepted for publication May 11, 2010. Reprints not available from the authors. Address for correspondence: Charles B. Cairns, MD, Department of Emergency Medicine, University of North Carolina, 170 Manning Dr, Chapel Hill, NC 27599; 919-8433045, fax 919-966-3049; E-mail [email protected]. REFERENCES 1. Institute of Medicine of the National Academies. Hospital-Based Emergency Care: At the Breaking Point. Washington, DC: National Academies Press; 2007. 2. Nathens AB, Rivara FP, Jurkovich GJ, et al. Management of the injured patient: identification of research topics for systematic review using the Delphi technique. J Trauma. 2003;54:595-601. 3. Courtney DM, Neumar RW, Venkatesh AK, et al. Unique characteristics of emergency care research: scope, populations, and infrastructure. Acad Emerg Med. 2009;16:990-994. 4. Glickman SW, Anstrom K, Li L, et al. Challenges in enrollment of minority, pediatric and geriatric patients in emergency and acute care clinical research. Ann Emerg Med. 2008;51:775-780. 5. Sun LH, Glod M. DC Metro Red Line crash. Washington Post. June 23, 2009. Available at: http://www.washingtonpost.com/ wp-dyn/content/linkset/2009/06/23/LI2009062301806.html? sid⫽ST2009062603770. Accessed October 25, 2009. 6. NIH Task Force on Research in the Emergency Setting: request for information: soliciting input on current needs in emergency

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medicine research. Available at: http://www.grants.nih.gov/grants/ guide/notice-files/NOT-NS-08-021.html. Accessed October 25, 2009. NOT-NS-08-021. Pitts SR, Niska RW, Xu J, et al. National Hospital Ambulatory Medical Care Survey: 2006 emergency department summary. August 6, 2008. No. 7. Available at: http://www.cdc.gov/nchs/ data/nhsr/nhsr007.pdf. Accessed November 10, 2008. Institute of Medicine of the National Academy of Sciences. Emergency Medical Services at the Crossroads. Washington, DC: National Academies Press; 2007. Hollander JE, Gaulton GN, Courtney DM, et al. Facilitating emergency care research networks: integration into the CTSA infrastructure. Acad Emerg Med. 2009;16:1005-1009. Margulies S, Hicks R; Combination Therapies for Traumatic Brain Injury Workshop Leaders. Combination therapies for traumatic brain injury: prospective considerations. J Neurotrauma. 2009;26: 925-939. Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007;24(suppl 1):S1-106. Nichol G, Thomas E, Callaway CW, et al; Resuscitation Outcomes Consortium Investigators. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008;300:1423-1431. Woolf SH. The meaning of translational research and why it matters. JAMA. 2008;299:211-213. American Academy of Neurology. Clinician Scientist Development Awards. American Academy of Neurology Web site. Available at: http://www.aan.com/go/foundation/research/development. Accessed October 25, 2009. Emergency Medicine Foundation. Career Development Grant Awards. Available at: http://www.emfoundation.org/WorkArea/ linkit.aspx?LinkIdentifier⫽id&ItemID⫽414. Accessed October 25, 2009. Morley P. Steady as a ROC: the Resuscitation Outcomes Consortium. Resuscitation. 2008;78:105-106. Pediatric Emergency Care Applied Research Network. The Pediatric Emergency Care Applied Research Network (PECARN): rationale, development, and first steps. Acad Emerg Med. 2003; 10:661-668. Neurological Emergencies Treatment Trials (NETT) Network. Neurological Emergencies Treatment Trials Web site. Available at: http://www.nett.umich.edu/nett/welcome. Accessed November 10, 2008. Cobb JP, Cairns CB, Bulger E, et al. The United States Critical Illness and Injury Trials Group: an introduction. J Trauma. 2009; 67(2 suppl):S159-160.

Cairns et al William G. Barsan, MD University of Michigan [email protected] Lorne Blackbourne, MD United States Army Institute for Surgical Research [email protected] Randall Burd, MD, PhD Children’s National Medical Center [email protected] Christopher Carpenter, MD, MSc Washington University [email protected] David Chang, PhD Johns Hopkins University Howard University [email protected] William Cioffi, MD Rhode Island Hospital [email protected] Edward Cornwell, MD Howard University [email protected] J. Michael Dean, MD, MBA University of Utah [email protected] Carmel Dyer, MD University of Texas, Houston [email protected] David Jaffe, MD Washington University [email protected]

Contributing Authors (External Participation)

Geoff Manley, MD, PhD University of California, San Francisco [email protected]

Charles B. Cairns, MD (cochair) University of North Carolina [email protected]

William J. Meurer, MD, MS University of Michigan [email protected]

Ronald V. Maier, MD (cochair) Harborview Medical Center University of Washington [email protected]

Robert Neumar, MD, PhD University of Pennsylvania [email protected]

Opeolu Adeoye, MD University of Cincinnati [email protected]

Robert Silbergleit, MD University of Michigan [email protected]

Darryl Baptiste, PhD Toronto Western Hospital [email protected]

Molly Stevens, MD, MSCE Medical College of Wisconsin [email protected]

APPENDIX

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Michael Wang, MD University of Miami [email protected]

Mary Kerr, PhD National Institute of Nursing Research [email protected]

Debra Weiner, MD, PhD Children’s Hospital Boston [email protected]

Naomi Kleitman, PhD National Institute of Neurological Disorders and Stroke [email protected]

David Wright, MD Emory University [email protected]

Jeffrey Kopp, MD National Institute of Diabetes, Digestive and Kidney Disease [email protected]

NIH and Federal Roundtable Participants

Walter J. Koroshetz, MD National Institute of Neurological Disorders and Stroke [email protected]

Robin Conwit, MD National Institute of Neurological Disorders and Stroke [email protected] Billy Dunn, MD Food and Drug Administration [email protected] Basel Eldadah, MD, PhD National Institute of Aging [email protected] Debra Egan, MS, MPH National Heart, Lung, and Blood Institute [email protected] Rosemarie Filart, MD, MPH National Center for Research Resources [email protected] Giovanna Guerrero, PhD National Institute of Neurological Disorders and Stroke [email protected] Dallas Hack, MD, Col Department of Defense [email protected] Michael Handigan, MD Emergency Care Coordinating Center [email protected] David Heppel, MD Health Resources and Services Administration [email protected] Richard Hunt, MD Centers for Disease Control and Prevention [email protected] Ramona Hicks, PhD National Institute of Neurological Disorders and Stroke [email protected] Scott Janis, PhD National Institute of Neurological Disorders and Stroke [email protected] Volume , .  : November 

Jukka Korpela, MD National Institute of Allergy and Infectious Diseases [email protected] Ryan Mutter, PhD Agency for Healthcare Research and Quality [email protected] Carol Nicholson, MD National Institute of Child Health and Human Development [email protected] Angela Martinelli, RN, PhD National Institute on Alcohol Abuse and Alcoholism [email protected] James Panagis, MD National Institute of Arthritis and Musculoskeletal and Skin Diseases [email protected] Jane Scott, ScD, MSN National Heart, Lung, and Blood Institute [email protected] Scott Somers, PhD National Institute of General Medical Sciences [email protected] George Sopko, MD National Heart, Lung, and Blood Institute [email protected] Veronica Thurmond, RN, PhD Department of Defense [email protected] Bob Zalutsky, PhD National Institute of Neurological Disorders and Stroke [email protected] Planning Group Roster External Members Charles B. Cairns, MD University of North Carolina [email protected] Annals of Emergency Medicine 549

NIH Roundtable on Emergency Trauma Research Ronald V. Maier, MD, PhD Harborview Hospital University of Washington [email protected]

Cairns et al Robin Conwit, MD National Institute of Neurological Disorders and Stroke [email protected]

NIH Members

Basel Eldadah, MD National Institute of Aging [email protected]

Scott Somers, PhD National Institute of General Medical Sciences [email protected]

Walter J. Koroshetz, MD National Institute of Neurological Disorders and Stroke [email protected]

Ramona Hicks, PhD National Institute of Neurological Disorders and Stroke [email protected]

Giovanna Guerrero, PhD National Institute of Neurological Disorders and Stroke [email protected]

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