HYPOVOLEMIC CIRCULATORY COLLAPSE: MECHANISMS AND OPPORTUNITIES TO IMPROVE RESUSCITATION OUTCOMES RELEASE DATE: February 24, 2003 RFA NUMBER: HL-03-015 National Heart Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) United States Army Medical Research and Materiel Command (USAMRMC) (https://mrmc-www.army.mil/) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.837, 93.838, 93.839, 12.420 LETTER OF INTENT RECEIPT DATE: April 23, 2003 APPLICATION RECEIPT DATE: May 23, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements 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 This initiative is intended to identify novel methods to improve resuscitation outcomes from severe blood loss and subsequent hypovolemic circulatory collapse. Applications are sought that propose innovative research approaches to identify the molecular, cellular, and pathophysiologic response of the whole organism to hypovolemia and to apply results of such approaches to the identification of potential, new approaches to out-of-hospital resuscitation following severe hypovolemia. RESEARCH OBJECTIVES Traumatic injury is the leading cause of death for individuals under age 44 in the United States. Overall, trauma results in approximately 150,000 deaths per year, and severe hypovolemia due to hemorrhage is a major factor in nearly half of those deaths. Rapid response and early intervention are key to improving survival since approximately one third of trauma deaths occur out-of-hospital and severe blood loss is a major cause of deaths occurring within 4 hours of injury. Current resuscitation strategies for hypovolemia due to severe blood loss typically include the immediate restoration of blood pressure through the use of intravenous fluids. However, results from recent animal studies suggest that rapid, high volume replacement during resuscitation often exacerbates bleeding and may result in increased mortality compared to either low volume or delayed fluid replacement. Clinical trial findings indicate that survival is not worsened, and may be improved, by limiting the initial fluid resuscitation, either by delaying the initiation or by titrating to a low systolic blood pressure (70 mmHg), so called permissive hypotensive resuscitation techniques. Another promising approach to fluid resuscitation appears to be the use of hypertonic saline solutions that require lower volumes of fluid and may have beneficial immuno-modulatory effects. Beyond these relatively straightforward approaches, initial patient management following severe blood loss is complicated by the fact that a number of individuals with severe blood loss do not respond to fluid restoration and/or the use of agents that increase vasomotor activity and peripheral resistance. These individuals have transitioned from reversible hypovolemia to hypovolemic circulatory collapse, and their resuscitation outcomes are dismal. Although the factors that contribute to the transition from reversible hypovolemia to circulatory collapse are not known, they likely include those associated with ischemia and reperfusion injuries. The response to volume loss consists of biphasic opposing actions that include activation of sympathetic and parasympathetic neural reflexes and stimulation of inflammatory and anti-inflammatory cytokine pathways. Thus there is release of epinephrine and norepinephrine as well as TNF- alpha and interleukins. These substances, in turn, may induce vascular decompensation, capillary leak, and organ dysfunction (for example, induction of severe bradycardia unresponsive to pharmacological intervention). These cascades of opposing events, and the balance between them, most likely contribute to development of hypovolemic circulatory collapse. The relative and direct contribution of different pathways to the development of circulatory collapse is unknown. Understanding mechanisms and developing approaches that improve hypovolemic circulatory collapse resuscitation outcomes is the primary goal of this initiative. Applications must clearly define the relationship of the proposed studies to successful out-of-hospital resuscitation. Both the National Heart, Lung, and Blood Institute (NHLBI) and United States Army Medical Research and Materiel Command (USAMRMC) have taken leadership roles in promoting resuscitation research through the organization of and continued involvement in the Post-Resuscitation and Initial Utility in Life Saving Efforts (PULSE) workshop. This research initiative is one expression of this ongoing partnership and represents a needed step for improving both civilian and military resuscitation outcomes. An understanding is needed of the relative roles of perfusion pressure, organs and organ systems (including the lung, heart, and vasculature), as well as neurohumoral and other local and systemic responses to sudden or severe blood loss that contribute to circulatory collapse and poor resuscitation outcomes. Studies should focus on relating results to the whole organism, and should be placed into the context of the potential for improving resuscitation outcomes. Responsive applications will include the use of appropriate mammalian models to characterize the early response to severe blood volume loss and transition to circulatory collapse. Clinical research of a mechanistic or observational nature using human subjects may be involved, in controlled conditions as during surgical procedures associated with massive blood loss; interventional studies in humans will NOT be considered responsive. Research Areas Examples of research that might address the response to exsanguination and the failure of fluid replacement resuscitation following severe hypovolemia and the transition to circulatory collapse are listed below. This list is not exhaustive and investigators are encouraged to develop additional approaches. They are encouraged to discuss these with NHLBI and USAMRMC staff identified in the WHERE TO SEND INQUIRIES section. o Use of genomics and proteomics, as well as traditional research approaches, to characterize the molecular and physiologic alterations involved in the transition between reversible hypovolemia and circulatory collapse. o Identification of factors such as the extent and rate of volume loss, nature of injury (i.e. blunt versus penetrating trauma), and environmental determinants (e.g., ambient temperature, 'response' times) that contribute to the transition between reversible hypovolemia and circulatory collapse. o The use of integrated systems biology, or other high-order systems approaches, to elucidate the influence of individual organs or organ systems in mediating microcirculatory dysfunction, capillary leak, and circulatory collapse. o Identification and evaluation in animal models of novel interventions to delay or prevent the onset of hypovolemic circulatory collapse. o The identification of markers for successful out-of-hospital resuscitation in a setting of severe blood loss. o Elucidation of autonomic factors contributing to the transition from reversible hypovolemia to circulatory collapse. MECHANISM OF SUPPORT This RFA will use the NIH R01 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is April 1, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see https://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NHLBI and USAMRMC each intend to commit approximately $2 million in FY 2004 to fund 10 to 12 new grants in response to this RFA. An applicant may request a project period of up to 4 years and a budget for direct costs of up to $250,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NHLBI and USAMRMC provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Since the total costs for a subcontract or consortium are included in the direct cost request, one additional module of $25,000 above the cap may be requested for the facilities and administrative costs associated with third party agreements. A module requested for this purpose must be clearly identified in the budget justification section of the application, and will be restricted for this purpose only at the time of award. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS For applications to be considered responsive to this RFA, the proposed studies must address the transition between reversible hypovolemia and circulatory collapse following severe blood loss. Studies investigating the development of multi-organ failure or sepsis will not be considered responsive and will be returned to the applicant without further consideration. Proposed studies may involve human subjects research of a mechanistic nature and only in a controlled environment (i.e. identification of biomarkers in surgery with severe blood loss). Clinical trials and human interventional studies are beyond the scope of this initiative and will be considered non-responsive. For those studies involving observational studies with human subjects, a data and safety monitoring plan is required. More information is available on the NHLBI web site at http://www.nhlbi.nih.gov/funding/policies/index.htm under the section entitled NHLBI Clinical Research. In addition to annual progress reports, the Principal Investigators of the grants funded under this RFA will be expected to attend and participate in yearly grantee meetings to present the findings of the research supported and to suggest future research directions. Funds for travel to such meetings must be incorporated into the standard NIH travel allowance for Principal Investigators. For planning purposes, assume the meetings will be held in Bethesda, MD. General Clinical Research Centers Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator should be included with the application. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: David M. Balshaw, Ph.D. Division of Heart and Vascular Diseases National Heart Lung and Blood Institute 6701 Rockledge Dr., Room 9194 (MSC 7940) Bethesda, MD 20892-7940 (20817 for Courier) Telephone: (301) 435-0504 FAX: (301) 480-1454 Email: BalshawD@nhlbi.nih.gov Andrea Harabin, Ph.D. Division of Lung Diseases National Heart Lung and Blood Institute 6701 Rockledge Dr., Room 10124 (MSC 7952) Bethesda, MD 20892-7952 (20817 for Courier) Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: HarabinA@nhlbi.nih.gov George Nemo, Ph.D. Division of Blood Diseases and Resources National Heart Lung and Blood Institute 6701 Rockledge Dr., Room 10142 (MSC 7950) Bethesda, MD 20892-7950 (20817 for Courier) Telephone: (301) 435-0075 FAX: (301) 480-0868 Email: NemoG@nhlbi.nih.gov Col. Robert Vandre, DDS Combat Casualty Care Research United States Army Medical Research and Materiel Command 504 Scott St Ft. Detrick, MD 21702-5012 Telephone: (301) 619-7919 FAX: (301) 619-7067 Email: Robert.Vandre@det.amedd.army.mil o Direct your questions about peer review issues to: Anne P. Clark, Ph.D. Chief, Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive 7214, MSC 7924 Bethesda, MD 20892-7924 (20817 for express/courier service) Telephone: (301)435-0270 FAX: (301)480-0730 Email: ClarkA@nhlbi.nih.gov o Direct your questions about financial or grants management matters to: Robert Vinson Grants Management Specialist Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive 7156, MSC 7926 Bethesda, MD 20892-7926 (20817 for express) Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: VinsonR@nhlbi.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: All applications must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applications requesting one module ($25,000) above the cap due to subcontract or consortium facilities and administrative costs associated with third party agreements must also be submitted in modular format and may request up to $275,000 per year in direct costs. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at https://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five collated sets of appendix material must be sent to Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES. Please note that applications delivered by individuals are no longer accepted; all applications must either come via courier delivery or the United States Postal Service (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html). APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. Principal investigators should not send supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI and the USAMRMC. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the NHLBI National Advisory Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 23, 2003 Application Receipt Date: May 23, 2003 Peer Review Date: October, 2003 Council Review: February 12, 2004 Earliest Anticipated Start Date: April 1, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_ 2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. Awards by the USAMRMC are made under the authority of 10 USC 2358. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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