Overview of DoD Resuscitation Fluid Research COL Jim Atkins, MD, PhD Director, Division of Military Casualty Research Walter Reed Army Institute of Research Program Area Manager for Resuscitation Studies in the Army Combat Casualty Care Research Program 10 January 2005 1
Overview of DoD Resuscitation Fluid Research Battlefield Resuscitation DoD and NIH Funded Research Prior Meetings and Collaborations Outcomes of This Panel 2
Battlefield Resuscitation: Non-Head Injured Casualties Traditional constraints of battlefield resuscitation: Austere, dangerous environment Supply limitations Limited medical training Potential future constraints include: Longer period of time before the medic can reach the casualty Increased difficulty in medical resupply Limited medical air evacuation 12 hours in Somalia 4-12 hours in Afghanistan (Transport times are relatively short in Iraq) Issues with military specific fluids: Drugs/fluids must be FDA approved Can t conduct clinical trials in U.S. for exact military indication Military market not large enough to support unique product 3
Battlefield Resuscitation: Non-Head Injured Casualties Panel selects hypotensive resuscitation to treat battlefield hemorrhage 1 Combat Fluid Resuscitation Conference 2001, Bethesda, MD Resuscitate non-head injured combat casualties to: Palpable radial pulse Ability to mentate Sustained systolic blood pressure of 85-90 mm Hg (if measure is available). Fluid of choice: Forward (battlefield)-colloid (500 cc) or colloid and crystalloid Aid station/forward surgical setting-isotonic crystalloid 4
Battlefield Resuscitation: Non-Head Injured Casualties Areas to Improve in the Cascade of Care Optimal battlefield resuscitation guidelines Clinical evaluation of the casualty? FDA approved fluid for trauma resuscitation (superior to LR)? Risk balance of hypotensive period length vs. CASEVAC risk Identification of Markers of Resuscitation Failure? Field device to test for biomarkers of impending failure (crashing)? Method at CSH to test for biomarkers Treat/Prevent the Resuscitation Failure? Field: small volume, shelf stable adjuvants? CSH: adjuvants, blood products, coagulopathy repair, fluids; altered protocol for patients held hypotensive for longer periods. Is the casualty likely to survive, with treatment? Fluid that can prevent shock/resus problems Is the evacuation riskier than the hypotensive period? Is the casualty deteriorating? What is the specific indication to be treated? Treat with fluids or adjuvants. Hemorrhaging Casualty y stay y? Treat?? Treat Treat with fluids, blood products, or adjuvants as indicated. n EVAC n Move On CSH? Treat 5 5
DoD and NIH Funded Research DTO Title: MD. 28 Fluid Resuscitation and Prolonged Life Sustainment on the Battlefield Objectives Develop life sustainment strategy for casualties that are expected to experience long delays before evacuation from the battlefield. Determine the best composition and use of resuscitation fluids. Develop adjunct therapy or drugs to improve outcomes. Develop drugs or strategies that sustain life in the absence of fluid resuscitation. Payoffs Decreased requirements for resuscitation fluids. Increased window of time in which the casualty may be evacuated. Decreased killed-in-action rate. Decreased blood requirements Decreased organ failure after successful resuscitation. 6 6
DoD and NIH Funded Research Major Accomplishments Animal studies predict that casualties may collapse without warning Full resuscitation (second resuscitation) may be complicated after prolonged hypotensive resuscitation. Late vascular decompensation in hemorrhagic shock is associated with a fall in blood levels of arginine-vasopressin. Administration of pharmacologic doses of AVP restores blood levels to those normal for shock and rescues the animals from imminent death. Hypertonic saline must be dose limited. Timing and rate of administration may be important. Studies indicated that L-lactated Ringers causes significantly less neutrophil activation and lung injury after hemorrhage/resuscitation than the racemic mixture of D- & L-lactated Ringers. HBOC alone may not be ideal for hypotensive resuscitation (under conditions where oxygen carrying capacity of blood is not critically low) 7
DoD and NIH Funded Research Research Tools at Hand Animal models have been developed to examine hypotensive resuscitation with delayed evacuation. Three models were established in two species (rat and pig). Models mimic severely hemorrhaged but potentially salvageable casualties on the battlefield. Some models without anesthesia. Prolonged hypotensive periods. Significant lactic acidosis. Portion that become unresponsive to fluid resuscitation. Models mimic some aspects of patients from urban trauma centers Complement activation. 8
Prior Meetings and Collaborations Combat Focus General Resuscitation Clinical Trial Focus 1999 Fluid Resuscitation Report 4 Institute of Medicine, Nat l Acad. Press, 1999 2000 PULSE Workshop, DC 5 (Circulation, 2001; 103, 1182-4) 2001 Combat Fluid Resuscitation, Bethesda Fluid Resuscitation in Combat, Toronto PULSE Trauma WG I, NIH 6 (SHOCK, 2002;17(3), 165-8) 2002 2003 2004 Clinical Research Methodology in Combat Resuscitation and Casualty Care, Toronto PULSE Trauma WG II, WRAIR 7 (J. Trauma, 2004; 57, 410-5) Wolf Creek Conference, Palm Springs Resuscitation Science Symposium 2003 AHA Scientific Sessions, Orlando 12 NIH/DoD R01 Awards for Basic Research to Improve Outcomes after Trauma Resuscitation Change in law (Title X, Sec. 980) allowing use of DoD funds for pre-hospital (community consent) clinical trials Formation of the Research Outcome Consortium 2005 Resuscitation Fluids for Use in Combat: Selection Criteria and Prioritization Resuscitation Science Symposium 2004 AHA Scientific Sessions, New Orleans Future Workshop on NIH/DOD Teaming Approach to Accelerate the Transition to Clinical Trials 9
Prior Meetings and Collaborations Post-resuscitative and initial Utility in Life Saving Efforts (PULSE) Initiative A shotgun marriage of researchers in CPR and trauma resuscitation. Initial workshop in 2000 12 NIH RO1 basic science grants awarded in 2002 Trauma Working Group published recommendations in 2002 and 2004 Encouraged the Resuscitation Science Symposium at the American Heart Assn. Scientific Sessions, annually since 2003. Created the Research Outcome Consortium for multi-center, international clinical trials in trauma 10 10
Outcomes of This Panel Applicants respond to Federal Funding Opportunity number W81XWY-BAA-AFRRF Panel reviews and ranks pre-proposals based on scientific merit and product maturity MRMC reviews regarding relevance to the combat situation Full proposals are requested from top 4-8 products and sent to AIBS for external review Awards of $100k-$1M/year through 2010, with the leading product receiving as much as $3M/year for clinical development 11
Outcomes of This Panel Not for Public Posting Short Term: Select candidate products for developmental funding under AFRRF Selection criteria for determining utility of future fluid resuscitation products in a combat scenario Mid-term (ideal outcomes): Longer Term: FDA Approval of one or more products that will reduce the number of soldiers KIA and mitigate the post-resuscitation morbidity Encourage development of the next generation of resuscitation fluids 12 Not for Public Posting
Overview of DoD Resuscitation Fluid Research 13
References Cited 1. Champion HR. Combat fluid resuscitation: introduction and overview of conferences. J Trauma 2003; 54(5)Supp:S7-S12 2. Adapted from Battlefield Resuscitation in Special Operations Forces 2004 presented by Mr. Marak, US Army Special Operations Command (USASOC), 31 Aug 2004, San Antonio, TX. 3. Handrigan MT, TB Bentley, JD Oliver, LS Tabaku, JR Burge, JL Atkins. Choice of fluid influences outcome in prolonged hypotensive resuscitation after hemorrhage in awake rats. SHOCK 2005; in press 4. Committee on Fluid Resuscitation for Combat Casualties, Institute of Medicine. Pope A, French G, Longnecker DE, eds. Fluid Resuscitation: State of the science for treating combat casualties and civilian injuries. Washington, DC: National Academy Press; 1999. 5. Weil MH, L Becker, T Budinger, K Kern, G Nichol, I Shechter, R Traystman, H Wiedemann, R Wise, M Weisfeldt, G Sopko. Workshop executive summary report: Post-resuscitative and initial utility in life saving efforts (PULSE). Circulation 2001;103:1182-1184. 6. Carrico CJ, J Holcomb, I Chaudry and the PULSE Trauma Work Group. Scientific priorities and strategic planning for resuscitation research and life saving therapy following traumatic injury: report of the PULSE Trauma Work Group. SHOCK 2002;17(3):165-168. 7. Hoyt DB, J Holcomb, E Abraham, JL Atkins, and G Sopko. Working Group on Trauma Research program summary report. J Trauma 2004;57(2):410-415. Uncited The Borden Institute and AMEDD Center and School. Emergency War Surgery. http://www.bordeninstitute.army.mil/emrgncywarsurg/default.html: 2004, Chapter 7. 14