The May Supplement 1 issue of Shock is accompanied by excellent articles and reviews from the 3rd Annual Conference of the Trauma Hemostasis and Oxygenation Research (THOR) Network from June 17 to 19, 2013, near Bergen, Norway. The intent of this symposium is well covered by Drs. Spinella and Strandenes (1) in their excellent overview. This now-annual conference is organized and sponsored by the Norwegian Naval Special Operation Commando in conjunction with the Norwegian Air Ambulance Foundation to reduce morbidity and mortality in patients with traumatic hemorrhagic shock in the prehospital phase. The network is composed of more than 150 members from 16 countries. This multidisciplinary network involves both military and civilian membership and involves Surgery, Critical Care, Emergency Medicine, Transfusion Medicine, Anesthesiology, Hematology, and Coagulation-based scientists. The focus of the 2013 symposium was on improved implementation of remote damage control resuscitation (RDCR), including training, ongoing research, and the potential development of future research, particularly translational clinical protocols. The basis of the symposium and ongoing research efforts is the paradigm shift from traditional crystalloid and colloid prehospital resuscitation for hemorrhagic shock to the increased use of damage control resuscitation using blood products and hemostatic agents in the prehospital phase. This symposium is an outstanding composition of basic science of the current understanding of trauma-induced coagulopathy, the gaps in our knowledge and inefficiencies in identifying the ideal resuscitation fluids, primarily based on blood and its components, the appropriate subpopulations for selective resuscitation approaches, and practical demonstrations of the current exportation to the prehospital setting for optimal patient care. Those interested in the severely injured patient with significant blood loss and the ensuing complications, primarily coagulopathy, will find this supplement an outstanding reference and update of the latest knowledge in this field.
REMOTE DAMAGE CONTROL RESUSCITATION
A series of articles define this concept, which is in its infancy, as critical to advancing the care of patients with life-threatening hemorrhage caused by injury, and present the evidence that prehospital treatment of critical hemorrhage will have a significant improvement in morbidity and mortality. A remaining major challenge identified by the investigators, but not resolved in this symposium, is the inability to accurately identify the subset of injured patients in the early stage of hemorrhagic shock–induced coagulopathy to focus intervention safely and before the clinically obvious sequelae of shock and coagulopathy.
Dr. Hooper and colleagues (2) address the challenges and possibilities for far-forward resuscitation. The authors review the recent advances in military trauma care and the rediscovery of major physiologic and clinical practices that had been lost from previous military engagements. Relevance to the civilian setting, primarily the prehospital phase in the far-forward or austere environment, is defined. The authors identify the need for improvements in technology and therapeutic agents. The authors further define the increasing ability to measure the extent and duration of shock, with the accumulating impact of global tissue hypoxia. The need for rapid intervention and reversal is well accepted; however, the ability to assess and monitor shock is extremely difficult, particularly with selective tissue insults such as traumatic brain injury. The primarily used clinical parameters such as lactate and base deficit highlight the need for further technology to monitor critical O2 delivery. The need for “hypotensive,” or preferably, “controlled,” volume resuscitation, as a more descriptive phrase, to prevent excess loss of critical blood volume is described. Similarly, the intriguing lost knowledge of benefits of whole-blood resuscitation in the massively injured is supported, as the ability to better select and process the whole blood, including elimination of contaminated units, evolves. Challenges of airway control and ventilation are defined, and approaches learned in the military setting can be easily adaptable to the civilian setting.
An additional article by Dr. Hooper and colleagues (3) further describes experience with advanced prehospital implementation of resuscitation techniques gained from military experience driven by the need for medical innovation in the austere environment of military engagement, including damage control resuscitation and the proven need for rapid medical evacuation. The authors describe many of the benefits learned, including the self-aid program and buddy use of mechanical aids to prevent hemorrhage, and empiric knowledge from clinical tracking through Tactical Combat Casualty Care of the US Military starting at the point of injury through resuscitation and definitive control. These advances have been implemented throughout NATO and across numerous military forces and nations. Damage control resuscitation was originally coined from the US Navy approach to disasters and applied to acute care in the far-forward arena. Use of limb tourniquets by the Israeli Defense Forces has now been broadly adopted. Use of an integrated echelon-based system links closely with ideal civilian practice. Early initial stabilization with aerial evacuation to higher echelons of definitive care with increasing capabilities of progressive invasive treatment and resources combine for a survival in the military that has never been achieved. In addition, improved blood bank capabilities throughout the military, shortening of blood bank storage, and better isolation and screening for infectious complications have all contributed. However, even in this extremely hazardous environment, only 10% to 15% of casualties require massive transfusion compared with the 2% to 3% commonly seen in the civilian practice, and, although variations still persist, there is increasing sharing and use of best practices to optimize overall protocols and delivery of care.
In a third article, Dr. Jenkins and colleagues (4) discuss two civilian model programs of resuscitation of the exsanguinating patient in the austere environment: one in rural Minnesota and the second during shipboard emergencies at sea, where identification, extraction, and transport times are markedly delayed and inadequate technology and medical supplies exist. In the rural setting of Minnesota, the Level I Trauma Center at the Mayo Clinic has extended their Massive Transfusion Protocol based on providing rapid availability of thawed plasma, along with tranexamic acid, far forward. Fresh-frozen plasma (FFP) is thawed and stored refrigerated and made available for rapid distribution through a helicopter-based system. Complications are mitigated, including transfusion-related acute lung injury, by using plasma from male donors with low-titer AB plasma. The logistics of adequate supplies and medical oversight, ongoing data collection, close follow-up to track complications, and impact on coagulopathy have been implemented. A similar far-forward program has been developed by FLEET Medical Operations for implementation on cruise ships for massive bleeding, most frequently of a GI source. Their system relies on the use of freshly obtained blood at the scene from donors, excluding family members and females to minimize risk, matching to known blood type from donor cards and patient data. The major concern is the rare but feasible transmission of disease, and the development of rapid exclusion tests will be critical to further development.
COAGULOPATHY OF TRAUMA
Maegele et al. (5) provide a detailed assessment of the current knowledge of the multiple interacting biologic aberrations seen in trauma-induced coagulopathy involving activation of the coagulation sequence, subsequent excessive consumption, and the impact of current resuscitation methods on the severity and progression of the coagulopathy. Included are the deficiencies in our understanding preventing advancement in treating coagulopathy. In addition to better use of clinical parameters to identify the patient at risk, improved technology for point-of-care assessment of prehospital coagulation status and measurement of the impact of prehospital interventions on the progression of the coagulopathy are critical.
During hemorrhagic shock from trauma, there is systemic activation from both tissue damage and augmentation through ongoing ischemia of multiple coagulation pathways. A major component is the protein-C pathway, with increased expression of thrombomodulin and endothelial protein-C receptor on the ischemic endothelium. Activation of protein-C, protein-S, and Factor V leads to inactivation of Factor VIII and subsequent inactivation of Factor V. The disruption of the endothelium from direct damage and subsequent ischemic injury expose the endothelial glycocalyx and release of heparin-like substances leading to autoheparinization. Along with depletion of protein-C and thrombomodulin, there is a hyperfibrinolysis and prolonged activation of partial thromboplastin time. In addition, there is ongoing consumption with rapid depletion of fibrinogen critical to stabilization of clot and depletion of all coagulation factors. Fibrinolysis degradation products lead to breakdown of clot stability and ongoing hemorrhage. Simultaneously, platelet dysfunction occurs rapidly after injury, even with isolated head injury. There is upregulation of platelet function, with subsequent downregulation and hypofunction. Finally, the bloody triad occurs with resuscitation, leading to hypothermia, acidosis, and hemodilution, further aggravating the coagulopathy. Resuscitation with component-deficient fluids leads to hemodilution and aggravation of functional clot formation. The initiation through, and direct linkage to, duration of hypoperfusion, with activation of the endothelium and further tissue damage and release of tissue by-products, all support the need for early recognition and institution of corrective approaches to minimize and reverse the coagulopathy.
The article by Schött (6) describes the variety of point-of-care monitors required for the measurement of basic hematocrit, hemoglobin, blood gas, lactate, and electrolyte parameters. Needed is the ability to transfer to the austere environment the recently developed functional analyses of coagulation, in particular, thromboelastometry. Because of the recognition of the complex interacting pathways involved, the current lack of functional analysis is critical to adequately monitor coagulation status. There are currently tests for prothrombin time/International Normalized Ratio, activated partial thromboplastin time, fibrinogen concentration, and viscoelastic thromboelastometry (ROTEM). However, the routine dispersion of these is extremely limited because of multiple logistics, including cost. A major deficiency with the currently available devices is the ability to measure platelet function in a point-of-care technology. Small, portable, battery capable and resilient technology is badly needed. Lastly, the challenge of point-of-care assessment and time delay, balanced against the benefit of rapid evacuation, are important considerations.
PREHOSPITAL FLUID RESUSCITATION
Dr. Medby (7), Norwegian Armed Forces Medical Services, provides a balanced overview of the current status and understanding of the benefits and risks of both crystalloids and colloids. The discussion covers all of the various available crystalloids, including hypertonic saline, and colloid-based solutions being used. In Table 1, the impact of each of the various solutions on the coagulation status is specifically addressed, highlighting that plasma is the only agent that does not have a negative effect on coagulation. Currently, the controversy as to which fluid is most appropriate for the severely injured patient remains unresolved. Although crystalloid seems to remain best in the routine setting for nonmassive volume resuscitation, in the austere environment, even for the less severely injured, the logistics in providing this bulky product far forward is an unresolved challenge. The authors conclude that neither the currently available crystalloids nor colloids are ideal for the remote setting. Currently, outside the United States, the most commonly used agent is freeze-dried plasma in RDCR protocols implemented by many military forces despite a lack of human trials confirming the benefit of plasma for hypotensive resuscitation. Thus, the challenge of defining the optimal fluid in the austere environment remains unresolved.
In one of three articles on the use of whole blood, Dr. Murdock and colleagues (8) review the studies suggesting survival advantage with early use of whole blood. During World War I and World War II, whole-blood transfusions were the primary treatment for military hemorrhage, treating both shock and coagulopathy. After World War II, the fractionation of whole blood into components became widely accepted and rapidly replaced whole-blood transfusion to conserve this scarce resource, to optimize directed therapy for specific deficiencies, and for the financial benefits of component therapy to support the blood banking system. However, there are few trials in massive transfusion settings that component therapy, in particular, packed red blood cells and crystalloids, was comparable to the use of whole blood. This in part because only 3% to 5% of injured patients in major trauma centers require massive transfusion and the overall impact on outcome has been difficult to discern. Recent observations during military conflicts have shown a benefit of reconstituting whole blood using the various components; however, this “reconstituted” whole blood still has deficiencies, resulting in a functionally anemic, thrombocytopenic, and coagulopathic product. Although military observations have reconfirmed the potential significant benefit of whole blood, it has not been widely embraced because of the ongoing safety concerns, primarily in the civilian setting, of disease transmission and immunologic side effects from donor whole-blood constituents. The authors propose the use of low-titer, leukocyte-reduced, and cold-stored type O whole blood to minimize the risk while still maintaining reasonable functional coagulation profile for up to 21 days. The authors propose that a randomized controlled trial (RCT) is indicated to analyze whole blood using improved technical capabilities of preparation, storage, and avoidance of infectious risk against balanced component resuscitation currently advocated for massive transfusion.
A second article assessing the use of whole blood from Dr. Strandenes and colleagues (9) further define the known risks of whole-blood transfusion. In the past, whole blood from donors with low titers of anti-A/B blood group antibodies had been favored but has been replaced by the use of specific ABO group whole blood, derived in large part from data in the civilian setting under controlled settings. Civilian studies demonstrate that low titer antibody in A/B plasma, even when mismatched, causes only rare and mild severity complications. The authors argue that because of the restrained conditions, disorganization, and logistic challenges in the austere environment, it is inappropriate to maintain ABO group–specific approaches. The complications with mismatched ABO-induced destruction of the red blood cells transfused and O-type plasma antibodies being mismatched and injuring recipients are minimized with the use of low-titer O-type whole blood rather than delay or limit critically needed transfusions.
To define current use and experience with whole blood, the unit-specific RDCR Protocol of the Norwegian Naval Special Operation Commando is detailed by Dr. Strandenes and colleagues as a potential model for others (10). The authors emphasize the logistic challenges of providing sufficient and functional components of red blood cells, plasma, and platelets in the austere environment. Accepting the lack of prospective trials documenting the effectiveness or benefit of whole blood, the authors present the unit-specific protocol development and education for collection and transfusion of whole blood in the far-forward setting. Options are warm fresh whole blood, WB stored at 22°C for less than 24 h, or WB cold-stored at 4°C for as long as 21 days, although less than 10 days is preferred to maintain functional hemostatic capability. Stored blood is preferably leuko-reduced, with a platelet-sparing filter before refrigeration. To use this protocol, all potential donors are screened for detection of transmittable diseases, particularly hepatitis B virus, hepatitis C virus, and human immunodeficiency virus, and all personnel are routinely prescreened and typed before deployment. In addition, blood type O personnel have their plasma screened for anti-A and anti-B antibodies to enable use of low-titer O-type donors for non–type-O patients. Using this protocol, the ability to obtain and transfuse warm fresh whole blood in the austere environment with limited logistics and support becomes feasible but needs to be tested under field conditions and carefully tracked for complications and outcomes.
In an analysis focused on transfusion of isolated red blood cells for shock and the impact on coagulopathy, Drs. Spinella and Doctor (11) provide a reasoned assessment of the current literature and implications for further development of protocols and preservation approaches for red blood cell transfusion. The evolution of current red blood cell storage was driven to optimize utilization of this limited resource and the apparent adequate oxygen delivery of the red blood cell in noncritically ill patients. However, there is increasing recognition in the hemorrhagic shock patient that the current methods for prolonged storage of red blood cells appear to block oxygen delivery, affect regional distribution through loss of deformability of the red blood cell, and impair nitric oxide release. In addition, a deleterious effect on both platelet function and thrombin generation is identified and, with the lack of optimal oxygen delivery, leads to further activation and consumption of coagulation factors, worsening coagulopathy. The authors again point out the recent literature showing an improved outcome and coagulation profile in patients transfused with either whole blood or platelets stored at 4°C. The authors argue that the use of fresh red blood cells within a 7- to 10-day period, or whole blood stored at 4°C up to 10 days, or platelets stored at 4°C to preserve function requires clinical trials to document efficacy to define the optimal approach.
An intriguing approach in field resuscitation of coagulopathy to avoid the known complications of red blood cell transfusion is to improve the availability and safety of plasma. In the first of two articles on this subject, Dr. Hervig and colleagues (12) review the use of plasma and its safety from a blood banker’s perspective. The conclusion of this panel of senior blood bankers was the need for improved plasma availability, but must be proven safe and sustainable, along with Level I evidence of benefit. The authors acknowledge that, although available evidence of prehospital use of plasma may improve RDCR is encouraging, Level I evidence is lacking. Despite this, there is increasing use of plasma in both the military far-forward position and is being introduced in civilian settings. Major concerns include blood group incompatibility will lead to recipient cell lysis from high-titer antibodies in the donor and danger of transfusion-induced acute lung injury. Randomized controlled trials are required as are improved techniques to eliminate transfusion of infectious agents. In addition, the ideal product, fresh-frozen or lyophilized freeze-dried FFP, is unknown. Fresh-frozen plasma can be stored and is feasible for delivery far forward, whereas lyophilized (freeze-dried) FFP eliminates the requirement for thawing. Currently, the preparation of lyophilized FFP is variable between countries and is not available in the United States. However, with the lack of wastage, cost should be improved and provide an appealing approach in the prehospital environment.
A plasma-first resuscitation protocol is presented by Dr. Moore and colleagues (13). This clinical trial involves ground ambulance systems using rapid prehospital thawing of frozen plasma for the severely injured civilian population. Dr. Moore and colleagues provide the scientific rationale for utilization of plasma early in the resuscitation of the massive-transfusion patient. Data suggest that moving the resuscitation to the prehospital phase will improve prevention of the early-onset coagulopathy during the very narrow window available for therapeutic intervention. Funded by the US Department of Defense, the multicenter field trial is entitled “Control Of Major Bleeding After Trauma” (COMBAT), “a prospective randomized study of fresh-frozen plasma versus crystalloid as initial prehospital fluid resuscitation.” The impact on trauma-induced coagulopathy will be assessed, as will outcomes such as mortality and physiologic criteria. The plasma used will be antibody depleted to prevent transfusion risk, and the impact of the various resuscitation modalities on the proteome of the patient will be studied in an attempt to identify the impact of the transfusions on inflammatory mediators, hemostasis, and homeostasis. The outcomes of this study are eagerly awaited.
There are two articles assessing the impact of platelet transfusion and methods for improved functional preservation. The history of platelet storage is presented by Dr. Pidcoke and colleagues (14). Currently, platelet storage is at room temperature, with constant agitation to maximize cell recovery and optimize persistence of the platelets in vivo after transfusion. Refrigerated platelets are cleared more rapidly from the circulation and, thus, are considered inferior in the oncologic patient where prevention of bleeding is the primary goal. In contrast, cold storage, 0°C to 6°C, is less conducive to bacterial overgrowth and maintains better hemostatic function, which explains, in part, the rapid removal of platelets from the circulation. However, in the massively bleeding patient, these attributes are preferable to control bleeding and clot formation. Recent trials confirm that platelets stored at 4°C are more hemostatic and reduce acute bleeding compared with platelets stored at room temperature. Although infrequent use and logistic problems of splitting the resource are major barriers, the authors propose clinical trials as warranted and strong consideration given to splitting the resource and using cold-storage platelets for hemostasis in the massively bleeding patient.
The second article on the use of platelets deals with preservation of function in vitro in apheresis platelets through improvements in storage and processing by Dr. Reddoch and colleagues (15). The metabolic and functional characteristics of apheresis platelets stored at 4°C versus 22°C are investigated. These studies confirm that the platelets stored at 4°C maintain a normal profile of metabolic activity, are more effective hemostatically, and release fewer proinflammatory mediators than platelets stored at room temperature for 5 days. Thus, in this critical in vitro study, there is confirmation of the improved quality and function of platelets stored in cold refrigerated conditions. Logistically, the preparation and delivery of platelets to the prehospital environment would require refrigeration. However, the enhancement in function makes this challenge worthwhile and, in the civilian setting, should be achievable.
In an article by Dr. Schöchl et al. (16), the current status of hemostatic therapy is summarized. The combination of rapid control of bleeding and supplemental hemostatic agents is believed to be the optimal approach in the early care of the severely injured bleeding patient. The administration of tranexamic acid is an integral step in most trauma systems for the patient with severe blood loss. As with other hemostatic agents, concern for thrombotic complications, when given to noncoagulopathic patients, remains unresolved. In addition, massive consumption during coagulopathy causes an early depletion of fibrinogen after severe hemorrhage. Currently, trials are testing fibrinogen infusions to maintain normal plasma levels early in resuscitation. Clinical investigations will help ensure that this early administration has the presumed benefit proposed of decreasing subsequent coagulopathic bleeding. Other ongoing studies, particularly with traumatic brain injury, demonstrate prothrombin complex concentrates (PCCs) may be beneficial in patients who are anticoagulated with vitamin K antagonists. A broader benefit of PCC in the severely injured bleeding patient, however, has not been confirmed, and the risk of excessive thrombosis has not been eliminated. Thus, a remaining critical need is delineation of the appropriate subpopulations for select thrombotic agent intervention to minimize undue risk.
CLINICAL TRIAL DATA
An overview and commentary on the use of both observational research data and RCTs as complimentary approaches for the analysis of interventions in transfusion medicine are presented by Dr. Vincent et al. (17). The multiple challenges in this complex clinical environment make it not feasible to rely on only formal RCTs. The authors and others (18) propose a rational utilization of the two primary approaches available using both observational trials and RCTs to optimize improvements in our understanding and documentation of benefit for advancement in care of the bleeding critically injured patient.
In this excellent article, Dr. Donald H. Jenkins and many of the key members of the symposium (19) cover the main findings presented during the symposium. The summary relates our current understanding of the physiology of acute trauma–induced coagulopathy. Current practice approaches are defined, and major gaps in our knowledge are identified. Lastly, appropriate trial design is presented. The impact of both the extent of shock and the duration of oxygen deficiency, now defined as oxygen debt, is increasingly recognized and measured. The multiple interacting pathways of coagulation leading to both a hypocoagulable and hypercoagulable state, which are frequently present simultaneously, are explained as currently, but incompletely, understood. The various logistic problems of providing care balanced with evacuation in the austere environment in far-forward locations are defined. The current use of hemostatic adjuncts to correct the coagulopathy by using labile blood components and biologics derived from blood includes our current limitations in knowledge. Lastly, our current status not only to poorly identify the existence of shock and coagulopathic state early in the disease process but also our inability to define when resuscitation is adequate remains a major challenge.
Optimal controlled, rather than hypotensive, resuscitation, because of delay in transfer and prolonged extrication versus the impact on inadequate perfusion, particularly in the setting of blunt trauma with severe CNS injury, remains an unachieved goal. The current range of practices in prehospital resuscitation in various military and civilian settings around the world is presented. Fresh whole blood is discussed as a potential ideal product for early resuscitation while needing to improve methods of preparation, storage, and elimination of complications such as disease transmission are explored. Studies looking at the impact of fibrinogen to optimize clot stability and strength and use of cold-storage preservation for optimal platelet function are reviewed. The current status of injectable hemostatics is covered, focusing on improved outcomes using tranexamic acid and the selective use of Factor VIIa and PCCs.
The major gaps in knowledge are identified, including 1) the inability to identify and monitor early shock and hypocoagulable state in the severely injured patient to identify the patient most likely to benefit from intervention and avoid the unnecessary risk of unnecessary interventions, 2) the ability to optimize controlled resuscitation with the need for adequate perfusion of critical organ injuries, 3) the ability to transport point-of-care technology necessary to measure intravascular volume and coagulation status far forward, 4) and identification of ideal blood components and their selective use. The ideal blood component or biologic and how to optimize preparation, storage, and delivery remain poorly elucidated, the major goal of the present symposium and the future of research in prehospital resuscitation.
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