John B. Holcomb

Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients

Objective:To determine the effect of blood component ratios in massive transfusion (MT), we hypothesized that increased use of plasma and platelet to red blood cell (RBC) ratios would result in decreased early hemorrhagic death and this benefit would be sustained over the ensuing hospitalization. Summary Background Data:Civilian guidelines for massive transfusion (MT ≥10 units of RBC in 24 hours) have typically recommend a 1:3 ratio of plasma:RBC, whereas optimal platelet:RBC ratios are unknown. Conversely, military data shows that a plasma:RBC ratio approaching 1:1 improves long term outcomes in MT combat casualties. There is little consensus on optimal platelet transfusions in either civilian or military practice. At present, the optimal combinations of plasma, platelet, and RBCs for MT in civilian patients is unclear. Methods:Records of 467 MT trauma patients transported from the scene to 16 level 1 trauma centers between July 2005 and June 2006 were reviewed. One patient who died within 30 minutes of admission was excluded. Based on high and low plasma and platelet to RBC ratios, 4 groups were analyzed. Results:Among 466 MT patients, survival varied by center from 41% to 74%. Mean injury severity score varied by center from 22 to 40; the average of the center means was 33. The plasma:RBC ratio ranged from 0 to 2.89 (mean ± SD: 0.56 ± 0.35) and the platelets:RBC ratio ranged from 0 to 2.5 (0.55 ± 0.50). Plasma and platelet to RBC ratios and injury severity score were predictors of death at 6 hours, 24 hours, and 30 days in multivariate logistic models. Thirty-day survival was increased in patients with high plasma:RBC ratio (≥1:2) relative to those with low plasma:RBC ratio (<1:2) (low: 40.4% vs. high: 59.6%, P < 0.01). Similarly, 30-day survival was increased in patients with high platelet:RBC ratio (≥1:2) relative to those with low platelet:RBC ratio (<1:2) (low: 40.1% vs. high: 59.9%, P < 0.01). The combination of high plasma and high platelet to RBC ratios were associated with decreased truncal hemorrhage, increased 6-hour, 24-hour, and 30-day survival, and increased intensive care unit, ventilator, and hospital-free days (P < 0.05), with no change in multiple organ failure deaths. Statistical modeling indicated that a clinical guideline with mean plasma:RBC ratio equal to 1:1 would encompass 98% of patients within the optimal 1:2 ratio. Conclusions:Current transfusion practices and survival rates of MT patients vary widely among trauma centers. Conventional MT guidelines may underestimate the optimal plasma and platelet to RBC ratios. Survival in civilian MT patients is associated with increased plasma and platelet ratios. Massive transfusion practice guidelines should aim for a 1:1:1 ratio of plasma:platelets:RBCs.

Combat wounds in operation Iraqi Freedom and operation Enduring Freedom.

BACKGROUND There have been no large cohort reports detailing the wounding patterns and mechanisms in the current conflicts in Iraq and Afghanistan. METHODS The Joint Theater Trauma Registry was queried for all US service members receiving treatment for wounds (International Classification of Diseases-9th Rev. codes 800-960) sustained in Operation Iraqi Freedom and Operation Enduring Freedom from October 2001 through January 2005. Returned-to-duty and nonbattle injuries were excluded from final analysis. RESULTS This query resulted in 3,102 casualties, of which 31% were classified as nonbattle injuries and 18% were returned-to-duty within 72 hours. A total of 1,566 combatants sustained 6,609 combat wounds. The locations of these wounds were as follows: head (8%), eyes (6%), ears (3%), face (10%), neck (3%), thorax (6%), abdomen (11%), and extremity (54%). The proportion of head and neck wounds is higher (p < 0.0001) than the proportion experienced in World War II, Korea, and Vietnam wars (16%-21%). The proportion of thoracic wounds is a decrease (p < 0.0001) from World War II and Vietnam (13%). The proportion of gunshot wounds was 18%, whereas the proportion sustained from explosions was 78%. CONCLUSIONS The wounding patterns currently seen in Iraq and Afghanistan resemble the patterns from previous conflicts, with some notable exceptions: a greater proportion of head and neck wounds, and a lower proportion of thoracic wounds. An explosive mechanism accounted for 78% of injuries, which is the highest proportion seen in any large-scale conflict.

Red blood cell transfusion: A Clinical practice guideline from the AABB

DESCRIPTION Although approximately 85 million units of red blood cells (RBCs) are transfused annually worldwide, transfusion practices vary widely. The AABB (formerly, the American Association of Blood Banks) developed this guideline to provide clinical recommendations about hemoglobin concentration thresholds and other clinical variables that trigger RBC transfusions in hemodynamically stable adults and children. METHODS These guidelines are based on a systematic review of randomized clinical trials evaluating transfusion thresholds. We performed a literature search from 1950 to February 2011 with no language restrictions. We examined the proportion of patients who received any RBC transfusion and the number of RBC units transfused to describe the effect of restrictive transfusion strategies on RBC use. To determine the clinical consequences of restrictive transfusion strategies, we examined overall mortality, nonfatal myocardial infarction, cardiac events, pulmonary edema, stroke, thromboembolism, renal failure, infection, hemorrhage, mental confusion, functional recovery, and length of hospital stay. RECOMMENDATION 1: The AABB recommends adhering to a restrictive transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients (Grade: strong recommendation; high-quality evidence). RECOMMENDATION 2: The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less (Grade: weak recommendation; moderate-quality evidence). RECOMMENDATION 3: The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized, hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence). RECOMMENDATION 4: The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration (Grade: weak recommendation; low-quality evidence).

The coagulopathy of trauma: a review of mechanisms.

BACKGROUND Bleeding is the most frequent cause of preventable death after severe injury. Coagulopathy associated with severe injury complicates the control of bleeding and is associated with increased morbidity and mortality in trauma patients. The causes and mechanisms are multiple and yet to be clearly defined. METHODS Articles addressing the causes and consequences of trauma-associated coagulopathy were identified and reviewed. Clinical situations in which the various mechanistic causes are important were sought along with quantitative estimates of their importance. RESULTS Coagulopathy associated with traumatic injury is the result of multiple independent but interacting mechanisms. Early coagulopathy is driven by shock and requires thrombin generation from tissue injury as an initiator. Initiation of coagulation occurs with activation of anticoagulant and fibrinolytic pathways. This Acute Coagulopathy of Trauma-Shock is altered by subsequent events and medical therapies, in particular acidemia, hypothermia, and dilution. There is significant interplay between all mechanisms. CONCLUSIONS There is limited understanding of the mechanisms by which tissue trauma, shock, and inflammation initiate trauma coagulopathy. Acute Coagulopathy of Trauma-Shock should be considered distinct from disseminated intravascular coagulation as described in other conditions. Rapid diagnosis and directed interventions are important areas for future research.

Transfusion of Plasma, Platelets, and Red Blood Cells in a 1:1:1 vs a 1:1:2 Ratio and Mortality in Patients With Severe Trauma: The PROPPR Randomized Clinical Trial

IMPORTANCE Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. OBJECTIVE To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. DESIGN, SETTING, AND PARTICIPANTS Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. INTERVENTIONS Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). MAIN OUTCOMES AND MEASURES Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. RESULTS No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. CONCLUSIONS AND RELEVANCE Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01545232.

Death on the battlefield (2001-2011): implications for the future of combat casualty care.

BACKGROUND Critical evaluation of all aspects of combat casualty care, including mortality, with a special focus on the incidence and causes of potentially preventable deaths among US combat fatalities, is central to identifying gaps in knowledge, training, equipment, and execution of battlefield trauma care. The impetus to produce this analysis was to develop a comprehensive perspective of battlefield death, concentrating on deaths that occurred in the pre–medical treatment facility (pre-MTF) environment. METHODS The Armed Forces Medical Examiner Service Mortality Surveillance Division was used to identify Operation Iraqi Freedom and Operation Enduring Freedom combat casualties from October 2001 to June 2011 who died from injury in the deployed environment. The autopsy records, perimortem records, photographs on file, and Mortality Trauma Registry of the Armed Forces Medical Examiner Service were used to compile mechanism of injury, cause of injury, medical intervention performed, Abbreviated Injury Scale (AIS) score, and Injury Severity Score (ISS) on all lethal injuries. All data were used by the expert panel for the conduct of the potential for injury survivability assessment of this study. RESULTS For the study interval between October 2001 and June 2011, 4,596 battlefield fatalities were reviewed and analyzed. The stratification of mortality demonstrated that 87.3% of all injury mortality occurred in the pre-MTF environment. Of the pre-MTF deaths, 75.7% (n = 3,040) were classified as nonsurvivable, and 24.3% (n = 976) were deemed potentially survivable (PS). The injury/physiologic focus of PS acute mortality was largely associated with hemorrhage (90.9%). The site of lethal hemorrhage was truncal (67.3%), followed by junctional (19.2%) and peripheral-extremity (13.5%) hemorrhage. CONCLUSION Most battlefield casualties died of their injuries before ever reaching a surgeon. As most pre-MTF deaths are nonsurvivable, mitigation strategies to impact outcomes in this population need to be directed toward injury prevention. To significantly impact the outcome of combat casualties with PS injury, strategies must be developed to mitigate hemorrhage and optimize airway management or reduce the time interval between the battlefield point of injury and surgical intervention. Understanding battlefield mortality is a vital component of the military trauma system. Emphasis on this analysis should be placed on trauma system optimization, evidence-based improvements in Tactical Combat Casualty Care guidelines, data-driven research, and development to remediate gaps in care and relevant training and equipment enhancements that will increase the survivability of the fighting force.

Causes of death in U.S. special operations forces in the global war on terrorism: 2001-2004

Background:Effective combat trauma management strategies depend upon an understanding of the epidemiology of death on the battlefield. Methods:A panel of military medical experts reviewed photographs and autopsy and treatment records for all Special Operations Forces (SOF) who died between October 2001 and November 2004 (n = 82). Fatal wounds were classified as nonsurvivable or potentially survivable. Training and equipment available at the time of injury were taken into consideration. A structured analysis was conducted to identify equipment, training, or research requirements for improved future outcomes. Results:Five (6%) of 82 casualties had died in an aircraft crash, and their bodies were lost at sea; autopsies had been performed on all other 77 soldiers. Nineteen deaths, including the deaths at sea were noncombat; all others were combat related. Deaths were caused by explosions (43%), gunshot wounds (28%), aircraft accidents (23%), and blunt trauma (6%). Seventy of 82 deaths (85%) were classified as nonsurvivable; 12 deaths (15%) were classified as potentially survivable. Of those with potentially survivable injuries, 16 causes of death were identified: 8 (50%) truncal hemorrhage, 3 (19%) compressible hemorrhage, 2 (13%) hemorrhage amenable to tourniquet, and 1 (6%) each from tension pneumothorax, airway obstruction, and sepsis. The population with nonsurvivable injuries was more severely injured than the population with potentially survivable injuries. Structured analysis identified improved methods of truncal hemorrhage control as a principal research requirement. Conclusions:The majority of deaths on the modern battlefield are nonsurvivable. Improved methods of intravenous or intracavitary, noncompressible hemostasis combined with rapid evacuation to surgery may increase survival.

Injury severity and causes of death from Operation Iraqi Freedom and Operation Enduring Freedom: 2003-2004 versus 2006.

BACKGROUND The opinion that injuries sustained in Iraq and Afghanistan have increased in severity is widely held by clinicians who have deployed multiple times. To continuously improve combat casualty care, the Department of Defense has enacted numerous evidence-based policies and clinical practice guidelines. We hypothesized that the severity of wounds has increased over time. Furthermore, we examined cause of death looking for opportunities of improvement for research and training. METHODS Autopsies of the earliest combat deaths from Iraq and Afghanistan and the latest deaths of 2006 were analyzed to assess changes in injury severity and causes of death. Fatalities were classified as nonsurvivable (NS) or potentially survivable (PS). PS deaths were then reviewed in depth to analyze mechanism and cause. RESULTS There were 486 cases from March 2003 to April 2004 (group 1) and 496 from June 2006 to December 2006 (group 2) that met inclusion criteria. Of the PS fatalities (group 1: 93 and group 2: 139), the injury severity score was lower in the first group (27 +/- 14 vs. 37 +/- 16, p < 0.001), and had a lower number of abbreviated injury scores >or=4 (1.1 +/- 0.79 vs. 1.5 +/- 0.83 per person, p < 0.001). The main cause of death in the PS fatalities was truncal hemorrhage (51% vs. 49%, p = NS). Deaths per month between groups doubled (35 vs. 71), whereas the case fatality rates between the two time periods were equivalent (11.0 vs. 9.8, p = NS). DISCUSSION In the time periods of the war studied, deaths per month has doubled, with increases in both injury severity and number of wounds per casualty. Truncal hemorrhage is the leading cause of potentially survivable deaths. Arguably, the success of the medical improvements during this war has served to maintain the lowest case fatality rate on record.

The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital.

BACKGROUND To treat the coagulopathy of trauma, some have suggested early and aggressive use of cryoprecipitate as a source of fibrinogen. Our objective was to determine whether increased ratios of fibrinogen to red blood cells (RBCs) decreased mortality in combat casualties requiring massive transfusion. METHODS We performed a retrospective chart review of 252 patients at a U.S. Army combat support hospital who received a massive transfusion (>or=10 units of RBCs in 24 hours). The typical amount of fibrinogen within each blood product was used to calculate the fibrinogen-to-RBC (F:R) ratio transfused for each patient. Two groups of patients who received either a low (<0.2 g fibrinogen/RBC Unit) or high (>or=0.2 g fibrinogen/RBC Unit) F:R ratio were identified. Mortality rates and the cause of death were compared between these groups, and logistic regression was used to determine if the F:R ratio was independently associated with survival. RESULTS Two-hundred and fifty-two patients who received a massive transfusion with a mean (SD) ISS of 21 (+/-10) and an overall mortality of 75 of 252 (30%) were included. The mean (SD) F:R ratios transfused for the low and high groups were 0.1 grams/Unit (+/-0.06), and 0.48 grams/Unit (+/-0.2), respectively (p < 0.001). Mortality was 27 of 52 (52%) and 48 of 200 (24%) in the low and high F:R ratio groups respectively (p < 0.001). Additional variables associated with survival were admission temperature, systolic blood pressure, hemoglobin, International Normalized Ratio (INR), base deficit, platelet concentration and Combined Injury Severity Score (ISS). Upon logistic regression, the F:R ratio was independently associated with mortality (odds ratio 0.37, 95% confidence interval 0.171-0.812, p = 0.013). The incidence of death from hemorrhage was higher in the low F:R group, 23/27 (85%), compared to the high F:R group, 21/48 (44%) (p < 0.001). CONCLUSIONS In patients with combat-related trauma requiring massive transfusion, the transfusion of an increased fibrinogen: RBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. Prospective studies are needed to evaluate the best source of fibrinogen and the optimal empiric ratio of fibrinogen to RBCs in patients requiring massive transfusion.

Survival with Emergency Tourniquet Use to Stop Bleeding in Major Limb Trauma

Objective:The purpose of this study was to determine if emergency tourniquet use saved lives. Summary Background Data:Tourniquets have been proposed as lifesaving devices in the current war and are now issued to all soldiers. Few studies, however, describe their actual use in combat casualties. Methods:A prospective survey of injured who required tourniquets was performed over 7 months in 2006 (NCT00517166 at ClinicalTrials.gov). Follow-up averaged 28 days. The study was at a combat support hospital in Baghdad. Among 2838 injured and admitted civilian and military casualties with major limb trauma, 232 (8%) had 428 tourniquets applied on 309 injured limbs. We looked at emergency tourniquet use, and casualties were evaluated for shock (weak or absent radial pulse) and prehospital versus emergency department (ED) tourniquet use. We also looked at those casualties indicated for tourniquets but had none used. We assessed survival rates and limb outcome. Results:There were 31 deaths (13%). Tourniquet use when shock was absent was strongly associated with survival (90% vs. 10%; P < 0.001). Prehospital tourniquets were applied in 194 patients of which 22 died (11% mortality), whereas 38 patients had ED application of which 9 died (24% mortality; P = 0.05). The 5 casualties indicated for tourniquets but had none used had a survival rate of 0% versus 87% for those casualties with tourniquets used (P < 0.001). Four patients (1.7%) sustained transient nerve palsy at the level of the tourniquet. No amputations resulted solely from tourniquet use. Conclusions:Tourniquet use when shock was absent was strongly associated with saved lives, and prehospital use was also strongly associated with lifesaving. No limbs were lost due to tourniquet use. Education and fielding of prehospital tourniquets in the military environment should continue.