TXA in Combat Casualty Care Does It Adversely Affect Extremity Reconstruction and Flap Thrombosis Rates?

Transcription

1 MILITARY MEDICINE, 180, 3:24, 2015 TXA in Combat Casualty Care Does It Adversely Affect Extremity Reconstruction and Flap Thrombosis Rates? CDR Ian L. Valerio, MC USN; LT Paul Campbell, MC USN; CPT Jennifer Sabino, MC USA; LT Donald J. Lucas, MC USN; CDR Elliot Jessie, MC USN; CDR Carlos Rodriguez, MC USN; CDR Mark Fleming, MC USN ABSTRACT Introduction: Tranexamic acid (TXA) is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin. In recent years, the military has adapted TXA s use in combat casualties suffering severe hemorrhagic injuries. The purpose of this study is to examine the association between TXA on complications such as venous thromboembolic events (VTEs) and flap-related thrombosis in combat trauma patients undergoing tissue transfer for extremity reconstruction. Methods: A retrospective chart review of war wounded undergoing extremity reconstructions from 2003 to 2012 at Walter Reed National Military Medical Center was completed. Data collected included patient demographics and administration of TXA. Outcomes measured included VTE rates and flap complications in TXA and non-txa cohorts. Results: From 2003 to 2012, 173 extremity flap procedures were performed (100 pedicle, 73 free flaps). TXA was used in 11% of all patients reviewed. The overall VTE rate was 23.7%; however, there were no documented VTEs in patients who received TXA. Total flap complications, 26% versus 21%, or flap failure, 5% versus 4%, ( p = and 0.564, respectively) did not differ significantly between those that received TXA versus those that did not. Conclusion: Given the increasing use of TXA in the combat casualties, concern over its impact on VTE rates and flap complications is of interest. However, in this early review, we did not find significant differences in patients who received TXA and those that did not. Further research is indicated to better determine the significance and the effect of TXA on complex limb salvages. INTRODUCTION Modern improvements and advancements within battlefield trauma resuscitation and surgery have had significant impacts on combat casualty survival rates. These constantly evolving paradigms and algorithms of in-theater care have been aimed at primarily saving life and have been associated with increased success. Through appropriate application of extremity tourniquet use for immediate hemorrhage control, refinements in body armor and protective gear, forward surgical teams, balanced resuscitation measures, more efficient in-theater transport capabilities, as well as advanced trauma and critical care capabilities, war-related mortality rates have been estimated to be less than 5% for those severely injured service members arriving at our combat medical treatment facilities. 1 3 Furthermore, the vast majority of mortalities during our recent conflicts, Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF), occurred before presentation to theater military treatment facilities and were deemed nonsurvivable regardless of medical care. 4 Of those injuries deemed to be survivable, the majority of mortalities (>90%) have been directly attributed to major Plastic and Reconstructive Surgery Service, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD This article was presented at the Military Health System Research Symposium Annual Meeting, Fort Lauderdale, Florida, August 14, 2013 and at the AMSUS: The Society of Federal Health Professionals 118th Annual Meeting, Seattle, Washington, November 5, The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Army, Department of Defense, or the U.S. Government. doi: /MILMED-D vascular disruption with subsequent hemorrhage. 4 Balanced resuscitation has effectively contributed to decreased mortality rates, but until recently, the use of medication to improve mortality in the presence of hemorrhagic shock was not widely used or understood. 3,5 Recently, tranexamic acid (TXA) has been shown to significantly reduce all-cause mortality in the civilian (CRASH-2 study) trauma populations and is associated with reduced mortality in military (MATTERs study) trauma populations. 5,6 TXA is a lysine analog that effectively inhibits fibrinolysis by blocking lysine-binding sites on plasminogen and its conversion to plasmin. By inhibiting the conversion to plasmin, there is a decrease in clot breakdown and an increase in clot stabilization. 6 When specifically focusing on the military trauma applications and results, application of TXA within the initial 3 hours of injury has had an absolute reduction in mortality by 13.7% for those critically injured casualties undergoing massive transfusion and an overall mortality rate reduction of 6.5%. 5 Given these significant findings and impact on survivability, the Tactical Combat Casualty Care (TCCC) guidelines were officially revised in August 2011 to specifically include the use of TXA in the tactical field care for any casualty with an anticipated need for blood transfusion (i.e., 1 or more amputations, penetrating torso trauma, or evidence of shock). 7 Despite the improved mortality rates with the use of TXA and its procoagulant profile, concern has been raised over the increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE) in those casualties who have received it in the course of their care. In the 24

2 MATTERs study, those military trauma patients that received TXA versus those who did not experience 2.4% versus 0.2% increased rate of DVT and a 2.4% versus 0.3% increased rate of PE, respectively. 5 Before the use of TXA, venous thromboembolic event (VTE) rates were already shown to be elevated within our military trauma populations, with the rates of DVT and PE estimated to range from 5% to 26% within the military cohorts. 2,8,9 These rates significantly exceed those reported within the general civilian trauma population (0.42%). 2,8,9 As greater numbers of war casualties are surviving, despite higher injury severity scores (ISS) and complex patterns of injury, the use of TXA have also increased. Increased survival rates have contributed to a corresponding rise in the need of extensive and continued reconstructive surgery measures. 10 With relatively high rates of DVT/PE in our military trauma patient populations, our reconstructive surgery team has become interested in the potential effects that TXA may have on soft tissue complications, flap transfers, and extremity reconstructions. 10 All of these reconstructions and ultimately their success is based on adequate perfusion and avoidance of potential clotting or thrombotic events. The formation of thrombosis within the vascular system of an extremity and/or within a flap or soft tissue coverage procedure can be potentially devastating; resulting in amputation, proximal advancement of present amputations, and/or further tissue losses. This study is one of the first to more closely examine thromboembolic and other complications in soft tissue extremity reconstructions for those war-injured casualties where TXA was used in their prior resuscitation events within the battlefield setting. The purpose of this study is to examine the association between TXA on complications such as VTEs and flap-related thrombosis in combat trauma patients undergoing tissue transfer for extremity reconstruction. METHODS A retrospective consecutive case series of severely injured combat casualties requiring soft tissue coverage and tissue transfers for extremity reconstruction was conducted. Walter Reed National Military Medical Center Institutional Review Board approval was obtained before the study. The study included those war-related casualties with extremity injuries undergoing limb salvage flap transfer procedures from Operation Iraqi Freedom and Operation Enduring Freedom and included those cases from 2003 to Data were collected from the patients electronic medical records at Walter Reed National Military Medical Center. Data collected included patient demographics, soft tissue and flap transfer types, ISS, timing of wound coverage, and whether administration of TXA occurred in their initial resuscitation events. Patients were also evaluated for VTE rates. Primary outcomes reviewed included flap success/failure rates, complications such as hematoma, venous congestion, and infection rates in both the TXA and non-txa treatment cohorts. Venous congestion was determined clinically and defined as venous congestion requiring additional intervention such as leeches or debridement. Infection was defined as positive tissue culture requiring additional intravenous antibiotics and/or operative debridement. The rate of VTE in each group was also evaluated. VTEs were diagnosed on duplex ultrasound or computed tomography of the chest and/or extremities ordered based on clinical suspicion. Descriptive variables were compared using Student s t-test for means and Mann Whitney for medians. Categorical variables were compared as a proportion using c 2 or Fischer s exact test, as appropriate. Significance was defined as two tailed p value Analysis was performed using IBM SPSS Statistics 22 (IBM, Armonk, New York). RESULTS During the 10-year-study period, a total of 173 limb salvage cases requiring soft tissue flap coverage procedures were performed at our institution on 149 wounded service members. The average age of these patients was 24 (range 19 45) with an average ISS of 22 (range 8 50). Eighty-nine (51%) of injuries treated were in the upper extremity and 84 (49%) in the lower extremity. Most patients were injured by improvised explosive device. During the study period, 11% of all patients received TXA during their in-theater resuscitation events. However, the use of TXA trended significantly upward after 2010, with 25% of all flap patients receiving TXA during the initial resuscitation event. The patients who received TXA were similar in terms of age and pre- and postoperative care. However, patients who received TXA had a significantly higher ISS (Table I). The overall VTE rate was 23.5% in patients undergoing extremity flap coverage procedures. The overall VTE rate was 23.5% in patients undergoing extremity flap coverage procedures. There were no patients who received TXA during initial resuscitation who went on to develop DVT or pulmonary embolus. The patients who did not receive TXA had a perioperative VTE rate of 26.6%. TXA use did not significantly increase total flap complications (26% versus 21%) or flap failure (5% versus 4%) in patients undergoing flap TABLE I. Patient Demographics TXA No TXA Mean (SD) Mean (SD) p Value Age 24 (4.0) 24 (5.0) Injury Severity Score 29 (7.2) 21 (10) Median (SD) Median (SD) p Value Procedures Prior 8.0 (4.5) 7.0 (4.2) Days to Flap 18 (55) 19 (21) Procedures After 2 (2.2) 3 (2.8) Hospital Days 48 (23) 49.5 (26) TXA, tranexamic acid 25

3 TABLE II. Tranexamic acid (TXA) Complications TXA No TXA n (%) n (%) p Value Total 5 (26) 33 (21) Infection 0 (0) 7 (5) Hematoma 3 (16) 12 (8) Venous Congestion 0 (0) 2 (1) Partial Necrosis 1 (5) 5 (3) Total Necrosis 1 (5) 2 (1) Flap Failure 1 (5) 6 (4) procedure ( p = and p = 0.564). There were also no differences when complications were broken down individually (Table II). DISCUSSION The application of TXA to patients suffering from hemorrhagic shock has been shown to significantly reduce mortality within both civilian populations; there is a similar association in military trauma population studies. By blocking the conversion of plasminogen to plasmin, this medication acts as an effective inhibitor of fibrinolysis and clot stabilization. 5,6 Given the high rates of battlefield casualties exhibiting trauma associated with severe hemorrhage, the benefit of TXA within the first 3 hours of initial battlefield injury is substantial. These casualties often suffer significant blast trauma, which typically results in serious extremity and polyextremity wounds, high rates of concomitant injuries including visceral, vascular, and traumatic brain, as well as casualties surviving despite high-associated ISS. The first reported benefit of employing TXA within our battlefield trauma population was readily supported by the findings from the MATTERs study. This study determined the number needed to treat for expected mortality benefit was rather low (i.e., 1 in 7). 5 Before 2010, TXA was sparingly used in combat casualty care, and only administered by deployed surgeons and/or anesthesiologists at their discretion. However, since 2010, based on the reported findings and benefits demonstrated by the civilian trauma CRASH-2 trial and suggested by the military trauma MATTERS trial, TCCC established a new set of guidelines firmly supporting the use of TXA within the algorithms of treating battlefield casualties encountering severe hemorrhagic associated events. 5, 6 These practices and application of TXA within our clinical care guidelines has likely contributed to the reported improved survival rates that this most recent conflict has seen. In fact, within our cohort of combat casualties requiring flap procedures for limb reconstruction, there was a trend toward increased use of TXA during their initial downrange care. This trend correlated directly with the TCCC guidelines that established the use of TXA for battlefield trauma in Given the improved mortality benefit from TXA application in combat casualty care, some concerns with potential increased thromboembolism rates, as seen in the MATTERs study, lead our research team to review its potential impact on a specific cohort of severely injured combat casualties that were noted and previously reported to have a rather high thromboembolism rate. 5,10 With service members surviving injuries despite higher associated ISS s, our institution encountered an increasing number of extremity and polyextremity reconstruction cases with need for soft tissue and flap transfers. 10 Although some of these extremity salvages likely benefitted downrange from application of temporary vascular shunting and timely vascular repairs, our experienced multidisciplinary surgical teams within our forward surgical units, coupled with rapid transport through the in-theater care systems, has likewise contributed to positive gains in survival of our war wounded. 11 As our group encountered the increasing numbers of limb salvage and extremity reconstructions, we noted an associated increased rate of DVT and PE within this cohort of patients. Our concern, thus, focused on the procoagulant profile and potential influence that downrange measures, including the role that use of TXA in this cohort, may have on the encountered high rate of DVT and PE as well as potential impact TXA may have on flap success or failure rates, complications, and thromboembolic events within our specific casualty care cohort. Despite a fairly small group identified as having received TXA, there was no statistically significant increase in flap failure rate, thromboembolic events, or complications in those patients receiving TXA compared to those who did not receive TXA in the course of their in-theater treatment. Additionally, our group did not find an increased risk for the development of infection, hematoma, venous congestion, and/or necrosis in the TXA versus non-txa groups. Conversely, there was also no improvement in flap outcomes if the patient had received TXA or not. Despite the increased risk of DVT/PE as highlighted by the MATTERs study, we did not see any negative thromboembolic or prothrombosis effect on our flaps with the use of TXA. A possible explanation for this may be the relatively quick clearance of TXA. The half-life of TXA in an individual without renal dysfunction is 3 hours, with 90% of the medication cleared in 24 hours. 12,13 The MATTERs and CRASH-2 study both highlight the importance of the administration of TXA within the first 3 hours of injury for maximal reduction in mortality; thus, TXA has a rapid onset of action and clearance likely contributing to low rates of complications within a subacute or chronic reconstruction setting. 5,6 Current TCCC guidelines reflect these studies and our patients received TXA early in their combat casualty care, which also may be a reason long-lasting or delayed vents associated with this medication did not occur within our study cohort. Since the majority of our extremity reconstruction and tissue flap transfers took place within a subacute period after the initial injury (i.e., 5 21 days), the short halflife of TXA, its rapid clearance, and relative necessary delay in extremity reconstruction with flap transfers can potentially account for why there were no statistically significant 26

4 increases in flap complications/failure in those patients who previously received TXA in their treatment course. The use of TXA has also been shown to attenuate the inflammatory response (IR) along with its antifibrinolytic capabilities. Jimenz et al 14 investigated TXA in patients undergoing cardiopulmonary bypass, and his group showed that TXA significantly reduced the IR by 35% compared to the placebo group. Cardiopulmonary bypass patients had significantly decreased rates of vasoplegic shock, decreased vasopressor use, and shorter times on mechanical ventilation when TXA was used. 14 In our combat casualties studied in the MATTERS trial, the primary benefit of TXA on mortality reduction was not evident until approximately 24 hours after its administration, but the benefit in mortality reduction has also has been hypothesized to stem from attenuation of IRs. 5 Prolonged IRs also has negative associated impact on traumatic extremity and flap reconstructions as it contributes to microcirculatory and cellular disarrangements that can contribute to increases in flap thrombotic events and failure Such inflammatory cascades can lead to states of shock and need for vasopressors for supportive care measures, both of which can be devastating to any extremity injury or potential soft tissue reconstructive procedure as these events may result in further cellular or tissue destruction and loss, contribute to higher amputation rates and/or conversion of distal amputations to more proximal amputations, as well as lead to further prothromboembolic events. By attenuating the massive IR, TXA may actually contribute to extremity and flap reconstruction success rates especially in critically injured and hemorrhagic shock patients that survive their initial devastating trauma, patients whom may not have previously lived to have such reconstructive measures performed otherwise. Some may call into question the validity of TXA increasing DVT/PE rates when comparing the MATTERs study versus the CRASH-2 study as well. Although the MATTERs study had a statistically significant increase in DVT/PE rates, there was no elevated risk in the CRASH-2 study. 6 However, this difference may be explained by more closely evaluating the population examined within each study. Patients in the CRASH-2 study had lower ISS on average, and not all patients who received TXA in this study required blood transfusions and/or surgery. The main mechanism of injury was blunt trauma within the CRASH-2 study as compared to the higher rates of penetrating and blast injuries studied within MATTERs. 5,6 The individuals in this study mirror those reported within MATTERs as our cohort were military combat casualties having higher ISS s, primarily blast-related trauma with many concomitant injuries, and severe extremity or polyextremity damage. MATTERs reported a higher VTE rate in patients receiving TXA, raising the concern of TXAassociated prothrombotic risk/events and potential effect on flap and extremity reconstruction outcomes required evaluation. However, the higher incidence of VTE and/or flap complications is complicated by the fact that patients who receive TXA are generally more injured than those who do not, giving them a higher risk at baseline. This study is, however, one of the first of its nature to report on the potential effects, associated complications, and outcomes of TXA use in soft tissue transfers and extremity reconstruction. Our study is limited by the relatively low number of combat casualties within our cohort receiving TXA during their initial resuscitation events. The study is not sufficiently powered to draw definite conclusions. However, the early results reported may be further supported as the number of war trauma cases surviving their battlefield injuries and receiving TXA will continue to rise as evidenced by our trends seen within this particular cohort reviewed. Additionally, our low study numbers were also affected by the use of one CONUS base medical institution and could be expanded as well to determine the greater impact this measure has had on reconstruction outcomes. Although the individuals studied had massive soft tissue and extremity damage requiring flaps and reconstruction, it is not possible to standardize their medical care between centers either. Each military trauma patient has varying factors contributing to potential differences in treatment such as timing of TXA administration, distance from a medical facility, number of procedures before reconstruction or coverage, reconstruction measures employed, immobility, amount of injuries, or generalized health comorbidities. Even though the majority of our patients sustained blast injuries, the extent of damage and injury pattern is unique to each individual and can be impossible to duplicate. CONCLUSION TXA is associated with reduced mortality in war wounded military trauma along with the civilian trauma population. Coupled with improved trauma care, medevac capabilities, and resuscitative efforts, war trauma mortality rates will continue to improve. The increasing trend in the need for tissue flap transfers and complex extremity reconstructions for previously nonsurvivable war injury patterns will parallel these survival curves and will continue to escalate as well. Along with the already elevated risk of VTE in military trauma patients, prothrombotic and embolic events contributes to increased amputation rates, further loss of tissue, and failed flap or extremity reconstructions. This study is one of the first to suggest that TXA is not associated with increased flap complications/failure. REFERENCES 1. Kotwal RS, Montgomery HR, Kotwal BM, et al: Eliminating preventable death on the battlefield. Arch Surg 2011; 146(12): Gillern SM, Sheppard FR, Evans KN, et al: Incidence of pulmonary embolus in combat casualties with extremity amputations and fractures. 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