James D. Ross

Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study

OBJECTIVE To quantify the impact of fibrinogen-containing cryoprecipitate in addition to the antifibrinolytic tranexamic acid on survival in combat injured. DESIGN Retrospective observational study comparing the mortality of 4 groups: tranexamic acid only, cryoprecipitate only, tranexamic acid and cryoprecipitate, and neither tranexamic acid nor cryoprecipitate. To balance comparisons, propensity scores were developed and added as covariates to logistic regression models predicting mortality. SETTING A Role 3 Combat Surgical Hospital in southern Afghanistan. PATIENTS A total of 1332 patients were identified from prospectively collected U.K. and U.S. trauma registries who required 1 U or more of packed red blood cells and composed the following groups: tranexamic acid (n = 148), cryoprecipitate (n = 168), tranexamic acid/cryoprecipitate (n = 258), and no tranexamic acid/cryoprecipitate (n = 758). MAIN OUTCOME MEASURE In-hospital mortality. RESULTS Injury severity scores were highest in the cryoprecipitate (mean [SD], 28.3 [15.7]) and tranexamic acid/cryoprecipitate (mean [SD], 26 [14.9]) groups compared with the tranexamic acid (mean [SD], 23.0 [19.2]) and no tranexamic acid/cryoprecipitate (mean [SD], 21.2 [18.5]) (P < .001) groups. Despite greater Injury Severity Scores and packed red blood cell requirements, mortality was lowest in the tranexamic acid/cryoprecipitate (11.6%) and tranexamic acid (18.2%) groups compared with the cryoprecipitate (21.4%) and no tranexamic acid/cryoprecipitate (23.6%) groups. Tranexamic acid and cryoprecipitate were independently associated with a similarly reduced mortality (odds ratio, 0.61; 95% CI, 0.42-0.89; P = .01 and odds ratio, 0.61; 95% CI, 0.40-0.94; P = .02, respectively). The combined tranexamic acid and cryoprecipitate effect vs. neither in a synergy model had an odds ratio of 0.34 (95% CI, 0.20-0.58; P < .001), reflecting nonsignificant interaction (P = .21). CONCLUSIONS Cryoprecipitate may independently add to the survival benefit of tranexamic acid in the seriously injured requiring transfusion. Additional study is necessary to define the role of fibrinogen in resuscitation from hemorrhagic shock.

Physiologic tolerance of descending thoracic aortic balloon occlusion in a swine model of hemorrhagic shock

BACKGROUND Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an emerging technique in trauma; however, the physiologic sequelae have not been well quantified. The objectives of this study were to characterize the burden of reperfusion and organ dysfunction of REBOA incurred during 30 or 90 min of class IV shock in a survivable porcine model of hemorrhage. METHODS After induction of shock, animals were randomized into 4 groups (n = 6): 30 min of shock alone (30-Shock) or with REBOA (30-REBOA) and 90 min of shock alone (90-Shock) or with REBOA (90-REBOA). Cardiovascular homeostasis was then restored with blood, fluid, and vasopressors for 48 h. Outcomes included mean central aortic pressure (MCAP), lactate concentration, organ dysfunction, histologic evaluation, and resuscitation requirements. RESULTS Both REBOA groups had greater MCAPs throughout their shock phase compared to controls (P < .05) but accumulated a significantly greater serum lactate burden, which returned to control levels by 150 min in the 30-REBOA groups and 320 min in the 90-REBOA group. There was a greater level of renal dysfunction and evidence of liver necrosis seen in the 90-REBOA group compared to the 90-Shock group. There was no evidence of cerebral or spinal cord necrosis in any group. The 90-REBOA group required more fluid resuscitation than the 90-Shock group (P = .05). CONCLUSION REBOA in shock improves MCAP and is associated with a greater lactate burden; however, this lactate burden returned to control levels within the study period. Ultimately, prolonged REBOA is a survivable and potentially life-saving intervention in the setting of hemorrhagic shock and cardiovascular collapse in the pig.

Tranexamic Acid and Trauma: Current Status and Knowledge Gaps with Recommended Research Priorities

ABSTRACT A recent large civilian randomized controlled trial on the use of tranexamic acid (TXA) for trauma reported important survival benefits. Subsequently, successful use of TXA for combat casualties in Afghanistan was also reported. As a result of these promising studies, there has been growing interest in the use of TXA for trauma. Potential adverse effects of TXA have also been reported. A US Department of Defense committee conducted a review and assessment of knowledge gaps and research requirements regarding the use of TXA for the treatment of casualties that have experienced traumatic hemorrhage. We present identified knowledge gaps and associated research priorities. We believe that important knowledge gaps exist and that a targeted, prioritized research effort will contribute to the refinement of practice guidelines over time.

Resuscitative endovascular balloon occlusion of the aorta: a gap analysis of severely injured UK Combat casualties

ABSTRACT The control of torso and junctional zone bleeding in combat casualties is particularly challenging because of its noncompressible nature. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has demonstrated promise in translational large animal and early clinical series as an effective resuscitation and hemorrhage control adjunct. However, it is unknown what proportion of combat casualties has an injury pattern and clinical course that is amenable to REBOA deployment. The prospective UK Joint Theatre Trauma Registry was used to retrospectively identify all UK military personnel who has sustained a severe combat injury, defined as an Abbreviated Injury Scale of three or greater, in the course of 10 years. Patients were then divided into three groups based on Abbreviated Injury Scale injury pattern: no indications for REBOA, contraindications (mediastinal, cervical, and axillary hemorrhage), and indications (torso and pelvic hemorrhage). From a total of 1,317 patients, 925 (70.2%) had no indication, 148 (11.2%) had a contraindication, and 244 (18.5%) had an indication for REBOA. Within the group with indications for REBOA, there were 174 deaths: 79 at the point of wounding, 66 en route to hospital, and 29 in-hospital deaths. The median (interquartile range) time to death in patients dying en route was 75 (42–109) min, and the median prehospital time for casualties admitted to hospital was 61 (34–89) min. One-in-five severely injured UK combat casualties have a focus of hemorrhage in the abdomen or pelvic junctional region potentially amenable to REBOA deployment. The UK military should explore REBOA as a potential en route hemorrhage control and resuscitation adjunct.

Comparison of novel hemostatic dressings with QuikClot combat gauze in a standardized swine model of uncontrolled hemorrhage.

BACKGROUND Uncontrolled hemorrhage is the leading cause of preventable death on the battlefield. The development, testing, and application of novel hemostatic dressings may lead to a reduction of prehospital mortality through enhanced point-of-injury hemostatic control. This study aimed to determine the efficacy of currently available hemostatic dressings as compared with the current Committee for Tactical Combat Casualty Care Guidelines standard of treatment for hemorrhage control (QuikClot Combat Gauze [QCG]). METHODS The femoral artery of anesthetized Yorkshire pigs was isolated and punctured. Free bleeding was allowed to proceed for 45 seconds before packing of QCG, QuikClot Combat Gauze XL (QCX), Celox Trauma Gauze (CTG), Celox Gauze (CEL), or HemCon ChitoGauze (HCG), into the wound. After 3 minutes of applied, direct pressure, fluid resuscitation was administered to elevate and maintain a mean arterial pressure of 60 mm Hg or greater during the 150-minute observation time. Animal survival, hemostasis, and blood loss were measured as primary end points. Hemodynamic and physiologic parameters, along with markers of coagulation, were recorded and analyzed. RESULTS Sixty percent of QCG-treated animals (controls) survived through the 150-minute observation period. QCX, CEL, and HCG were observed to have higher rates of survival in comparison to QCG (70%, 90%, and 70% respectively), although these results were not found to be of statistical significance in pairwise comparison to QCG. Immediate hemostasis was achieved in 30% of QCG applications, 80% of QCX, 70% of CEL, 60% of HCG, and 30% of CTG-treated animals. Posttreatment blood loss varied from an average of 64 mL/kg with CTG to 29 mL/kg with CEL, but no significant difference among groups was observed. CONCLUSION These results suggest that the novel hemostatic devices perform at least as well as the current Committee on Tactical Combat Casualty Care standard for point-of-injury hemorrhage control. Despite their different compositions and sizes, the lack of clear superiority of any agent suggests that contemporary hemostatic dressing technology has potentially reached a plateau for efficacy.

Intra-operative correction of acidosis, coagulopathy and hypothermia in combat casualties with severe haemorrhagic shock

We assessed acidosis, coagulopathy and hypothermia, before and after surgery in 51 combat troops operated on for severe blast injury. Patients were transfused a median (IQR [range]) of 27 (17–38 [5–84]) units of red cell concentrate, 27 (16–38 [4–83]) units of plasma, 2.0 (0.5–3.5 [0–13.0]) units of cryoprecipitate and 4 (2–6 [0–17]) pools of platelets. The pH, base excess, prothrombin time and temperature increased: from 7.19 (7.10–7.29 [6.50–7.49]) to 7.45 (7.40–7.51 [7.15–7.62]); from −9.0 (−13.5 to −4.5 [−28 to –2]) mmol.l−1 to 4.5 (1.0–8.0 [−7 to +11]) mmol.l−1; from 18 (15–21 [9–24]) s to 14 (11–18 [9–21]) s; and from 36.1 (35.1–37.1 [33.0–38.1]) °C to 37.4 (37.0–37.9 [36.0–38.0]) °C, respectively. Contemporary intra‐operative resuscitation strategies can normalise the physiological derangements caused by haemorrhagic shock.

Adding bupivacaine to high-potassium cardioplegia improves function and reduces cellular damage of rat isolated hearts after prolonged, cold storage

Background: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. Methods: After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 μm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4°C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. Results: All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate–pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. Conclusions: Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade.

A Laparoscopic Swine Model of Noncompressible Torso Hemorrhage

BACKGROUND Hemorrhage persists as the leading cause of potentially preventable civilian and military death. Noncompressible torso hemorrhage (NCTH) is a particularly lethal injury complex, with few contemporary prehospital interventions available. Various porcine models of hemorrhage have been developed for civilian and military trauma research. However, the predominant contemporary models lack key physiologic characteristics including the natural tamponade provided by an intact abdominal wall. To improve physiologic and clinical relevance, we developed a laparoscopic model of NCTH. This approach maintains both the integrity of the peritoneum and the natural tamponade effect of an intact abdominal wall while preserving the intrinsic physiologic responses to hemorrhage. Furthermore, we present data quantifying the contribution of the swine contractile spleen in the context of uncontrolled hemorrhage. METHODS Anesthetized adult male Yorkshire swine underwent a laparoscopic Grade V liver injury, with or without open preinjury splenectomy. Animals were observed without intervention for a total of 120 minutes after injury to simulate point of injury, transport time, and arrival at hospital. RESULTS Shed blood–to–body weight ratio did not differ among groups; however, mortality was higher in splenectomized animals (67% vs. 33%). Cox regression modeling demonstrated a critical time point of 45 minutes and blood pressure as significant predictors of mortality. CONCLUSION This study describes a model of NCTH that reflects clinically relevant physiology in trauma and uncontrolled hemorrhage. In addition, it quantitatively assesses the role of the swine contractile spleen in the described model.

Advances in understanding adenosine as a plurisystem modulator in sepsis and the Systemic Inflammatory Response Syndrome (SIRS)

Adenosine is a ubiquitous molecule that influences every physiological system studied thus far. In this review, we consider the influence of this purine nucleoside on some of the physiological systems affected during sepsis and SIRS. In the control of perfusion and cardiac output distribution, endogenous adenosine appears to play an important role in regulating perfusion in various vascular beds. Some of this control is mediated by stimulation of adenylyl cyclase, while part occurs by stimulating the production of nitric oxide. In the heart, adenosine may act as an inhibitory modulator of TNF-alpha expression. With regard to innate immune responses the effects of adenosine vary considerably, and are complex. However, the dominant responses relevant to SIRS indicate attenuation of inflammatory responses. Many of the effects of adenosine may also involve modulating oxyradical-mediated response. This occurs via increased oxyradical production via adenosine degradation (xanthine oxidase pathway), or limiting inflammatory oxyradical generation. Attempts to exploit the beneficial responses to adenosine have met with some success, and are considered here.

Aortic Hemostasis and Resuscitation: Preliminary Experiments Using Selective Aortic Arch Perfusion With Oxygenated Blood and Intra-aortic Calcium Coadministration in a Model of Hemorrhage-induced Traumatic Cardiac Arrest

OBJECTIVES Selective aortic arch perfusion (SAAP) uses a thoracic aortic balloon occlusion catheter for heart and brain perfusion in cardiac arrest to achieve return of spontaneous circulation (ROSC). SAAP with oxygenated stored blood was studied in a model of hemorrhage-induced cardiac arrest. The study hypothesis was that intra-aortic calcium coadministration would be required to maintain normal aortic arch blood ionized calcium during SAAP and to achieve ROSC. METHODS Twelve anesthetized, domestic swine underwent severe hemorrhage and liver injury resulting in cardiac arrest. Whole blood and packed red blood cells (RBCs) stored in citrate anticoagulant served as perfusates for SAAP. Experiments were performed with four combinations of SAAP with oxygenated stored blood and intra-aortic calcium gluconate infusion: 1) whole blood without calcium, 2) whole blood with calcium, 3) lactated Ringers-diluted packed RBCs with calcium, and 4) normal saline-diluted packed RBCs with calcium. Aortic arch blood ionized calcium was monitored. Occurrence of ventricular dysrhythmias, success rate for ROSC, and the need for simultaneous intra-aortic calcium infusion were assessed. RESULTS Selective aortic arch perfusion using whole blood without intra-aortic calcium (n = 2) resulted in severe aortic blood ionized hypocalcemia, refractory ventricular fibrillation, and no ROSC. SAAP using whole blood with intra-aortic calcium (n = 4) resulted in ROSC in all four animals. Two of four developed ventricular fibrillation that was successfully defibrillated. SAAP using packed RBCs with intra-aortic calcium resulted in ROSC in all six animals, but the intra-aortic calcium dose needed to maintain normal aortic arch blood ionized calcium levels was one-third of that needed for SAAP with whole blood. Dilution of packed RBCs with lactated Ringers (n = 2) resulted in formation of small clots in the perfusion circuit which were not seen with packed RBCs diluted with normal saline (n = 4). CONCLUSIONS Selective aortic arch perfusion with stored whole blood or packed RBCs requires simultaneous intra-aortic calcium infusion to overcome citrate anticoagulant calcium binding, avoid refractory ventricular fibrillation, and allow for ROSC.