Blast is one of the major causes of injury and death in recent armed conflicts. With increased use of improvised explosive devices (IEDs) in Iraq and Afghanistan, more than 71% of combat casualties are caused by explosions (1). Bombings, however, are not reserved to military settings (2, 3). For example, more than 1,300 bombing incidents are reported annually by the Bureau of Alcohol Tobacco and Firearms (3), whereas Mellor and Cooper (4) report 828 servicemen killed by terrorist explosions during the 14-year Irish conflict. However, terrorist bombings can have a high rate of immediate survivors (5).
In general, terrorist bombings typically result in significantly different injury patterns, higher injury severity scores, and more body regions involved when compared with conventional trauma complexity (6–8). In addition to these physical injuries producing tissue damage and wound-related hemorrhage (9), various physiological vagal responses (10–12) have been described. Of interest is the association between these explosions and the development of acute coagulopathy of trauma (COT). In a retrospective review of combat casualties, Simmons et al. (13) showed that victims of explosion or blast, whatever the degree of injury, have deeper microcirculation impairment and more severe COT than victims of gunshot wounds, as defined by a higher international normalized ratio.
Blast injuries can generally be divided into four principal categories (9, 14). In primary blast injury, damage is caused by the impact of the blast wave or shock wave produced by the explosion. This shock wave mainly injures air-containing organs such as lung and bowels as it generates shear stress at the air-liquid interfaces. In secondary blast injury, damage is caused by the impact of fragments or other missiles coming from the explosive device itself or from the surroundings and accelerated by the blast. This can lead to penetrating or nonpenetrating injuries and fragment injuries. The tertiary blast injuries are caused by the projection of the victim by the blast, for example, causing a fall. This can cause major blunt injuries or amputations. The quaternary blast injury category represents all the side effects of the bomb, like burns, toxic chemical inhalation, or radiation exposures.
The biophysical dynamics of the primary blast wave have been well described (15, 16), and such blast-related injuries have been reported (8, 17). However, the contribution of primary blast injury to the development of COT remains to be elucidated. This study was designed to assess changes in coagulation parameters in a “primary” blast injury model in pigs to determine whether the blast wave overpressure itself can be responsible for acute COT. Our hypothesis is that primary blast injury induces a hypocoagulation state indicative of acute COT.
Experiments were carried out by the French Army Institute of Biomedical Research (IRBA) and financed by the French Direction Générale de l’Armement, “Etudes sur la protection du combattant débarqué—Studies on the protection of the dismounted soldier.” This unit is nationally accredited for animal experiments. This study was approved by the institute’s ethics committee and was performed in accordance with the European directive on animal experiments (2010/63/UE). Most of the coagulation analyses were carried out by the US Army Institute of Surgical Research on frozen plasma.
Thirteen female Large White pigs (designated P1 to P13; mean weight [±SD], 58 ± 12 kg) sustained primary blast thoracic trauma. Pigs were housed 5 days before the beginning of the experiments in a certified animal facility to acclimate them to their new surroundings.
Animals were premedicated with an intramuscular ketamine injection (50 mg/kg) (ketamine chlorhydrate; Panpharma, France), and anesthesia was given by an intravenous perfusion of ketamine (25 mg/kg per h) and sufentanyl (0.1 μg/kg, before surgical procedure, sufentanyl citrate; Merck, USA). The airway was protected by tracheal intubation, and spontaneous ventilation was preserved. Ventilation efficiency was monitored with EtCO2, SpO2 (S5, Datex-Ohmeda, Finland), PO2, and PCO2 (i-STAT analyzer with CG4+ cartridges; Abbott, USA). Heart rate (HR), mean arterial pressure (MAP), and total body surface–indexed cardiac output were monitored using a PICCO arterial line placed in the left carotid artery (Pulsion Medical Systems SE, Germany). As previously described (18), intrathoracic pressure impulse was recorded with a Reson TC4013 pressure sensor (Reson A/S, Denmark) placed in the esophagus. After the blast, the animals did not receive any specific care.
After the blast, pigs were observed for 60 min and then euthanized by anesthesia overdose and exsanguination. During autopsy performed by a medical examiner, the following injuries were recorded: thoracic wall injuries (rib fractures), intrathoracic injuries (lung contusion, cardiac contusion, hemo/pneumothorax), intra-abdominal injuries (hollow and solid organ injuries), and macroscopic intracerebral hemorrhage.
The threat corresponded to a blast overpressure exposure under open-field conditions. To cause sufficient pulmonary injuries, consistent with clinical and morphological changes, the explosive load was chosen referring to the Bowen tolerance curves (19) revisited by Bass et al. (20) to achieve the 50% survival curve. Hence, a 400-kPa peak overpressure and 2.5-ms positive-phase duration were targeted. Because of supplying issues, the explosive charge used was either a pentrite-based formulation called “Plastrite” with 1.17 TNT equivalent or C4 with 1.34 TNT equivalent. This change in the explosive charges did not impact the overpressure signature curve. The threat was characterized in terms of duration and peak overpressure level. The corresponding impulse (integral of the overpressure curve, i.e., the area under the curve) of the incident blast wave overpressure was recorded at the same range area as the animal by a pencil probe 137A22 (PCB Piezotronics, USA). Physical signals were recorded at 1-MHz sampling rate. To reproduce an IED scenario, charge was close to the ground (height of burst, 33 cm), and the animals were placed at 1.33 m from the ground in the Mach stem at a distance of 3 m of the explosive charge. The animals were suspended on a net hammock in prone position, facing the right side to the explosive charge.
Blood samples were drawn at baseline (15 min before the blast, T0), 30 min (T30), and 60 min (T60) after the blast. The following analyses and operations were conducted on fresh whole blood at the experimental scene immediately after blood draw or after a specific resting time.
Platelet count was assessed on a SCIL Vet ABC Plus blood analyzer (ScilVet, France) set for swine species after blood collection in EDTA.
Arterial PO2, arterial PCO2, arterial SO2, venous SO2, base excess, arterial pH (pH), and arterial lactate concentration were measured on an i-STAT analyzer with CG4+ cartridges (Abbott, USA) in heparinized blood from carotid and central venous catheters.
On a ROTEM delta system (Tem Innovations, Germany), citrated blood was analyzed immediately after blood draw using in-tem (exploring intrinsic coagulation pathway), ex-tem (exploring extrinsic pathway), and fib-tem (assessing the fibrinogen function by inhibiting the platelets function) following company recommendations. For ex-tem and in-tem tests, CT (clotting time), clot formation time, alpha (angle), MCF (maximal clot strength), and LY30 (lysis rate at 30 min) were recorded. For fib-tem, just MCF was recorded.
To assess platelet function, whole-blood aggregation was determined using an impedance aggregometer (Multiplate, Dynabyte Medical GmbH, Germany). Collagen (COLTest, Verum Diagnostica GmbH, Germany) was used as agonist with a final concentration 4.5 mg/L. According to company recommendations, after 30 min of resting time, whole blood from citrate tubes (Dynabyte Medical GmbH, Germany) was mixed with CaCl2 and agonist and tests were run in duplicate for 12 min. The area under the aggregation curve was recorded.
After centrifugation (3,000g, 10 min, 4°C, twice), platelet-poor plasma (PPP) from citrate tubes was flash frozen and stored at −80°C to be shipped and analyzed later.
No later than 3 weeks after collection, the following analyses were conducted at the USAISR on the previously frozen plasma after thawing.
Prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III activity, von Willebrand factor activity, and fibrinogen concentration were measured in PPP using the Sta-R Evolution system (Diagnostica Stago, USA).
A calibrated automatic thrombogram (CAT) was performed in PPP using the Thrombinoscope software and a Thrombinograph (Stago, France), following company recommendations. Results are given as endogenous thrombin potential, peak of thrombin generation, and lag time for thrombin generation (lag).
Platelet activation was also assessed by flow cytometry on a BD Accuri C6 flow cytometer (BD Biosciences, USA) but only on four surviving animals. Monoclonal antibodies for CD61 (GP IIIa), CD62P (P-Selectin), and isotypes were purchased from ABD Serotec (UK). Bovine lactadherin (Haematologic Technologies, Inc, USA) binding to phosphatidylserine (PS) was also measured. Five microliters of citrated fresh whole blood was incubated with antibodies in buffered saline at room temperature for 15 min. Two milliliters of PBS was added to tubes for immediate analysis. The platelet gate was established by forward and side scatter and CD61 positivity. Results are given as the percentage and geometric mean fluorescence intensity of P-Selectin–positive platelets and percentages of PS-positive platelets.
Plasma microparticles (MPs) were analyzed by flow cytometry on a BDFacs Canto II RUO (BD Biosciences, USA) equipped with a forward scatter PMT to detect particles smaller than 1 μM. Bovine lactadherin from Haematologic Technologies, Inc (USA), and CD62P antibodies from ABD Serotec (UK) were used to stain the MP. Ten microliters of previously frozen (−80°C, <15 days) thawed plasma was incubated with antibodies in 100 μL of 0.1-μm filtered HBSS for 30 min on ice immediately after thawing. One milliliter of 0.1-μm filtered HBSS was then added, and specimens were analyzed. Absolute concentration of MP was determined using BD TruCount tubes (BD Biosciences, USA). Results are given as absolute plasma concentration of total MPs, P-Selectin–positive MPs, and PS-positive MPs.
Where normal distribution and equal variance were verified, results are given as mean (±SD), and a paired Student t test was performed to compare data from T0 to T60. Where normal distribution and equal variance were not verified, results are given as median (interquartile range), and a Wilcoxon signed-rank test was performed to compare data from T0 to T60 using JMP 10 software (SAS, USA). A P < 0.05 was considered significant.
The pressure–time history recorded in the same range area as the animal was close to an ideal Friedlander wave (Fig. 1). The mean blast wave maximal overpressure was 463kPa (±73); its mean duration was 2.35 ms (±0.29); and its mean impulse was 241 (±27) kPa.ms. Figure 1 shows a typical record of the intrathoracic overpressure during the blast. Because of instrumentation failure during the blast, data could not be obtained from animals P1 and P12. The mean maximal intrathoracic pressure impulse was 197 (±126) kPa.ms.
Of the 13 animals, three died prematurely before T60 after the blast (P5, P6, P11). Of the others, one died just after the last blood draw at T60 (P3). Typically, all the animals presented with pulmonary contusions and some rib marks on the lungs as illustrated in the gross pathology (Fig. 2). No animals showed evidence of myocardial contusion, hemothorax/pneumothorax, or rib fracture. Laryngeal petechial marking was not reported, likely because of prior laryngeal intubation. All animals had diffuse subperitoneal hemorrhage, and two presented with intestinal rupture (Fig. 2). No sign of significant hemorrhage in the abdominal cavity (hemoperitoneum, pelvic hematoma) was recorded. One of the animals (P10) presented with intracerebral hemorrhage. No solid organ injury was observed.
Data were only available for four animals because of blast damage to instrumentation. Changes were not significant between baseline and T60 for HR (157/min [97 – 162/min] vs. 149/min [85 – 150/min]), MAP (77 [51 – 110] mmHg vs. 60 [50 – 102] mmHg) or indexed cardiac output (5.8 [3.9 – 7.1] L/min per m2 vs. 4.5 [3.4 – 6.1] L/min per m2).
Of the surviving animals, only one showed severe respiratory failure and gas exchange impairment (P12), but, overall, the decreases of arterial PO2, arterial PCO2, arterial SO2, and SvO2 during the experiment were not statistically significant (Fig. 3). However, animals developed signs of shock after the blast, with a significant drop in pH (7.34 [±0.07] vs. 7.27 [±0.11]; P = 0.0210), rise in lactate concentration (5.1 [±4.6] mmol/L vs. 7.8 [±4.5] mmol/L; P = 0.0234), and development of a base deficit (0.5 [±6.1] mEq/L vs. –3.2 [±5.5] mEq/L; P = 0.0266) (Fig. 4). Arterial blood gas could not be sampled in animals P3 and P8.
Table 1 shows the coagulation parameters. For CAT assays, data are available from only nine animals; baseline data were not available for one of the surviving animals (P4). No differences in PT were observed between T0 and T60, but aPTT was significantly shorter at T60. Von Willebrand factor activity levels were higher at T60 than T0, but no differences were observed in fibrinogen levels or antithrombin III activity. With respect to thrombin generation, only lag time was significantly shorter at T60 than T0, whereas peak and total thrombin generation was similar at both times. Figure 5 shows the values obtained from ROTEM for in-tem and ex-tem tests. Except for shorter in-tem and ex-tem CT (P = 0.0020 and P = 0.0117, respectively), no statistically significant differences were found between baseline and T60 in other ROTEM parameters. Fib-tem MCF showed no difference between T0 and T60, indicating no functional change in fibrinogen.
All the results on platelet activity and activation are contained in Table 1. No significant differences were detected in platelet aggregation or other parameters of platelet function or microparticles between T0 and T60. However, for technical issues, platelet activation data from flow cytometry were only available from four animals. Neither ex-tem nor in-tem MCF showed any difference between T0 and T60, further supporting indications that no differences in platelet function developed between these times.
The simple shock wave obtained in the present experiment was of very good quality and highly reproducible. One of the assets of an open-field blast experiment is the ability to get a more realistic threat close to a Friedlander wave: the single peak overpressure (caused by the Mach stem pathway) is followed by a negative pressure phase after the peak (15). This can be difficult to obtain, with blast tube experiments reproducing a part only of the blast wave (21). Also, the present setting was designed to simulate as close as possible the primary blast part of an IED environment with the explosive charge placed on the ground.
The recorded peak overpressure and duration placed the threat very close to the “50% mortality” line described by Bass et al. (20), the weight of the animals being close enough not to have to adjust the blast duration. This resulted in a mortality rate of 33% at 1 h in our experiment.
The animals presented with multiple internal injuries totally consistent with a severe primary blast injury (22–24). Even if the pulmonary gas exchange was in general statistically not perturbed in all but one animal, signs of shock developed after the blast. Furthermore, the intrathoracic overpressure was consistent with our previous work on blunt thoracic trauma associated with lung contusion (18).
Unfortunately, because of technical issues, it was only possible to record physiological data (HR, MAP, cardiac output) on a few animals, making data analysis underpowered. However, lactate level, pH, and base excess at 1 h after injury showed the beginning of a shock state.
With a high proportion of military casualties resulting from explosive devices, the question of blast-related coagulopathy has become a topic of high interest. Previous studies have reported coagulation dysfunctions after blast injuries (25, 26), and others have documented the blood product use after terrorist bombing in both civilian and military settings (27–29). After traumatic injury, coagulopathy reported has generally been associated with hypothermia, acidosis, consumption of coagulation factors, and dilution caused by excessive fluid resuscitation (30). More recently, Brohi et al. (31) described a “shock-induced COT” in a prospective study involving more than 200 trauma patients. They assessed the correlation between impaired coagulation and tissue hypoperfusion and showed that COT is linked to tissue hypoperfusion and damage, suggesting a link to protein C pathway activation. This concept was later supported by two other studies (32, 33). However, hemorrhage is not the only cause of shock in trauma patients. During thoracic trauma, vagal nerve–mediated reflex caused by the rapid distension of the C-fibers in the lung can cause, in seconds, bradycardia and decreased cardiac output. This autonomic nervous reflex is also responsible for hypotension by myocardial impairment and can be observed after primary blast injury (10–12). Another cause of blast-induced hypotension could be attributed to the rapid release of nitric oxide from the pulmonary circulation (34). The retrospective study of Simmons et al. (13) showing that victims of explosion or blast, the degree of injury and the circulation parameters (heart rate, blood pressure) being equal, have deeper microcirculation impairment and more severe COT than victims of gunshot wounds, suggesting than blast is responsible, by itself, for a part of the COT.
In our experiments, however, a very large panel of coagulation testing did not reveal any sign of COT after the primary blast injury but, on the contrary, suggested a tendency for the development of a hypercoagulable state despite signs of shock in the animals and consistent with studies from the United Kingdom (Kirkman, personal communication). Although aPTT and CT (both in- and ex-tem) were significantly shortened, other global coagulation parameters (PT, clot formation time, CAT lag time) tended to be lower after the blast. Circulating platelets did not show any change 1 h after the primary blast injury. The expression of activation markers (P-Selectin, PS) did not change, in addition to the global activity (aggregability) and circulating platelet count. Finally, the concentration of PS microparticles known to be procoagulant (35) and possibly generated during blunt trauma (36) did not change. The elevation of von Willebrand factor plasma concentration is likely caused by the well-known release from Weibel-Palade bodies as a result of endothelial activation and injury.
Still, these findings remain consistent with the recent results of Chai et al. (25) who studied basic coagulation parameters in rats exposed to primary blast and burn injuries and found no evidence of COT associated with isolated primary blast injury. Similarly, Park et al. (36) observed a hypercoagulable state associated with an increase in MP after trauma.
This study is subject to several limitations. First, the use of animals makes the extrapolation of these findings to the human uncertain because of species differences in response to injury. This is especially true concerning the porcine coagulation system, known to be very strong (37). Second, physiological data like HR or blood pressure were limited. Lastly, the number of subjects was low; however, the results are very consistent in rejecting the hypothesis that primary blast injury causes acute COT.
In conclusion, this study presents a highly reproducible and consistent isolated blast injury in large mammals with, to our knowledge, the most comprehensive coagulation testing in response to primary blast injury. We observed that isolated primary blast injury does not cause a typical acute COT in the first hour after explosion but seems to lead to an early hypercoagulable state. However, the addition of hemorrhage leading to deeper shock and more severe tissue damage in complex blast injuries could lead to a COT as described by Brohi et al. (31) but requires additional investigation.
The authors thank Christian Aglioni, William Menini, and Joel Mosnier for their scientific collaboration as well as Sebastien De Mezzo and Stephane Heck for their technical engineering support.
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Keywords:© 2015 by the Shock Society
Explosion; blunt trauma; coagulation; thoracic trauma