TY - JOUR
AU1 - Qin,, Hao
AU2 - Yang,, Lei
AU3 - Liu,, Daocheng
AU4 - Chen,, Sixu
AU5 - Lyu,, Mingrui
AU6 - Bao,, Quanwei
AU7 - Lai,, Xinan
AU8 - Liu,, Huayu
AU9 - Chen,, Qiang
AU1 - Zong,, Zhaowen
AB - Abstract Introduction: Solid abdominal organ hemorrhage remains one of the leading causes of death both on the battlefield of modern warfare and in the civilian setting. A novel, temporary hemostatic device combining CELOX and direct intra-abdominal physical compression was invented to control closed SAOH during transport to a medical treatment facility. Materials and methods: A swine model of closed, lethal liver injury was established to determine hemostasis. The animals were randomly divided into group A (extra-abdominal compression), group B (gauze packing), group C (intra-abdominal compression), group D (CELOX coverage), and group E (intra-abdominal compression and CELOX coverage) with six swines per group. Survival time (ST), blood loss (BL), vital signs, pathologic examination, and CT-scan were monitored to further observe the effectiveness of the device. Results: Group E had an average 30-minute extension in ST (74.3 ± 15.4 minutes versus 44.0 ± 13.8 minutes, p = 0.026) with less BL (46.0 ± 13.0 versus 70.8 ± 8.2 g/kg, p = 0.018), and maintained mean arterial pressure≥70 mmHg and cardiac output ≥ 3.5 L/minute for a longer time. No significant differences were observed in ST and BL of groups B and E, and there were no marked differences in ST and BL of groups A, C, and D. No CELOX clots were noted in the spleen, pancreas, lungs, heart, kidneys, or the adjacent large vessels in groups D and E. Compared to group A, the CT-scan showed better hepatic hemorrhage control in group E. Conclusions: The device, which combined 20 g of CELOX particles and 20 pieces of CELOX (8 g) sponge tablets with 50-mmHg intra-abdominal compression for 10 minutes, prolonged the ST by an average of 30 minutes with less BL. It was not markedly different from the full four quadrants gauze packing of liver in hemostatic effect, with no CELOX clot formation in other organs. 1. INTRODUCTION Hemorrhage accounts for up to 90% of all potentially survivable (PS) deaths on the battlefield1,2 and is one of the leading causes of death in the civilian setting3,4. Hemorrhage is categorized by anatomic location (ie extremity, junctional, or truncal bleeding)1,2,5. To achieve hemostasis before reaching a military medical treatment facility (pre-MTF), the tactical combat casualty care (TCCC) guidelines advocated the use of extremity and junctional tourniquets as the primary tool for hemostasis 6,7; for hemorrhage that could not be controlled by tourniquets, TCCC advocates the use of hemostatic dressings and hemostatic adjuncts8; body armor or other equipment can prevent thoracic injuries to a certain extent; however, it is still a big challenge to treat intra-abdominal hemorrhage (IAH), because of the increasing mortality in IAH in comparison with other anatomic location hemorrhages. Moreover, the majority deaths of IAH occur in pre-MTF, where a definitive surgery could not be performed1,2,5. A review of casualty-associated mortalities in pre-MTF in Operation Iraqi Freedom and Operation Enduring Freedom of U.S. military (2001–2011) found that 67.3% of hemorrhage deaths were caused by truncal injuries, followed by junctional (19.2%) and extremity (13.5%) hemorrhage; truncal injuries were thoracic (36%) and abdominopelvic (64%)2. Meanwhile, solid abdominal organ hemorrhage (SAOH) due to injury in the liver, kidneys, or spleen accounted for the majority of mortality cases (44.6%, 3188 deaths/7152 cases)9. The closed SAOH caused by blunt trauma was usually overlooked, and it required focused assessment sonography in trauma or diagnostic peritoneal lavage for diagnosis, and needed an operating room or interventional suite for definitive hemostasis2,5,9. However, it is difficult to meet these needs in pre-MTF in wartime or disasters because of the mass casualties, and now there is no well-recognized, effective, and safe hemostatic measure that can intervene SAOH in pre-MTF10. To address this capability gap, we invented a temporary hemostasis device composed of CELOX and direct intra-abdominal physical compression to buy time to definitive surgery in the MTF for casualties with SAOH. The US experiences in Iraq and Afghanistan showed CELOX, a hemostatic agent, was highly effective at controlling hemorrhage for extremity and junctional regions when used on the battlefield11,–13. CELOX is also effective and safe to control hemorrhage in the truncal surgery14,15. In this article, the hemostatic effect of our device was verified in the swine model of closed, lethal liver injury. 2. METHODS 2.1. Introduction of the hemostatic device The device was equipped with a double-cavity structure (Fig. 1); one injection cavity was prefilled with CELOX particles (20 g; Medtrade Biopolymers, Crewe, UK) and the other injection cavity was prefilled with high-expansion, compressed sponge tablets containing CELOX ingredients (20 pieces, 10 × 10 × 1 mm, each containing approximately 0.4 g of CELOX; Guangzhou Master Meditech Co, Ltd, Guangzhou, China) that could expand 80-fold after absorbing blood. On the basis of our preliminary experiments, 20 g of CELOX and 20 pieces of sponge tablets were sufficient to cover the raw surface of the liver in the injury model, and the combination of particles and tablets facilitated CELOX contacting with the wound, thus preventing CELOX from dislocation by the active bleeding16. In addition, this device had a scalpel and an inflatable airbag (a silicone product, 15 cm in diameter and 3 cm thick, which was not easily deformed when pressed) as accessories; the former one was used for opening the abdomen and the latter one for providing physical compression. Figure 1 Open in new tabDownload slide The hemostatic device for solid abdominal organ hemorrhage. Figure 1 Open in new tabDownload slide The hemostatic device for solid abdominal organ hemorrhage. 2.2. Establishment of a swine model of closed, lethal liver injury All animal procedures were performed in accordance with protocols approved by the Army Medical University Institutional Animal Care and Use Committee. Swines were observed for 3 days to ensure a good state of health and were fasted for 12 hours and had no access to water for 4 hours before surgery. After anesthesia with ketamine (30 mg/kg) and atropine (0.04 mg/kg), the swines were placed in the supine position with head and limbs fixed, and an intravenous indwelling needle was placed in the ear vein to maintain the anesthesia through the intravenous injection of 3% sodium pentobarbital (6 mg/h/kg). Hair was scraped and skin was disinfected on the abdomen, neck, and groin bilaterally. The skin and subcutaneous tissues were dissected in the groin, and the right femoral artery and vein were separated with single-lumen vascular catheters. The femoral artery catheter was connected to a Philips IntelliVue MP60 monitoring system (Boeblingen, Germany). The femoral vein catheter was used as an infusion channel during resuscitation. The body temperature was measured through the anus. According to the liver injury model reported by Duggan et al.17, a closed lethal liver injury swine model was made with two cutting lines. The abdomen was opened through a mid-abdominal incision. One line was perforated within 1 cm of the lateral margin of the left and right medial lobes approximately 10 cm from the distal tip of the organ, such that pulling the cutting line resulted in full transection of the left and right medial liver lobes. Another line was positioned approximately 10 cm from the distal tip running anteroposteriorly along the midline between the right and left medial lobes and perforating the intrahepatic portal vein. Finally, two lines were attached to the distal tip of the medial liver lobes to allow retraction of the transected lobes after the initial injury. All lines were externalized through the laparotomy incision. Routine abdominal fascial closure was performed using no.1 nylon suture (Ethicon, Somerville, New Jersey, USA). According to the definition of the American Association of the Surgery of Trauma, pulling the cutting lines resulted in a standardized grade IV liver injury in the model18 (Fig. S1). 2.3. Experimental grouping Thirty-four healthy local adult male swines, weighing 50.5 ± 2.2 kg, were used. Four swines that died within 10 minutes after the administration of anesthesia were excluded from the study. Thirty swines were divided into five groups (six per group) used a computer-generated random table. Extra-abdominal pressure (50 mmHg) was applied at the navel for 10 minutes in group A based on a previous study19. The extra-abdominal pressure ≤ 50 mmHg was safe, with no immediate postoperative complications observed. The abdomen was opened again in group B through the mid-abdominal incision, and the liver was packed with medical absorbent gauze (8 cm [length] × 6 cm [width] × 8 [layers], with four pieces on the top and the bottom, while two pieces on the left and the right). Interventions were performed by the hemostatic device in groups C, D, and E. The device entered the abdomen through the junction of the right midclavicular line and the rib bow with an incision by the scalpel accessory. The raw surface and the edge of the liver were determined by perceiving the texture of the tissue with the head of device, so that the CELOX could cover the bleeding edge as evenly as possible. Group C received intra-abdominal compression alone for 10 minutes. Group D received CELOX particles (20 g) and the sponge tablets (20 pieces). Group E received CELOX particles (20 g) and the sponge tablets (20 pieces) plus intra-abdominal compression for 10 minutes. The incisions in groups C, D, and E were sutured after the surgical procedure. On the basis of our preliminary experiments16, the intra-abdominal pressure of 50 mmHg was also the optimal pressure for compressing the liver directly with no apparent liver necrosis after 10 minutes of compression. The compression in the four groups (A, B, C, and E) was applied by the same researcher with the hemostatic device, and a pressure sensor was placed under the inflatable airbag to display the compression pressure digitally, so that the operator could maintain the compression force according to the digital value. 2.4. Monitoring indicators Death was defined as apnea and asystole for five continuous minutes. From 10 minutes before liver injury to animal death, the vital signs, such as heart rate (HR), mean arterial pressure (MAP), and cardiac output (CO), were monitored continuously. The lactate level in arterial blood was measured twice (10 minutes before liver injury and 30 minutes after liver injury) for each animal. The survival time (ST) from live injury to death was recorded for each animal, and the amount of blood loss (BL, weight of intra-abdominal blood/weight of swine [g/kg]) was estimated by collecting the intra-abdominal blood, including blood in the abdominal cavity, free blood clots, and blood clots in the wound. Liver, spleen, pancreas, lungs, heart, kidneys, celiac trunk, common hepatic artery, inferior vena cava, hepatic vein, and portal vein were then extirpated for pathologic examination. The animals in groups A and E underwent liver CT-enhanced scans 20 minutes before liver injury, 5 minutes after liver injury, and 30 minutes after liver injury. 2.5. Statistical analysis The data were analyzed using SPSS 22.0 statistical software (SPSS, Chicago, Illinois, USA). Continuous numerical variables were expressed as the mean ± standard deviation and analyzed using a two-sample t-test or one-way analysis of variance (ANOVA). The Fisher least significant difference test was used as a post hoc test for pairwise comparisons of group means following one-way ANOVA. In all cases, p < 0.05 (two sided) was considered statistically significant. 3. RESULTS There were no significant differences in body weight, rectal temperature, HR, lactate level, MAP, and CO at 10 minutes before injury among all groups (p > 0.05). 3.1. Survival time, blood loss, and lactate level There were no significant differences in the mean lactate level among all the groups at 30 minutes after the liver injury (groups A to E: 5.43 ± 0.95, 5.33 ± 0.84, 5.38 ± 1.16, 5.63 ± 0.68, 5.17 ± 1.07 mmol/L, respectively; p = 0.95). Descriptive statistics for ST and BL was shown in Table I. The experimental animals were divided into two groups according to ST (30–60 minute versus > 60 minute) and the animals with a ST > 60 minute had less BL (26.1 ± 7.3 versus 33.7 ± 4.6 g/kg, p = 0.002). ST and BL were not significantly different between groups B and E, and group A had a shorter ST and a greater BL compared to groups B and E (ST: B versus A, p < 0.001; E versus A, p < 0.001; BL: B versus A, p < 0.001; E versus A, p < 0.001). ST of Group C was longer than group A (p = 0.011) but shorter than group E (p = 0.045). BL of Group C was not significantly different from group A (p = 0.115) but greater than group E (p = 0.010). There were no significant differences in groups A and D. Table I Descriptive statistics of survival time and blood loss Group A Group B Group C Group D Group E N (6) MBL#(36.1 ± 3.5 g/kg) N (6) MBL(22.7 ± 5.3 g/kg) N (6) MBL(31.5 ± 5.8 g/kg) N (6) MBL(34.4 ± 4.1 g/kg) N (6) MBL(23.7 ± 5.3 g/kg) MST* (minute) 30–60 5 35.2 ± 3.0 0 / 3 33.1 ± 3.7 5 34.8 ± 4.4 1 22.9 > 60 1 40.6 6 22.7 ± 5.3 3 30.0 ± 7.9 1 32.3 5 23.8 ± 5.9 Total 43.3 ± 10.9 79.2 ± 9.9 60.2 ± 8.0 49.0 ± 11.9 73.2 ± 12.1 Group A Group B Group C Group D Group E N (6) MBL#(36.1 ± 3.5 g/kg) N (6) MBL(22.7 ± 5.3 g/kg) N (6) MBL(31.5 ± 5.8 g/kg) N (6) MBL(34.4 ± 4.1 g/kg) N (6) MBL(23.7 ± 5.3 g/kg) MST* (minute) 30–60 5 35.2 ± 3.0 0 / 3 33.1 ± 3.7 5 34.8 ± 4.4 1 22.9 > 60 1 40.6 6 22.7 ± 5.3 3 30.0 ± 7.9 1 32.3 5 23.8 ± 5.9 Total 43.3 ± 10.9 79.2 ± 9.9 60.2 ± 8.0 49.0 ± 11.9 73.2 ± 12.1 *MST: mean survival time #MBL: mean blood loss. Open in new tab Table I Descriptive statistics of survival time and blood loss Group A Group B Group C Group D Group E N (6) MBL#(36.1 ± 3.5 g/kg) N (6) MBL(22.7 ± 5.3 g/kg) N (6) MBL(31.5 ± 5.8 g/kg) N (6) MBL(34.4 ± 4.1 g/kg) N (6) MBL(23.7 ± 5.3 g/kg) MST* (minute) 30–60 5 35.2 ± 3.0 0 / 3 33.1 ± 3.7 5 34.8 ± 4.4 1 22.9 > 60 1 40.6 6 22.7 ± 5.3 3 30.0 ± 7.9 1 32.3 5 23.8 ± 5.9 Total 43.3 ± 10.9 79.2 ± 9.9 60.2 ± 8.0 49.0 ± 11.9 73.2 ± 12.1 Group A Group B Group C Group D Group E N (6) MBL#(36.1 ± 3.5 g/kg) N (6) MBL(22.7 ± 5.3 g/kg) N (6) MBL(31.5 ± 5.8 g/kg) N (6) MBL(34.4 ± 4.1 g/kg) N (6) MBL(23.7 ± 5.3 g/kg) MST* (minute) 30–60 5 35.2 ± 3.0 0 / 3 33.1 ± 3.7 5 34.8 ± 4.4 1 22.9 > 60 1 40.6 6 22.7 ± 5.3 3 30.0 ± 7.9 1 32.3 5 23.8 ± 5.9 Total 43.3 ± 10.9 79.2 ± 9.9 60.2 ± 8.0 49.0 ± 11.9 73.2 ± 12.1 *MST: mean survival time #MBL: mean blood loss. Open in new tab 3.2. Changes in the MAP and CO To observe the changes in MAP and CO, the ST was further divided into four groups: 10 minutes before injury to 10 minutes after injury (−10–10 minutes), 11 minutes to 30 minutes after injury (11–30 minutes), 31 minutes to 60 minutes after injury (31–60 minutes), and more than 60 minutes after injury (>60 minutes) (Fig. 2). The MAP of 70–105 mmHg and CO of 3.5–5.5 L/minute were reported to provide adequate blood circulation support for swines20. In the current study, almost all animals had met this standard at an ST ≤ 30 minutes，and six animals in groups B and five animals in group E reached this standard at 31–60 minutes, and four animals in groups B, and two in group E reached this standard at > 60 minute. Figure 2 Open in new tabDownload slide Changes in CO and MAP from 10 minutes before liver injury to death in each swine. Figure 2 Open in new tabDownload slide Changes in CO and MAP from 10 minutes before liver injury to death in each swine. 3.3. Pathologic examination and CT scan In comparison with common blood clots of group A, the CELOX blood clots of group E had increased red thrombi with smaller gaps, and a tight connection between the clot and CELOX (Figs. 3-A1 and E1). In group E, the liver tissue at the incision made by the cutting lines had central vein destruction, hepatic sinus congestion, and leukocyte infiltration (Figs. 3-A2 and E2). In groups D and E, no CELOX was found in the spleen, pancreas, lungs, heart, kidneys, or the adjacent large vessels. The hepatic portal cross section of the liver CT scan showed that the intrahepatic signal of group E was more even, and the hemorrhage infiltration range of group E was smaller compared with group A (Figs. 3-A5 and E5). Figure 3 Open in new tabDownload slide Pathologic examination and CT scan in groups A and E. “BC” means blood clots, “CG” means CELOX granules, “CV” means central vein, “LC & LI” means liver congestion and leukocyte infiltration, “PH” means porta hepatis, and “LCA” means leakage of contrast agent for CT-scan. Figure 3 Open in new tabDownload slide Pathologic examination and CT scan in groups A and E. “BC” means blood clots, “CG” means CELOX granules, “CV” means central vein, “LC & LI” means liver congestion and leukocyte infiltration, “PH” means porta hepatis, and “LCA” means leakage of contrast agent for CT-scan. 4. DISCUSSION The survival of IAH is significantly associated with the time between injury and a required intervention9,21. Rapid and massive loss of blood without effective hemostasis leads to hypotension, coagulopathy, acidosis, infection, and multiple organ failure, and these complications usually result in an increase in mortality, even after successful resuscitation22. According to a study of U.S. combat fatalities with hemorrhage in 2001–2009, truncal hemorrhage caused 48% of mortalities after admission to an MTF5. Delayed intervention was one of the most common reasons for mortality, and there were no effective means to control hemorrhage on the battlefield2. A novel, self-expanding polyurethane foam (SPF) developed by Sharma and King was reported to be a promising device for the treatment of noncompressible abdominal hemorrhage23. The SPF was polymerized into a solid compact to provide intra-abdominal compression and stop bleeding by injecting two liquid substances into the closed abdominal cavity24,25. However, SPF could induce bowel injury and thus it was not approved by the Food and Drug Administration (FDA) for the uncertainty of safety in clinical practice24,25. Our hemostatic device combined the effectiveness and safety of CELOX with direct physical intra-abdominal compression, which was effective to control SOAH and easy to operating. It was designed to provide a critical care in pre-MTF during the wartime or disasters. Compared with other hemostatic agents approved by FDA (zeolites-, montmorillonite-, kaolin-, and procoagulant-based, etc.), the chitosan-based CELOX has the same or even better hemostatic effect11–13,26. The zeolite-based agents such as QuikClot rapidly absorb water in an exothermic reaction; the montmorillonite-based agents such as WoundStat and the kaolin-based agents such as Combat Gauze are recommended only for external use; and the procoagulant-based such as dry fibrin sealant are expensive; while CELOX can function under conditions of low temperature and coagulation disorders, and has a nonthermal reaction with an antibacterial effect27. It is also easy to remove and low in cost26,27. In this study, there was no significant difference between the gauze packing of liver (group B) and CELOX plus direct intra-abdominal physical compression (group E). The full four quadrants packing used in group B is the damage-control surgery recommended by the US military for the hemorrhage of liver injury, and this procedure could extend the survival time and increase the possibility of further definitive treatment28. However, gauze packing must be done in an operating room, which is usually unavailable on battlefield. We evaluated the synergy between CEOLX and intra-abdominal compression by comparing the ST and BT of groups C, D, and E. There was no significant difference in ST and BL between groups D and A. The possible reason for that was the CELOX did not press the bleeding site efficiently in group D. The ST of group C was significantly superior to group A but inferior to group E, which indicated the 10 minutes of intra-abdominal compression alone could not stop bleeding. A cohort of 42,135 adult patients with truncal injuries in the civilian setting revealed that the overall median total prehospital time was 37 minutes, and the overall mortality was 7.9%29. In addition, the mean and median times of flight from the site at which the injury occurred to the hospital was < 20 minutes in the Casualty Evacuation Missions Conducted by the 160th Special Operations Aviation Regiment during the Afghanistan Conflict30. Our hemostasis device used in group E offered a lower BL and a higher MAP and CO for a longer time, and extended an average of 30 minutes in ST compared to group A (74.3 ± 15.4 minutes versus 44.0 ± 13.8 minutes). Thus, a 30-minute extension should increase the possibility for effective treatment. 4.1. Limitations Our study had following limitations: First, the small sample size might lead to bias, and larger studies were required to confirmed the conclusion of our study. Second, direct intra-abdominal physical compression, which could not be provided by the study device itself, is one of the main reasons for controlling SAOH. Therefore, the device should be further improved, so that it could automatically provide and maintain appropriate compression pressure. Finally, the relationship between the dose of CELOX and ST should be evaluated in the future larger sample size study. 5. CONCLUSION The efficacy of the novel, temporary hemostasis device was verified by experiments in the swine model of closed, lethal liver injury. The intervention, which combined CELOX with intra-abdominal compression, prolonged ST by an average of 30 minutes with less blood loss and a higher level MAP and CO. It was not markedly different from the full four quadrants gauze packing of liver in hemostatic effect, with no CELOX thrombosis or embolus formation in other organs or large vessels. Conflict of interest All authors report no conflict of interest. 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For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Efficacy of a Temporary Hemostatic Device in a Swine Model of Closed, Lethal Liver Injury
JF - Military Medicine
DO - 10.1093/milmed/usz372
DA - 2020-06-08
UR - https://www.deepdyve.com/lp/oxford-university-press/efficacy-of-a-temporary-hemostatic-device-in-a-swine-model-of-closed-deOfL5o4MM
SP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -