Uncontrolled hemorrhage is a major cause of mortality in surgery and trauma. After trauma, one-third of civilian patients and one-half of all combat casualties die as a result of exsanguination.1–3 Hemorrhage may be caused by direct injury to blood vessels and by trauma-induced coagulopathy, so-called nonsurgical bleeding. Damaged blood vessels can be repaired, whereas diffuse microvascular bleeding that is associated with a coagulopathy is not correctable by surgical intervention. Trauma-related coagulopathy, which is a significant factor in mortality, is caused by hemorrhage, resulting in the loss, consumption, and dysfunction of platelets and coagulation factors, exacerbated by hemodilution, acidosis, and hypothermia.4–8 Coagulation abnormalities occur with greater severity in trauma patients with head injuries, followed in decreasing order by those with gunshot wounds, blunt trauma, and stab wounds.9
Although replacing lost blood volume and components would appear to be the logical treatment for severe hemorrhage, this is not as simple or effective as it sounds. The transfusion of large quantities of colloid, crystalloid solutions, or red blood cell replacement, dilutes clotting factors. Massive transfusion invariably results in a coagulopathy and is associated with significant increases in mortality.8,10 Trauma patients who are hypothermic and acidotic develop clinically significant bleeding despite adequate blood, plasma, and platelet replacement.11 Although fresh blood might alleviate these problems, this is rarely practicable or available in sufficient quantities.
Recent advances have provided physicians with new technologies for achieving hemostasis in severely bleeding patients. The aim of this article is to focus on the potential role of the modified Rapid Deployment Hemostat (mRDH) bandage in surgery, and in civilian and combat-related trauma.
Hemorrhage in Surgery and Trauma Patients
In most cases, elective surgery is associated with an anticipated need for and readily achieved hemostasis.8 Major surgical trauma can sometimes present the surgeon with an unanticipated or extreme hemostatic challenge. This is distinct from blunt force and penetrating trauma. Such injuries are characterized by irregular wounds that often incorporate damage to several tissues at once (e.g., skin, bone, and vessels). By nature, this occurs at some distance from medical expertise, although there are marked differences in the clinical characteristics and management of civilian and combat trauma patients.
In civilians, blunt trauma tends to predominate, there are usually few logistical issues involved in managing the patient, and the treatment goal is to save the life at any price.3,4 In a mostly urban study conducted in the United States in 1992, gunshot wounds accounted for 42%, and car accidents for 38%, of civilian trauma deaths.2 Rural counties recorded a similar rate of gunshot trauma, although most of these were suicides rather than homicides.12 Rapid transfer of civilian trauma patients to a nearby hospital with its expertise and facilities is of obvious benefit. Even with rapid transport, a coagulopathy is a frequent complication in the civilian trauma patient, with a US study recording 28% of patients with abnormal prothrombin time and 8% with abnormal partial thromboplastin time on arrival at hospital.13 Similarly, 20% of patients with severe penetrating trauma (stabbing or gunshot) suffered coagulopathy in an Australian study.14
In some locations, historical differences between civilian and combat trauma patients, for example, blunt trauma versus penetrating trauma, is being reduced by the rising incidence of civilian penetrating wounds from guns, knives,15 and bomb blast injuries as a result of terrorist activities. The major similarity between trauma in both civilian and combat settings is the need to gain rapid control of profusely bleeding wounds, both in the field and in the hospital environment.
Advances in Surgery and Trauma Hemostasis
Several pharmacological agents have been reviewed for their potential to reduce the transfusion burden during major (cardiac, hepatic, and orthopedic) surgery and in trauma. These include the protease inhibitor aprotinin, lysine analog anti-fibrinolytics (tranexamic acid and epsilon aminocaproic acid), and desmopressin, a modified form of vasopressin which is used to promote the release of von Willebrand factor and recombinant activated factor VII in patients with coagulation disorders such as hemophilia A&B and type I von Willebrand disease.16,17 Desmopressin is useful in patients with impaired coagulation disorders such as von Willebrand disease, mild hemophilia A and thrombocytopenia, bleeding due to uremia, and liver failure or aspirin use.16,17 However, the general lack of efficacy of all of these agents in surgical settings and/or potential problems of storage and administration indicate that these pharmacological therapies may be of limited practical use. Recombinant activated factor VII, despite its promise in treating trauma-related coagulopathy, reducing mortality in patients with intracerebral hemorrhage, and reducing the number of trauma patients needing massive blood transfusions, observed limitations of its efficacy when used as the sole treatment will likely limit its use.18,19
Recently, there have been two studies published that indicate that coronary artery bypass patients who received aprotinin have a higher mortality compared with those who received aminocaproic acid or no antifibrinolytic agent at all.20,21 These studies have resulted in the removal of aprotinin from the market by its manufacturer. In addition, in a large study22 involving 6,000 coronary artery bypass or heart-valve surgery patients who required red-cell transfusions, it was found that red cell storage time is a critical factor in these outcomes. Red cells stored for more than 2 weeks were associated with significantly increased risk of postoperative complications and reduced survival. Standard practice currently allows for the use of red cells stored for as long as 42 days, which is well beyond the safe time frame indicated by the study.22
The mRDH (Marine Polymer Technologies, Danvers, MA) bandage is a recently developed product for surgery and trauma designed to be applied directly onto the bleeding wound to promote clotting.23,24 The mRDH bandage is biocompatible, and FDA approved for surgical and trauma use. No harmful effects have been reported associated with its application. It is easy to use, requires no preparation, and is stable and lightweight. In addition, the mRDH bandage adheres to a wound with a greater tenacity with which it then controls bleeding. Most significantly, the mRDH bandage has a unique, multifactorial mechanism of action, which is responsible for its observed efficacy. Given recent publications regarding aprotinin and transfusion with older stored blood,22 the increased utility of the mRDH bandage becomes a viable option in surgery and trauma.
Several additional hemostatic bandages have been tested and accepted for battlefield use by the Army to address combat-related bleeding, including the Hemcon chitosan bandage, Quickclot (zeolite granules)25 and Woundstat (smectite granules).25,26 These products have been compared recently for efficacy in controlling bleeding in a swine model of lethal extremity arterial hemorrhage.25 A review of the literature on prehospital hemostatic dressings has also summarized the published data on these, and several other hemostatic agents.26 Data in these articles support the conclusion that Woundstat is superior to the both Hemcon and Quickclot, both of which have been replaced by Woundstat for battlefield use by the Army. All Army medics were being supplied with the Woundstat product until late 2008 and early 2009. The use in the battlefield setting of this product has recently been halted because it has been observed that the use of Woundstat applied directly onto injured blood vessels may lead to harmful blood clots.
mRDH Surgery/Trauma Bandage: Mechanism of Action
The mRDH bandage is comprised of a lyophilized matrix of fully acetylated, poly-N-acetyl glucoasmine (pGlcNAc) containing nanofibers.27 The nanofibers' structure, dimensions, and physicochemical properties are the key to the hemostatic efficacy of the mRDH bandage. When blood contacts the matrix of pGlcNAc nanofibers, plasma proteins are rapidly bound and adsorbed. The nanofibers in the bandage interact with platelets by specific platelet receptors (β3 subunit of integrin complex GPαIIbβ3 and integrin GP1b)28 stimulating their activation leading to the onset of the coagulation cascade. In addition, the nanofibers bind and cause agglutination of RBCs, altering their morphology, leading to their activation and direct participation in clotting.29,30 The combination of platelet and RBC receptor-based contact with the bandage results in thrombin generation and fibrin mesh formation. A hemostatic plug forms, which is augmented by additional vasoconstrictive effects due to release of both thromboxane by activated platelets and endothelin-1 by endothelium in contact with the bandage.31,32 The vasoconstrictive effect was demonstrated and confirmed in vitro. The pGlcNAc nanofibers produced a dose-dependent contraction of isolated rat aortic rings.31 The vasoconstriction effect was totally abolished when the aortic segments' endothelial layer was removed, and it was significantly diminished in the presence of an inhibitor of the endothelin-1 receptor. Thus, the pGlcNAc materials produce vasoconstriction that is mediated by endothelin-1.31,32
The ability of the pGlcNAc materials to rapidly agglutinate erythrocytes has been observed using scanning electron microscopy.29,33 The agglutination is mediated by direct contact of red blood cells with the nanofibers.34 The RBCs undergo a morphologic change, from normal discoid to a stomatocytic morphology.29,33 This RBC shape change results in the exposure of phosphotidylserine on the RBC surface, which in turn leads to the localized conversion of prothrombin to thrombin.29 Thus, the pGlcNAc nanofibers that comprise the mRDH bandage are able to activate RBCs to participate directly in fibrin polymerization and clot formation.29,30 This newly observed property of RBCs is present as a direct result of the specific interaction of the pGlcNAc fibers in the mRDH bandage with the Band 3 surface receptor on red blood cells, and thus providing a strong contribution to the overall hemostatic activity of the bandage.29
Platelet activation is an important component of pGlcNAc-mediated hemostasis.34 Direct contact of platelets with pGlcNAc nanofibers and morphologic changes characteristic of full platelet activation have been observed.28,33,35 This is accompanied by fiber-induced surface expression of the activation marker.
P-selectin, activated αIIbβ3 integrin complex and phosphatidylserine, and increased intracellular free calcium concentrations.28,35 The close interaction of the matrix of pGlcNAc nanofibers in the mRDH bandage with interspersed platelets promotes the development of a physiologic fibrin clot. Once fibrin polymerization begins, a tertiary matrix is produced as the fibrin polymerizes within fiber mesh. The platelet, pGlcNAc, erythrocyte, fibrin mesh forms a hemostatic plug that results in hemostasis.
The hemostatic mechanism of action of the pGlcNAc fiber material making up the mRDH bandage, therefore, incorporates several molecular and cellular mechanisms acting in concert, vasoconstriction, agglutination, and platelet and red blood cell activation.28–36
mRDH Bandage: Efficacy
The hemostatic effectiveness of fully acetylated pGlcNAc nanofiber-based materials was observed in a variety of indications and formulations.37–42 The mRDH bandage has proven to be efficacious for control of both venous and arterial hemorrhage, including patients suffering a coagulopathy.26,43,44 The bandage has been tested for its ability to control venous bleeding in a porcine model mimicking human grade IV hepatic injury.25,26 Hepatic injuries of this type are common after blunt trauma and are often complicated by a coagulopathy, with mortality of >50% attributable to exsanguination.25,26 The porcine model incorporated hepatic injury (avulsion of the left lateral lobe), hypothermia (core body temperature was maintained at 33–34°C using intra-abdominal ice packs), and dilutional (45% of blood volume was replaced with crystalloid) coagulopathy, documented by thromboelastography.25 The animals (n = 10) received standard abdominal packing (gauze) or packing plus the mRDH trauma bandage, followed by closure of the abdomen. The abdomen was packed during a Pringle maneuver, a well-established surgical technique that will reduce hepatic blood flow. After 1 hour, the packing was removed, and the animals resuscitated, closed and monitored for a further 2 hours. Compared with gauze alone, the mRDH trauma bandage plus gauze reduced mortality (100–20%, p < 0.05), blood loss (from 1.19 mL/kg/min ± 0.13 mL/kg/min to 0.26 mL/kg/min ± 0.13 mL/kg/min, p < 0.001) and intravenous fluid requirements (from 1.57 mL/kg/min ± 0.28 mL/kg/min to 0.58 mL/kg/min ± 0.27 mL/kg/min, p < 0.05) during the 3-hour follow-up.24
The ability of the mRDH bandage to achieve hemostasis is not limited to low pressure, low flow, hemorrhage because it has also proved efficacious in higher flow situations.44 This was demonstrated in a prospective observational clinical study in humans, which examined the hemostatic efficacy of the mRDH trauma bandage in patients with hepatic injury who had failed all other available methods of hemostasis (including two cases in which Recombinant activated factor VII was administered without effect).43 This was a challenging real-life emergency scenario, in clinically coagulopathic patients with grade V (n = 2), grade IV (n = 5), or grade III (n = 3) injury. Complete cessation of bleeding was achieved in 9 of 10 patients within 5 minutes, including one patient with iliac vein laceration.43 The survival rate of 90% (one patient died because a retrohepatic vein laceration was missed) was remarkable considering the expected mortality of hepatic injuries of grade III to grade V of 24% to 80%.43,45
The mRDH bandage is also effective in controlling high pressure/high flow arterial bleeding.26,44 One arterial hemorrhage study tested the hemostatic capabilities of the mRDH bandage in a porcine aortic laceration model.44 This injury, which is lethal within minutes in untreated animals, mimics a severe battlefield or civilian gunshot wound. The animals (n = 10) underwent a 4 mm aortic punch that was allowed to bleed for 5 seconds before application of standard US Army First Aid Field Bandage or the mRDH bandage, with compression applied for 10 minutes. The bandages were removed after 2 hours and animals were monitored for a further 30 minutes.44 Compared with the standard dressing, the mRDH bandage reduced mortality (100–20%, p < 0.001) and blood loss (from mean 1,071 to 234 mL, p < 0.01) during the 2.5-hour follow-up.44 In a similar porcine model (1 cm aortic incision, n = 15), the mRDH bandage was able to stop bleeding in 100% of cases, findings that were significant (p < 0.01) compared with gauze control (20%) or fibrin bandages (40%).26
The hemostatic capabilities of the mRDH bandage have also been assessed in a porcine femoral injury model.26 This injury, which is rapidly lethal in untreated animals, simulates a severe extremity wound involving skin, muscle, bone, and artery. The animals (n = 11) underwent injury (arteriotomy followed by catheter insertion) to the femoral artery, which was allowed to bleed for 30 seconds, combined with tibial fracture and adductor muscle excision. The dressings were applied with compression for 5 minutes, and the animals were monitored for 30 minutes. Compared with gauze, the mRDH bandage reduced blood loss by 63% (p = 0.01).26
As with the other hemostatic products, the majority of the work on the mRDH bandage has been conducted in animals. In the area of trauma medicine, randomized placebo-controlled studies are rarely possible. Trauma patients are often unable to provide consent. Furthermore, there is little time available on patient presentation in which to make assessments of eligibility, and with the exception of basic endpoints (such as mortality), there it is often insufficient time or expertise (in the field) for making complex measurements.45 In a recently completed clinical registry study, mRDH bandage was used in treating 106 trauma victims to control bleeding (General Surgery News–February 2010). Thirteen physicians participated in the registry at 10 Level I trauma centers in the United States, and at an Army Field hospital in Iraq. Wounds varied widely and the use of the bandage was at the discretion of the physician. Successful control of bleeding was reported in 82% of the patients, and partial control in another 11%.
Comparisons of the mRDH With Other Topical Hemostatic Dressings
Recent advances have provided a number of promising new topical hemostatic dressings for application to severely bleeding wounds in the hospital, prehospital, and trauma settings. A survey46 of several of these new dressings, also including the RDH bandage (an mRDH prototype), summarizes the relative efficacy of the products based on data in the published literature. The dressings most similar to the mRDH compared in the article include: the Hemcon bandage, a chitosan-based product; Surgicel, consisting of oxidized cellulose; Gelfoam, consisting of collagen/gelatin; and Avitene, consisting of microfibrillar collagen. The authors list both positive and negative features of these dressings and conclude that none of them meet the set of criteria that they set forth for an ideal hemostatic agent. Several newer dressings have emerged in the past few years, including Woundstat, Celox, ACS+, Stasilon, and an advanced version of the Hemcon bandage. The relative efficacy of these products is compared in swine arterial and venous bleeding studies, published in several articles.25,26,47–49 The mRDH bandage was not included in these comparative studies. Two very recent studies50,51 provide comparative efficacy and safety data for smectite granules (Woundstat) and the newly developed kaolin gauze (Combat Gauze) in a swine hemorrhage model. The smectite granule-based product is an effective hemostat but is associated with substantial local inflammatory injury to blood vessels and can enter the systemic circulation and pose additional safety problems such as distal thrombosis in vital organs. The Combat Gauze is a less effective hemostat but free of complications.
The mRDH bandage has emerged as one of the most promising new products. Containing entirely fully acetylated pGlcNAc nanofibers, this product has a unique hemostatic mechanism of action that incorporates vasoconstriction, erythrocyte agglutination, and red blood cell and platelet activation. Animal studies confirm that the mRDH bandage stops both venous and arterial bleeding, even in the presence of a coagulopathy. A small prospective study in humans supports these findings, because the mRDH trauma bandage was able to increase survival after liver trauma.
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