enhance the healing of chronic leg ulcers [11]. The suggested potential mechanism involves a pro-inflammatory stimulus within the wound tissue by activation of the resident macrophage population, which generates pro-inflammatory cytokines and subsequently an influx of monocytes and T-lymphocytes into the wound that may trigger the wound into the healing phase [11]. The two types of formulations available for clinical use are povidone iodine and cadexomer iodine. Povidone iodine is available as liquid formulations and as impregnated tulle dressings, whereas cadexomer is available in powder form and as ointments and dressings. Cadexomer iodine is a starch-based porous material in the form of spherical particles which contain 0.9%
iodine. The Iodosorb dressing by Smith & Nephew effectively removes the barriers of bacteria, slough, debris and excess exudates, and is effective for the treatment of chronic exudating wounds. The broad spectrum antimicrobial action is provided by the sustained release of iodine and the desloughing action is provided by the unique cadexomer matrix. Iodosorb is also available in gel and powder form. Inadine® are povidone iodine dressings by Johnson & Johnson consisting of knitted viscose fabric impregnated with a polyethylene glycol base containing 10% povidone iodine. This low adherent dressing is indicated for the prophylaxis and treatment of infection in minor burns, leg ulcers, superficial skin-loss injuries and as a dressing for adjunctive therapy in the treatment of infected ulcerative wounds.
7.2.12 Polyhexamethylene Biguanide Antimicrobial Dressings
Polyhexamethylene biguanide (PHMB) is a commonly used antiseptic, and is also known as polyhexanide and polyaminopropyl biguanide. It is used in a variety of products including wound-care dressings, contact lens cleaning solutions, perioperative cleansing products and swimming pool cleaners. It has been reported to be very effective if packing the dressing into the wound is required [12]. It has also been reported that PHMB promoted contraction and aided wound closure to a significantly greater extent than octenidine and placebo [13]. Kerlix™ AMD antimicrobial gauze and Curity™ AMD antimicrobial gauze sponge by Covidien are examples of PHMB- impregnated dressings. Clinical studies suggest that this dressing is an effective barrier against bacterial colonisation. Suprasorb® X + PHMB wound dressings by Lohmann
& Rauscher support moist wound management and contain 0.3% PHMB.
form a net to hold the clot in place in addition to aiding stopping blood loss and initiating other phases in the wound-healing cycle. In normal wounds, the naturally formed blood clot helps to stop the bleeding and blood loss. However, in the event of major wounds, such as battlefield wounds, civilian victims of vehicle accidents, street violence, wilderness accidents and construction incidents; the severe blood loss due to arterial bleeding is life threatening. Rapid haemostasis is crucial not only for decreasing mortality in these conditions, but also for optimal recovery.
In clinical practice, haemostatic intervention is generally achieved by the application of compression, a ligature or tourniquet. Other local and chemical agents such as fibrin sealants, absorbable haemostatic agents with or without thrombin, collagen, gelatin matrices, regenerated oxidised cellulose, bone wax, glucosamine-containing polymers, chitosan-based dressings, medicinal plant extracts and minerals have also been applied.
An area of increasing concern in haemostatic intervention is lethal haemorrhage from sites that are not suitable for the application of tourniquets or compression dressings.
It is reported that about 50% of combat fatalities and significant cases of civilian trauma fatalities are attributed to uncontrolled haemorrhaging. These fatalities may be prevented by prompt application of any materials that can achieve haemostasis.
However, most materials have some drawbacks as discussed later. There are many haemostatic agents proposed to facilitate haemostasis in cases of severe bleeding.
An ideal haemostatic agent would be easy to use, highly effective, biocompatible, durable and inexpensive. Characteristics of an ideal haemostatic agent for pre-hospital/
battlefield use are as follows:
• Should be capable of stopping large vessel arterial and venous bleeding within 2 min of application to an actively bleeding wound through a pool of blood.
• Should not have any requirement for mixing or pre-application preparation.
• Should be simple and capable of application by a wounded victim or medic.
• Should be lightweight and durable.
• Should have a long shelf life in extreme environments.
• Should be safe to use with no risk of injury to tissues or transmission of infection.
• Should be inexpensive.
Ancient people began to stuff bleeding holes with fabric material and apply pressure as a practical application of cause and effect which subsequently led to increased survivability. Historically, Hippocrates used caustics to achieve haemostasis. The term haemostasis comes from the ancient Greek ‘Haeme’ meaning blood and ‘stasis’
meaning halting, hence haemostasis means the ‘halting of the blood’. The origin of
haemostatic agents was first referred to in the Battle of Troy, which dates back as far as ancient Greece. It started with the practical knowledge that excessive bleeding caused inevitable death. Several materials including vegetable, herbs and materials of mineral origin were used on large wounds by the Greeks and Romans [14]. Greater knowledge of the haemostasis process was developed by the Egyptians based on the study of the mummification process. They knew that many veins and arteries run throughout the human body, and the physicians during that period realised that if they were plugged, blood could not flow out of the body. In ancient Egypt, a combination of wax, barley and grease was also used as a haemostatic agent. The modern era of haemostasis began with the use of gelatin by Carnot [15]. ‘Antiseptic wax’ was developed by Horsley in 1886, which is a mixture of beeswax, salicylic acid and almond oil [16]. Oxidised cellulose was introduced in 1942, oxidised regenerated cellulose was developed in 1960 and gelatin foam in 1945. Microfibrillar collagen was developed in 1970 by Hait [17]. Chitosan-based agents were approved by the FDA in 2003. Recently, a mineral-based agent has been introduced by the US Army Institute of Surgical Research. A plant extract-based haemostatic agent was introduced in Turkey in 2007.
7.3.1 Fibrin Sealants
Fibrin sealants were one of the first modern haemostatic agents used clinically [18].
The advent of technology for the production of highly concentrated fibrinogen in the 1960s led to the usage of fibrin-based haemostats. However, in 1970, the FDA prohibited its use because of the concern of viral transmission. In 1989, the FDA approved the first fibrin sealant, Tisseel, manufactured by Baxter. Tisseel is a two- component fibrin sealant. One solution contains human fibrinogen and a synthetic fibrinolysis inhibitor, aprotinin, which also helps to prevent the premature degradation of the fibrin clot. The second solution contains human thrombin and calcium chloride.
When these two solutions are mixed they combine and mimic the final stages of the body’s natural clotting cascade to form a rubber-like mass (fibrin clot as shown in Figure 7.2), which adheres to the wound surface and achieves haemostasis and sealing or gluing of tissues. Tisseel is indicated for use as an adjunct to haemostasis in patients undergoing surgery when the control of bleeding using conventional surgical techniques is impractical. It is effective even in heparinised patients and is completely resorbed in 10−14 days. Tisseel exhibited a significantly faster control of bleeding and decreased post-operative blood loss, which led to the commercialisation of various other fibrin sealants such as Evisel® and Evarrest® by Ethicon, CrossealTM by Omrix Pharmaceuticals Ltd., Beriplast®, Biocol®, VitagelTM by Orthovita, Tachosil® and Artiss by Baxter, and so on. However, the limited use of fibrin sealants led to the development of other novel haemostatic products which are more familiar to clinicians at present.
Figure 7.2 Scanning electron microscopy image of fibrin clot formation after mixing of the two-component fibrin sealant
7.3.2 Gelatin Haemostats
The first gelatin-based haemostatic agent was gelfoam, which is a compressed sponge of absorbable gelatin prepared from purified porcine skin. The actual mechanism of blood clotting is yet not known but appears to be physical, i.e., it can hold many times its weight of blood and other fluids and hence concentrates cells. One theory proposed by Jenkins and co-workers is that the clotting effect of gelfoam may be due to the release of thromboplastin from platelets, which occurs when the platelets entering the sponge become damaged upon contact with the walls of numerous intervening spaces. Thromboplastin interacts with prothrombin and calcium to produce thrombin, and this sequence of events initiates the clotting reaction. Surgifoam® is another absorbable haemostat manufactured by Ethicon and is available as a gelatin powder or foam, and is indicated for wound closure and as a haemostat. Gelatin can also be applied in combination with purified thrombin, which can enhance the haemostatic properties of gelatin sponges. A product which uses human-derived thrombin is Floseal®, which is a gelatin-based haemostatic agent approved by the FDA in 1999 and is manufactured by Baxter. It is a crosslinked gelatin granular product which reduces the swelling of the granules in vivo. Ease of use, availability and effectiveness
in haemostasis make gelatin-based haemostatic agents a popular tool in reducing surgical morbidity due to blood loss.
Bone wax has been used in bone surgeries for a long time, however, complications such as allergy, granuloma and infection interfere with bone healing; bone wax is not suitable for combat/accident casualty care. Absorbable gelatin sponges, made from denatured collagen, are mostly used on low pressure bleeding. Microfibrillar collagen induces fast haemostasis which is promoted by platelet aggregation. However, placing this material at the site is difficult as it sticks to application tools or gloved fingers to a greater extent than the targeted site. Oxidised regenerated cellulose is mainly used for the control of oozing or mild bleeding from broad surfaces. TraumaDEXTM is composed of microporous starch-based microspheres, with an average size of 20 µm, and is poured directly into the bleeding wound which clots in 30 s to 1 min. Dry fibrin sealant dressings consist of human fibrinogen, calcium chloride and fibrin with a textile backing. A rapid deployment dressing haemostat is composed of poly-N- acetyl-glucosamine and clotting is achieved via red cell aggregation, platelet activation and activation of the clotting cascade. A HemCon® chitosan bandage is a freeze-dried chitosan-based dressing which enhances platelet function and incorporates red blood cells into the clot formed at the site of the wound; however, these modern haemostats are expensive.
7.3.3 QuickClot®
QuickClot® is a zeolite granular haemostatic agent poured directly into the wound, which absorbs fluid resulting in the accumulation and concentration of clotting factors and platelets. QuickClot® was the first-to-market haemostatic agent (2002) and had been used for many years by the US forces in Iraq and Afghanistan for stabilising life- threatening injuries. Kaoline, the main component of QuickClot® is a white alumina silicate clay material which has been known to activate blood clotting in vitro. A paper published in 1958 by Margolis [19] demonstrated its activation effect and this process can take place even when calcium and platelets are absent [20]. During the Boston bombing incident, the application of kaolin-impregnated gauze (combat gauze) helped to activate the clotting cascade and has been shown to be effective to staunch bleeding on the battlefield [21].
7.3.4 WoundStatTM
WoundStatTM (TraumaCure, Bethesda, MD, USA) is an inorganic haemostat approved by the FDA in August 2007. It is a nonmetallic clay mineral (smectite) which swells when exposed to water/blood and forms a clay material of high plasticity
and strong tissue adhesiveness. It shows high survival in lethal extremity arterial haemorrhage cases. However, significant endothelial and transmural damage was observed in WoundStatTM-treated vessels, which also exhibited thrombi and embedded WoundStatTM residues. Although it has been proved to be an effective haemostatic agent, use of WoundStatTM was associated with a substantial local inflammatory response and neurovascular changes up to 5 weeks post-injury [22]; consequently, the US Army halted the use of WoundStatTM powder, only months after approving it.