Burns

Small animal burn injuries can be some of the most challenging cases that the veterinarian will be called upon to manage, and a thorough understanding of the pathophysiology of burn injury is crucial to maximizing the chance of successful treatment. Fortunately, our knowledge of burn pathophysiology has greatly increased in the past decade, and much of this knowledge has already been put into practice in the clinical management of burn cases. As with many other areas of veterinary medicine, much of the clinical and basic science literature comes from human medicine, and this chapter draws heavily from those resources. For purposes of clinical application, it is fortunate that many advances in the treatment of human burns are based largely on data derived from animal experimentation, in which the dog is a common model. This fact gives relevance for veterinary application of the human literature; however, care must still be exercised in the interpretation and application of the human literature to animals owing to the important anatomic and physiologic differences between humans and animals. This chapter reviews historical and recent advances in the understanding of burn pathophysiology and identifies areas for application of this information to the clinical management of burns in small animal practice.

Classification of Burn Injuries

Burns are classified into one of four types based on etiology [1,2]: Thermal burns are caused by exposure to temperature extremes (either high or low) sufficient to cause cellular damage. Chemical burns are caused by exposure to chemicals that cause tissue necrosis via chemical reactivity or thermal effects. Electrical burns are suffered when electrical current of sufficient amperage and voltage to cause cell death passes through the patient. Radiation burns are caused by exposure to ionizing radiation at levels that cause acute cell death; this injury is most commonly seen either from exposure to solar radiation, or as a side effect of radiation therapy for neoplastic disease, and will not be specifically discussed in this chapter. Knowledge of the source of the burn and the mechanism by which it inflicts injury is vital to the proper initial care of the burn patient; e.g., copious lavage for many chemical burns, rapid cooling of tissues exposed to high heat, gentle rapid rewarming of frozen tissues, etc.

With few exceptions, the primary organ system involved is the integument. Some types of burn injuries, notably chemical, electrical, and radiation, may have gastrointestinal or other primary sites of injury, and thermal burns that primarily involve the integument often have systemic effects, but the skin is normally the first and most important site of injury because it is usually the location where the initial damage occurs that leads to systemic sequelae and, therefore, is the focus of most of the investigation in burn pathophysiology and therapeutics.

Thermal Burns

Technically, thermal burns include injuries caused by exposure to either excessive heat (hyperthermic burns) or excessive cold (hypothermic burns). In this chapter, the use of the term "thermal burns" will deal with the former, whereas the term "frostbite" will be used for the latter. Thermal burns are subclassified according to the heat source, i.e., a flame or fire, scalds from hot liquids or gases, and burns from direct contact with a hot object [3]. Thermal burns occur when heat is transferred to the tissues in one of three ways: via conduction, convection, or radiation. Conduction is the most common source of thermal injury and occurs when the body is in direct contact with a hot object such as a heating pad or boiling water. Convection is the transfer of heat via airborne currents, such as the superheated air that comes from a fire. In radiation burns, energy in the form of electromagnetic radiation travels through the air until it strikes the body and is converted into heat; heat lamps can produce burns via this process [1]. Burn severity has historically been classified according to the depth of tissue destruction; this classification system has proven useful for treatment planning and prognostication. Partial-thickness burn injuries can be divided into two categories. First-degree burns are superficial injuries involving only the epidermis, with erythema as the only observable change. Because the dermis is not involved, skin integrity is maintained, with no blistering or open wounds, and rapid, scar-free healing occurs without medical intervention.

First-degree burns are painful, because nociceptors in the epidermis are stimulated at the time of the injury. Second-degree burns are partial-thickness injuries of the skin that involve the dermis. In addition to pain and erythema, these injuries are characterized by blister formation and exudation of fluid (note: blisters are common in humans, but rare in dogs and cats owing to differences in dermal histologic structure). Partial-thickness burns can vary from superficial to deep, but at least some of the dermis and adnexa survive the injury so that scarring is usually absent. Complete healing usually requires 2 to 3 weeks in uncomplicated cases. Full-thickness burns can be further divided into three categories. Third-degree burns extend through the skin to the level of the subcutaneous tissues; some classification schemes recognize two further categories; fourth-degree burns, extending to the underlying muscle, and fifth-degree burns involving bone [2]. Depth of tissue destruction is directly proportional to factors that concentrate heat in the area of the injury; i.e., temperature to which the tissue is heated, and duration of exposure or contact [4]. Failure of cellular function and tissue necrosis follow a predictable progression as the temperature of the skin increases. Between 40 and 44°C cellular enzymatic activity is affected, resulting in sodium pump failure. Epidermal sloughing (partial-thickness burn) results if skin is heated to 60°C for more than 1 second, and skin temperatures above 70°C produce full-thickness burns [5].

Local Response to Thermal Burn Injury

The local burn injury has been divided into three functional and anatomic areas; moving outward from the center of the burned area, the innermost area is the zone of coagulation (also known as the zone of necrosis or destruction). Complete loss of tissue viability occurs within this zone; the therapeutic goal in this area is debridement. The next area is the zone of stasis; in this area, heat-induced changes in erythrocytes reduce their deformability and reduce their ability to flow through microscopic vessels. This is compounded by reduction in microvessel luminal area owing to increased extraluminal pressure from tissue edema brought about by inflammation and subsequent increase in capillary permeability. The increase in local capillary permeability in response to burn injury is not an all-or-none phenomenon, but rather is a graded response based on the severity of the injury. In a scalded canine hindlimb model, the capillary permeability, as measured by local lymph flow and protein content, increased with increasing scald temperature [6]. Taken together, these changes cause sluggish blood flow and tissue hypoxia; in this intermediate zone, tissue either proceeds to necrosis or healing depending on further insults sustained and/or the effectiveness of treatment, making this area the principle focus of burn therapy. Finally, the outer zone of hyperemia is the area of the local inflammatory response to the burn. Tissue in the zone of hyperemia remains viable and will proceed to healing if no further insult is sustained [7].

The local response to burn injury is similar to that of other inflammatory lesions, and is characterized by local vasodilation, an increase in vascular permeability, edema, and migration of inflammatory cells into the injured area [8]. The burned tissue and resident inflammatory cells at the time of injury are the primary source of chemokines that initiate the inflammatory response, including endotoxin [9], prostaglandin E2 [10], histamine, and activated complement.

Immediately after thermal injury, an upregulation of blood flow to the burned area occurs. Administration of the autonomic blocker hexamethonium ablates this response, indicating that this regional arteriolar vasodilation appears to be at least partly under postganglionic autonomic control [12]. Local upregulation of nitric oxide (NO) production also plays an important role in the regional vasodilatory response to burn. Several studies have demonstrated an increase in NO production in thermally injured tissue [13] and in the surrounding non burned skin as well [14]. NO is well known as a potent vasodilator that increases blood flow in local tissue beds in response to a variety of inflammatory stimuli including burns. NO has been demonstrated to act directly and also indirectly, by potentiating the release of other vasodilatory molecules such as substance P [15].

Vascular permeability also increases in the periwound tissues after burn injury. The increase in permeability is mediated by the activation of the inflammatory cascade and is a graded phenomenon, i.e., transvascular flux of fluid and protein is directly proportional to the severity of the burn [6]. Increased vascular permeability, coupled with increased blood flow, leads to burn wound edema. Extravascular migration of neutrophils is partly a consequence of increased vascular permeability and partly mediated via direct effects on neutrophil diapedesis. Expression of the adhesion molecules CD11b/CD18 and adhesion to vascular endothelium are enhanced in neutrophils that are incubated in the presence of burn serum; this effect is blocked by the administration of monoclonal antibodies to the adhesion molecules [16].

Interestingly, burn wounds seem to lack the ability of normal surgical wounds to stimulate their own healing. When angiogenic activity of wound fluid from surgical wounds, skin graft (donor) wounds, and burn wounds was compared, burn wound fluid was found to be completely lacking in ability to stimulate endothelial cell migration or proliferation, and contained less than 5% of the levels of fibroblast growth factor-2 (FGF-2) of surgical wound fluid [17].

Most of the interest in the local burn response concerns the acute post-burn period, because so many life-threatening side effects begin with the acute burn wound. For those patients that survive, the burn wound enters a chronic stage that may result in wound healing problems as the skin attempts repair. In first- and second-degree burns the epidermis may be damaged but the basement membrane remains intact, and skin healing is generally rapid and uncomplicated. Third- and higher-degree burns present a problem, because necrosis of the dermis means that the overlying basement membrane is gone. The basement membrane is a necessary surface to direct the migration of stem cells onto the wound from the stratum basale of the surrounding unburned skin. As with any injury involving loss of the basement membrane, healing is by scar formation as fibroblasts enter the wound and lay down a collagenous matrix. Two chronic pathophysiologic processes that may affect burn wounds in small animals are scar contracture and post-burn blistering.

Wound contraction is the process by which motility of fibroblasts and myofibroblasts within the matrix exerts force that reduces the open wound area. This is a generally beneficial process, especially in dogs and cats that have more abundant skin on the body. It reduces the amount of tissue exposed to dehydration and contamination, and it stops when the burn is completely covered with new epithelium [18]. In contrast, scar contracture, although involving the same underlying mechanisms, is considered a pathologic process because it continues after the wound has been epithelialized [18]. Scar contracture results in pain and loss of mobility, and can be particularly debilitating when it is extensive or occurs over a joint or in an area with minimal skin mobility [19]. The degree of contracture appears to be proportional to the amount of scar tissue; therefore, prevention of contracture is directed toward prevention of excessive scar formation. Treatment of contracture is accomplished by surgical excision of the existing scar and application of a graft or flap to the resultant defect [20].

Post-burn blistering is a relatively common complication in human burn patients [21]. Although uncommon in animals, we have also observed this phenomenon in a dog. After a large burn wound has healed by second intention, blisters may spontaneously appear, rupture, and heal in a continuous cycle. Immunohistochemical and ultrastructural analysis of the blisters reveals that the basement membrane displays areas of discontinuity and detachment from the dermis [22]. One hypothesis is that defective reorganization of the basement membrane may be associated with observed ultrastructural aberrations of dermal fibroblasts [23].

Systemic Response to Thermal Burn Injury

Pulmonary System

The most important and far-reaching effect of thermal burn injury on the pulmonary system is from smoke inhalation.

Smoke inhalation occurs commonly as an intercurrent injury with thermal burn. Besides the often serious and even fatal local (pulmonary) effects, smoke inhalation also profoundly exacerbates the systemic sequelae of burn injury. The pathophysiologic response of the lung to smoke inhalation can be divided into several components: pulmonary edema, atelectasis, increased alveolar pressure, and deactivation of pulmonary surfactant [24]. These highly interdependent events combine to lead to the development of the acute respiratory distress syndrome (ARDS) that is one of the major complications of burn injury [25].

The etiologic agents of smoke inhalation injury are numerous and interrelated, and include cytokines, eicosanoids, activated neutrophils, nitric oxide (NO), free radicals, and neurotransmitters such as substance P [26,27]. Three major sources of cytokines appear to be involved in the cytokine-mediated pulmonary injury and dysfunction following a burn. The first source is cytokines released from the burned tissue; the second source is the lung, which has been damaged by smoke inhalation; the third is the intestinal tract, which conveys cytokines to the lungs via the mesenteric lymphatics. These cytokines appear to act synergistically with bacteria and endotoxin to maximize increases in pulmonary vascular permeability and apoptosis of alveolar cells [28].

Pulmonary edema begins to develop soon after smoke inhalation, as fluid, mucus, and neutrophils accumulate within alveoli and airways [29,30]. The eicosanoid thromboxane A2, synthesized and released from pulmonary tissue in response to smoke inhalation, plays a major role in the pathophysiology of smoke inhalation. Increased pulmonary lymph concentration of thromboxane A2 post-smoke exposure is associated with a parallel increase in pulmonary transvascular flux and vascular resistance, both systemic and pulmonary. The increased pulmonary vascular resistance appears to be primarily caused by an intense but transient venoconstriction [24]. Inhibition of thromboxane A2 with a thromboxane A2 synthase inhibitor significantly attenuates these changes [29].

Nitric oxide (NO) is another systemic mediator of inflammation that is involved in pulmonary edema after burn injury [26,31,32]. Significant increases in NO in plasma and pulmonary lymph are seen within 24 hours post-burn owing to upregulation of inducible NO synthase and are associated with increases in pulmonary microvascular permeability, cardiac depression, and hemoconcentration [32]. NO appears to affect vascular permeability differently between species: in an ovine model, leakage of fluid increased while protein flux remained at normal levels [33], while in the rat, transvascular albumin flux increased by 100%. Pulmonary compliance also decreases after a burn; this effect is caused partially by pulmonary edema and partly by reduction in production of pulmonary surfactant [34].

Part of the complexity of smoke inhalation injury stems from the complex chemical composition of the inhaled smoke. Most burned small animals with smoke inhalation are exposed in an indoor environment such as a house fire. The smoke from house fires contains over 200 toxic substances [35]. Principal among these are carbon monoxide (from incomplete combustion of wood), hydrogen cyanide (from combustion of nitrogen-containing products, i.e., nylon, formica, melamine, wool), and inorganic acids HCl, HF, and HBr (from polyvinyl chloride, teflon, neoprene, and various plastics).

Carbon monoxide toxicity occurs via three mechanisms:

1. Binding to hemoglobin and reducing its oxygen carrying capacity;
2. Carboxyhemoglobin formation, which results in a leftward shift of the oxyhemoglobin dissociation curve, reducing oxygen delivery to the tissues; and
3. Binding with myoglobin to reduce oxygen availability to muscle, especially cardiac and skeletal.

Hydrogen cyanide binds with mitochondrial cytochrome oxidase, thereby preventing oxygen utilization by cells. Hydrogen chloride and the other diatomic halide acids are all intensely irritating to respiratory mucous membranes, producing laryngospasm and bronchospasm at concentrations found in smoke [36]. Smoke inhalation also causes a dose-dependent injury to tracheobronchial epithelium and lung parenchyma via free hydroxyl and carbon radicals contained in the smoke and also via the accompanying neutrophilic infiltration [35].

Cardiovascular System

Hypovolemia and Vascular Dysfunction

Loss of fluid volume from the vascular space is one of the early pathophysiologic changes seen with severe burns. Within 10 minutes after a burn, systemic vascular permeability to fluid and albumin increases, via myosin-mediated contraction of vascular endothelial cells, which increases the intercellular gap size in the endothelium [37]. Direct damage to endothelial cells, mediated by complement activation, histamine, and oxygen free radicals from the burn site [11], exacerbates the process and causes further interstitial edema and loss of vascular fluid volume [38].

The burn wound is another source of fluid loss via evaporative losses that are 4 to 20 times greater than for normal intact skin [39]. These losses can constitute a significant source of the fluid loss that leads to hypovolemia in large burns. The cumulative effect of hyperpermeability and fluid loss is to create profound hypovolemia within the first few hours after a large burn. Hypovolemia and reduced RBC deformability combine to cause hyperviscosity of the blood. This problem is compounded by systemic vasoconstriction, which is mediated by the sympathetic response to baroreceptor and nociceptor afferents [40,41] and is proportional to the severity of the burn [42,43]. The combined effects of hypovolemia, hyperviscosity, and vasoconstriction in turn lead to hypoperfusion and metabolic acidosis [44,45].

Myocardial Effects

Direct myocardial effects also constitute a portion of the pathophysiology of burn shock. Left ventricular contractility was significantly decreased during the 6-hour post-burn observation period in dogs after a 50% total body surface area burn [46]. This impaired contractility is paralleled by a significant increase in intracellular Ca++ of cardiac myocytes [47]. At least a portion of this post-burn myocardial Ca++ influx and contractile dysfunction is mediated via the increased translocation of gut bacteria, endotoxin, and cytokines, and the ensuing systemic inflammatory response syndrome [48]. In one experiment, depopulation of the gut with oral antibiotics reduced post-burn myocardial levels of TNF-α and other cytokines and improved myocardial contractility [49]. Increased sympathetic input is another stimulus that causes cardiomyocytes to synthesize and release increased levels of TNF-α and other cytokines, resulting in defects in cardiac contraction and relaxation [50].

Smoke inhalation also causes decreased cardiac output [29,51] and myocardial damage via the toxic effects of carbon monoxide, which decreases myocardial oxygen delivery and utilization. In a canine model, smoke inhalation caused an increase in carboxyhemoglobin, decreased ATP production by cardiomyocytes, and zymographic and histopathologic evidence of myocardial necrosis [52].

Gastrointestinal System

The GI system can be profoundly affected by large burns, and in turn, is a major effector organ for the syndrome of shock, sepsis, and multiple organ failure that follows severe burns. Studies have demonstrated that, after a severe burn, loss of GI barrier function occurs, with translocation of gut bacteria, endotoxin, and cytokines, leading to septic shock [53-56]. Burn injury has been demonstrated to increase the rate of apoptosis of gut mucosal cells, with no effect on mucosal proliferation; this may be an important aspect of the loss of GI mucosal integrity seen after burns [57]. Post-burn GI motility is also impaired via a nitric oxide-dependent mechanism; inducible NOS expression by neurons of the myenteric plexus appears to play a significant role [58].

The liver is also affected by burn injury. Burns cause increased oxidative stress in hepatocytes, marked by a decrease in liver glutathione level and increases in malondialdehyde (MDA) and myeloperoxidase (MPO) activity at 24 hours post-burn [59]. Hepatocyte turnover is also increased post-burn, as demonstrated by increases in both apoptosis and proliferation [60]. Liver synthetic function is also affected. Upregulation of certain products such as acute-phase proteins and downregulation of others has been noted by 3 days post-burn [61].

Renal System

The incidence of acute renal failure in seriously burned human patients ranges from 1.3% to 38% and is associated with a high mortality rate, between 73% and 100% [62]. Burn severity (as percentage of total body surface area) is an independent predictor of the likelihood of acute renal failure and associated mortality [63]. A number of contributory factors including hypotension [63], hypoalbuminemia [63], hemoglobinemia, myoglobinemia [63], sepsis [63,64], reduced cardiac output, and systemic vasoconstriction have been identified, with elevated levels of stress hormones (catecholamines, vasopressin, angiotensin, and aldosterone) implicated in the mechanism [65]. Atrial natriuretic peptide (ANP), which is also elevated in post-burn patients, may play a protective role by increasing renal blood flow and urine output. Dogs receiving a constant norepinephrine infusion responded to exogenous ANP administration with improvement in renal and hemodynamic parameters [65].

Acute renal failure may also develop as a late consequence of burn injury. The etiology is thought to be multifactorial, including late effects of renal ischemia, sepsis, nephrotoxic effects of antibiotics or other drugs, and renal glomerular deposition of proteins such as hemoglobin and myoglobin and other cellular debris from necrotic cells [1,64].

Hematologic Responses

Burn injury produces an immediate and long-lasting reduction in circulating erythrocyte numbers. This so-called "burn anemia" results from increase in red cell loss coupled with decreased erythropoiesis. Up to 10% of the circulating red cell mass may be trapped and destroyed in a large burn [66], but this only accounts for a portion of the total red cell losses - human burn patients average 12% loss of red cell mass within 6 hours of a large (15 to 40% TBSA) burn and may lose up to 18% of their red cell mass within 24 hours [67]. Within 1 hour of a burn injury, plasma free hemoglobin levels increase. Increased hemolysis occurs owing to a combination of factors. First, increased osmotic fragility appears to be caused by damage to the RBC membrane from activated complement, neutrophils, and oxygen free radicals [68]. Second, a decrease in erythrocyte deformability is caused by oxidative stress and subsequent lipid peroxidation of the red cell membrane [69,70]. In spite of the loss of RBC mass, which stimulates an appropriate elevation in erythropoietin release from the kidneys, erythropoiesis is nonetheless depressed [71,72]. Reduced erythropoiesis appears to be caused by an erythroid inhibitory protein [73] and as a secondary effect of decreased iron availability [72]. Administration of supplemental exogenous erythropoietin helps restore red cell mass after a burn [74].

Burn injury also produces significant negative effects on leukocyte production and function. For example, lymphoid apoptosis is upregulated after burn injury, and may be linked to a parallel upregulation of TNF-α [75]. Burn injury also caused a downregulation of chemotactic cytokine production by mouse T cells, resulting in increased susceptibility to sepsis. This effect appears to be mediated via the sympathetic nervous system. Chemically sympathectomized mice had normalized cytokine production and improved resistance to sepsis. In vitro, T cells from burned mice or from normal mice treated with norepinephrine also demonstrated reduced cytokine production [76].

Neurologic System

Effect of Pain on Burn Wound Response

Burns cause intense pain; even full-thickness burns, in which cutaneous nociceptors are destroyed, can still be painful because the full-thickness burn is surrounded by tissue that is damaged but not completely destroyed [77]. In this area of damaged tissue, peripheral nociceptors are activated by the burn injury, sending afferent input along A delta and C fibers [78]. Cellular damage and the ensuing inflammatory response also cause the release of chemical mediators of pain (kinins, prostaglandins), which further sensitize local nociceptors, causing a hyperalgesic state [77]. The intense pain stimulates a massive sympathetic discharge, which in turn drives many of the cardiovascular changes of burn shock. Even after the initial burn shock has been treated, chronic pain in burn patients continues to stimulate a chronic, albeit lower level of catecholamine release that mediates a number of the metabolic and organic derangements seen in burn patients [78].

Other Neuromodulators of the Burn Wound Response

Besides the modulation of burn pain and its secondary effects, the peripheral nociceptor system is also involved in the initiation of the local inflammatory response to burn injury through its effect on vasomotor tone and chemotaxis of inflammatory cells. Scald injury of the rat hindpaw induced release of substance P and calcitonin gene-related peptide (CGRP) from peripheral sensory neurons. Both of these substances induced vasodilation in the injured tissue. In addition, neuropeptides have been demonstrated to induce chemotaxis and activation of neutrophils, eosinophils, mast cells, and monocytes following tissue injury [79] and have been demonstrated to play a role in the development of ARDS following smoke inhalation [27].

Metabolic and Endocrine Changes

Burn injury induces profound changes in energy and protein metabolism. These changes are initiated by two primary events: local effects, i.e., release of pro-inflammatory cytokines (TNF-α, IL-6, IL-8) and oxidant stress from cell lysis, and systemic effects from increased release of catabolic hormones (primarily cortisol and catecholamines).

Post-burn metabolism follows a biphasic course. There is a period of hypometabolism immediately after injury (the "ebb phase", which occurs during the shock), followed by a hypermetabolic state (the "flow phase"), during which basal energy expenditure increases by over 100% compared with pre-burn [80,81]. This change is caused by several conditions at the local and systemic levels. Loss of the barrier function of skin means that large amounts of body water are lost to evaporation; along with the water loss, significant heat is lost as the heat of evaporation. The hypothalamic "set point" is also elevated post-burn by 1 to 2°C in response to the release of cytokines and eicosanoids as part of the inflammatory process. The energy "cost" of this increased thermogenesis is paid via increases in non-productive metabolic work that consumes energy and produces heat. For instance, there is a 450% increase in triglyceride-fatty acid cycling and a 250% increase in glycolytic-gluconeogenic cycling in post-burn patients [82].

Protein and carbohydrate metabolism are also altered in the post-burn state. Amino acid utilization for energy production is increased, producing a decline in lean body mass as body protein is catabolized. This negative energy and nitrogen balance differs significantly from that of simple starvation. In simple starvation, body adipose stores supply 90% of the basal energy requirement, and lean body mass accounts for only 5% to 8% of the body's energy needs. In the postburn state, relative insulin resistance caused by increased catabolic hormones (glucagon, cortisol, and catecholamines) results in a completely different energy consumption profile, in which only 50% of the body's energy needs are supplied by adipose tissue and lean body mass accounts for 30% [83]. Upregulation of hepatic gluconeogenesis and relative insulin resistance results in a persistent hyperglycemic/catabolic state marked by glucose intolerance and hyperinsulinemia, with reduced rate of glucose extraction by peripheral tissues (muscle, fat, etc.). Increased glucose uptake is limited to the burn wound, which has a high energy requirement for anaerobic glycolysis by inflammatory and endothelial cells and fibroblasts [82]. This so-called "burn diabetes" is a serious complication of burns in both the acute and chronic stages, as prognosis deteriorates with increasing loss of lean body mass [83].

Application of Burn Pathophysiology to Treatment

The treatment of human patients with burns over a large percentage of the body surface area has gone through an interesting progression. Initially, the entire focus was on the burn site, and various bandaging, enzymatic, and other local treatments were developed for non-surgical debridement. The problem with the local therapy focus was that a high percentage of patients died of systemic complications of their burns, so attention was turned to developing treatments for burn shock and the other systemic complications of burn injuries.

More recently, the focus of treatment for patients with large full-thickness burns has once again turned to the local site, as the connection between the burned area and systemic pathophysiology has become clear. Today, large full-thickness burns are treated by complete surgical excision of the burn eschar as soon as the patient can be made stable enough for surgery. The benefit of this strategy is obvious: the burn eschar is the stimulus that drives the inflammatory reaction, leading to the entire cascade of local and systemic events described above. Early complete escharectomy removes this stimulus and effectively converts the burn - a major physiologic threat - into a comparatively benign, large, clean, open wound. Systemic post-burn levels of endotoxin and E-selectin (but not TNF-α or interleukin-10) were significantly reduced at 1 and 3 days after escharotomy in human burn patients [9].

In one clinical study of severely burned children, administration of the anabolic agent oxandrolone improved net nitrogen balance, lean body mass, and expression of genes for muscle protein synthesis when compared with controls [84].

Early enteral feeding has been demonstrated to ameliorate some of the GI effects of burns. By reversing the increased rate of apoptosis seen in mucosal epithelium after burn injury, early enteral feeding helps to maintain mucosal integrity [57]. This may be particularly important owing to the connection between loss of mucosal integrity and post-burn septic shock.

Frostbite

Frostbite may be seen when animals suffer lengthy exposure to cold, especially those that are injured or debilitated. Under these conditions, the extremities are most often affected, particularly the pinnae [85] and digits. The flank folds are also predisposed to frostbite owing to the extreme thinness of the skin in this region. Frostbite may also be encountered as an iatrogenic condition when cryotherapy is delivered improperly [86]. Three pathophysiologic mechanisms cause the tissue damage seen in frostbite: tissue freezing, hypoxia, and release of inflammatory mediators. These events occur simultaneously and work synergistically, as the pathologic changes caused by one exacerbates the others [87,88].

Tissue freezing causes cell damage in two ways. Freezing causes formation of ice crystals, both intracellularly and extracellularly. Initially, extracellular ice crystals damage the cell membrane, leading to disruption of the osmotic gradient and intracellular dehydration. As tissue temperature continues to fall, intracellular ice crystals form and expand, causing direct physical disruption of the cell membrane and cell death. Freezing also causes direct cell damage via denaturation of cell membrane lipid-protein complexes [87,88].

Local hypoxia is induced by cold-induced vasoconstriction. Initially, as tissues cool, local vascular beds respond with alternating cycles of vasoconstriction and vasodilation, the "hunting reaction" [87]. Vasoconstriction causes decreased blood flow via decreasing vessel diameter; also blood viscosity increases. The vasodilatory phase brings partial thawing of frozen tissue and the reestablishment of blood flow. This is the freeze-thaw cycle that causes the greatest amount of tissue damage. After repeated cycles, vessel thrombosis occurs, leading to a continuous hypoxic state. The combined effects of direct cellular damage and tissue hypoxia stimulate the release of inflammatory cytokines (prostaglandins, thromboxanes, bradykinin, histamine) and activation of the inflammatory cascade, much the same as that seen in thermal burn injury. Activation of the inflammatory cascade leads in turn to clotting activation and intravascular thrombosis, completing the "vicious cycle" [87,88].

Current concepts in frostbite treatment focus on taking advantage of knowledge of the mechanisms of injury.

Treatment includes:

1. Rapid rewarming of the frozen tissues, but not under "field conditions" where re-freezing may occur and exacerbate injury;
2. Fluid therapy to improve local circulation; and
3. NSAIDs to combat activation of the inflammatory and clotting cascades [87].

Chemical Burns

Chemical burns occur either through chemical reaction with cellular components, or via thermal effects when the chemical(s) in question produces an intense exothermic or endothermic reaction. The degree of tissue damage is proportional to the toxicity of the chemical, its quantity and concentration, and the duration of exposure [1]. Chemical burns tend to continue until the chemical in question is neutralized by reaction with tissue components (or by another externally applied chemical), or is washed off or sufficiently diluted during first aid treatment. Different classes of chemicals have different modes of tissue toxicity. Acids act as powerful oxidizing agents that disrupt protein structure and function by insertion of oxygen atoms into peptide bonds. Alkalis are reducing agents that denature protein through reduction of amide bonds that crosslink polypeptide chains; these reactions can be intensely exothermic, causing simultaneous thermal burns. Hydrocarbons act as lipid solvents that disrupt the cytoplasmic membrane [1]. Vesicants are chemical agents that cause blistering; therefore, the definition for this group of compounds is a functional rather than chemical one [89]. One agent in this group, the chemotherapeutic agent doxorubicin, is of special interest and concern because of its common use in veterinary medicine and high level of tissue toxicity when extravasated during administration. The exact mechanism of doxorubicin tissue toxicity is not known. One theory is that it may be a result of intercalation of doxorubicin with cellular DNA. Another theory is that enzymatic reduction of doxorubicin results in the formation of free radicals, which are the actual toxic constituents [89]. Doxorubicin is particularly toxic to tissues because, unlike many other chemical agents, it is not neutralized during the course of reaction with cellular constituents. Therefore, after doxorubicin causes cellular necrosis, it is released with the lysis of the cell and is able to continue its local tissue toxicity [89]. Current recommendations for doxorubicin extravasation include surgical excision, local injection with hyaluronidase to promote vascular uptake of the drug, thereby diluting it, and infiltration of the site with DMSO or other free radical scavengers such as dexrazoxane. The latter, a metal ion chelator, was developed as a cardioprotectant to reduce doxorubicin-induced cardiomyopathy. It has also shown promise as a treatment for doxorubicin extravasation in humans and has also been used in veterinary patients [90]. The proposed mechanism of action is that dexrazoxane protects tissues against free radical damage by iron-doxorubicin complexes by binding iron and thus making it unavailable.

Electrical Burns

Electrical burns in small animal patients are not common; most occur as oral burns, owing to chewing of electrical cords, or as a result of improper grounding of the patient when electrocautery is used. Heat, generated from the resistance of the tissues to current flow, is the major component of electrical injury. Joule's law (J = I2RT) describes these relationships and indicates that heat production is directly proportional to tissue resistance and time of exposure, and proportional to the square of the amperage [1,91]. Tissue resistance is particularly important in determining the distribution and severity of the wound, with more resistant tissues suffering greater damage than less resistant ones. In particular, bone has a much higher electrical resistance than the surrounding muscle and fascia and also dissipates heat more slowly owing to its higher density. The net effect is that the superficial skin injury in electrical burns can appear to be relatively minor, while muscle, fascia, and neurovascular structures adjacent to bone have sustained severe damage [91]. This is an important consideration in prognostication and treatment of injuries where bone lies close beneath the area of visible burn, such as with electrical burns of the oral cavity.

Conclusions

Burns, particularly large ones, are among the most physically devastating and clinically challenging wounds that the veterinarian will treat. Virtually all body systems are impacted to one degree or another, with many complex interactions between systems. Although many of the critical pathophysiologic events begin at the local level, systemic sequelae often are the ultimate determinants of patient morbidity and mortality, and the application of the knowledge of these processes can have a major impact on burn mortality rates. Reported mortality rates from human burn centers have declined dramatically in the past 30 years. For example, a recent review of 1818 patient records at the Boston Shriners Burns Hospital compared mortality from two time periods, 1974 to 1980 and 1991 to 1997. The study showed an overall 88% reduction in mortality and a 57% reduction in mortality for the most severely burned (60 to 100% TBSA) patients [92]. These gains have been attributed to the adoption of aggressive fluid resuscitation, early escharectomy, improvements in sepsis prevention and pain control, and nutritional support [92-94]. Similar application of burn pathophysiologic principles may well yield comparable results for veterinary medicine.