Pathophysiology of burn injury
patient to be approximately 1% TBSA and then to transpose that measurement visually onto the wound for a determination of its size. This method is crucial when evaluating burns of mixed distribution.
Children have a relatively larger portion of the body surface area in the head and neck, which is compensated for by a relatively smaller surface area in the lower extremities. Infants have 21% of the TBSA in the head and neck and 13% in each leg, which incrementally approaches the adult proportions with increasing age. The Berkow formula is used to accurately determine burn size in children.
Systemic changes
The release of cytokines and other inflammatory mediators at the site of injury has a systemic effect once the burn reaches 30% of total body surface area (TBSA). Cutaneous thermal injury greater than onethird of the total body surface area invariably results in the severe and unique derangements of cardiovascular function called burn shock. Shock is an abnormal physiologic state in which tissue perfusion is insufficient to maintain adequate delivery of oxygen and nutrients and removal of cellular waste products. Before the nineteenth century, investigators demonstrated that after a burn, fluid is lost from the blood and blood becomes thicker; and in 1897, saline infusions for severe burns were first advocated [11, 12]. However, a more complete understanding of burn pathophysiology was not reached until the work of Frank Underhill [13]. He found that unresuscitated burn shock correlates with increased hematocrit values in burned patients, which are secondary to fluid and electrolyte loss after burn injury. Increased hematocrit values occurring shortly after severe burn were interpreted as a plasma volume deficit. Cope and Moore showed that the hypovolemia of burn injury resulted from fluid and protein translocation into both burned and nonburned tissues [14].
Over the last 80-years an extensive record of both animal and clinical studies has established the importance of fluid resuscitation for burn shock. Investigations have focused on correcting the rapid and massive fluid sequestration in the burn wound and the resultant hypovolemia. The peer-reviewed litera-
ture contains a large experimental and clinical database on the circulatory and microcirculatory alterations associated with burn shock and edema generation in both the burn wound and non-burned tissues. During the last 40-years, research has focused on identifying and defining the release mechanisms and effects of the many inflammatory mediators produced and released after burn injury [15].
It is now well recognized that burn shock is a complex process of circulatory and microcirculatory dysfunction that is not easily or fully repaired by fluid resuscitation. Severe burn injury results in significant hypovolemic shock and substantial tissue trauma, both of which cause the formation and release of many local and systemic mediators [16–18]. Burn shock results from the interplay of hypovolemia and the release of multiple mediators of inflammation with effects on both the microcirculation as well as the function of the heart, large vessels and lungs. Subsequently, burn shock continues as a significant pathophysiologic state, even if hypovolemia is corrected. Increases in pulmonary and systemic vascular resistance (SVR) and myocardial depression occur despite adequate preload and volume support [18–22]. Such cardiovascular dysfunctions can further exacerbate the whole body inflammatory response into a vicious cycle of accelerating organ dysfunction [17, 18, 23]. Hemorrhagic hypovolemia with severe mechanical trauma can provoke a similar form of shock.
Hypovolemia and rapid edema formation
Burn injury causes extravasation of plasma into the burn wound and the surrounding tissues. Extensive burn injuries are hypovolemic in nature and characterized by the hemodynamic changes similar to those that occur after hemorrhage, including decreased plasma volume, cardiac output, urine output, and an increased systemic vascular resistance with resultant reduced peripheral blood flow [16, 18, 24–26]. However, as opposed to a fall in hematocrit with hemorrhagic hypovolemia due to transcapillary refill an increase in hematocrit and hemoglobin concentration will often appear even with adequate fluid resuscitation. As in the treatment of other forms of hypovolemic shock, the primary initial therapeutic goal is to quickly restore vascular volume and to pre-
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serve tissue perfusion in order to minimize tissue ischemia. In extensive burns ( > 25 %TBSA), fluid resuscitation is complicated not only by the severe burn wound edema, but also by extravasated and sequestered fluid and protein in non-burned soft tissue. Large volumes of resuscitation solutions are required to maintain vascular volume during the first several hours after an extensive burn. Data suggests that despite fluid resuscitation normal blood volume is not restored until 24 – 36 hours after large burns [27].
Edema develops when the rate by which fluid is filtered out of the microvessels exceeds the flow in the lymph vessels draining the same tissue mass. Edema formation often follows a biphasic pattern. An immediate and rapid increase in the water content of burn tissue is seen in the first hour after burn injury [25, 28]. A second and more gradual increase in fluid flux of both the burned skin and non-burned soft tissue occurs during the first 12 to 24 hours following burn trauma [17, 28]. The amount of edema formation in burned skin depends on the type and extent of injury [25, 29] and whether fluid resuscitation is provided as well as the type and volume of fluid administered [30]. However, fluid resuscitation elevates blood flow and capillary pressure contributing to further fluid extravasation. Without sustained delivery of fluid into the circulation edema fluid is somewhat self-limited as plasma volume and capillary pressure decrease. The edema development in thermal injured skin is characterized by the extreme rapid onset of tissue water content, which can double within the first hour after burn [25, 31]. Leape et al. found a 70% to 80% water content increase in a full-thickness burn wound 30 minutes after burn injury with 90% of this change occurring in the first 5 minutes [26, 32, 33]. There was little increase in burn wound water content after the first hour in the nonresuscitated animals. In resuscitated animals or animals with small wounds, adequate tissue perfusion continues to ‘feed’ the edema for several hours. Demling et al. used dichromatic absorptionmetry to measure edema development during the first week after an experimental partial-thickness burn injury on one hind limb in sheep [28]. Even though edema was rapid with over 50% occurring in the first hour, maximum water content did not occur until 12 to 24 hours after burn injury.
Altered cellular membranes and cellular edema
In addition to a loss of capillary endothelial integrity, thermal injury also causes change in the cellular membranes. Baxter found in burns of > 30% a systemic decrease in cellular transmembrane potentials as measured in skeletal muscle away from the site of injury [20]. It would be expected that the directly injured cell would have a damaged cell membrane, increasing sodium and potassium fluxes, resulting in cell swelling. However, this process also appears in cells that are not directly heat-injured. Micropuncture techniques have demonstrated partial depolarization in the normal skeletal muscle membrane potential of -90 mV to levels of -70 to -80 mV; cell death occurs at -60 mV. The decrease in membrane potentials is associated with an increase in intracellular water and sodium [34–36].Similar alterations in skeletal membrane functions and cellular edema have been reported in hemorrhagic shock [34, 36] also in the cardiac, liver and endothelial cells [37–39]. Early investigators of this phenomenon postulated that a decrease in ATP levels or ATPase activity was the mechanism for membrane depolarization, however, other research suggests that it may result from an increased sodium conductance in membranes or an increase in sodium-hydrogen antiport activity [35, 38]. Resuscitation of hemorrhage rapidly restores depolarized membrane potentials to normal, but resuscitation of burn injury only partially restores the membrane potential and intracellular sodium concentrations to normal levels, demonstrating that hypovolemia alone is not totally responsible for the cellular swelling seen in burn shock [40]. A circulating shock factor(s) is likely to be responsible for the membrane depolarization [41–43], but surprisingly, the molecular characterization of such a circulating factor have not been elucidated; suggesting that it has a complex structure. Data suggests it has a large molecular weight, > 80 KDalton [44]. Membrane depolarization may be caused by different factors in different states of shock. Very little is known about the time course of the changes in membrane potential in clinical burns. More importantly, we do not know the extent to which the altered membrane potentials affect total volume requirements and organ function in burn injury or even shock in general.
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Mediators of burn injury
Many mediators have been proposed to account for the changes in permeability after burn, including histamine, b serotonin, bradykinin, prostaglandins, leukotrienes, platelet activating factor, and catecholamines, among others [10, 45–49]. The exact mechanism(s) of mediator-induced injury are of considerable clinical importance, as this understanding would allow for the development of pharmacologic modulation of burn edema and shock by mediator inhibition.
Histamine: Histamine is most likely to be the mediator responsible for the early phase of increased microvascular permeability seen immediately after burn. Histamine causes large endothelial gaps to transiently form as a result of the contraction of venular endothelial cells [50]. Histamine is released from mast cells in thermal-injured skin; however, the increase in histamine levels and its actions are only transient. Histamine also can cause the rise in capillary pressure (Pc) by arteriolar dilation and venular contraction. Statistically significant reductions in burn edema have been achieved with histamine blockers and mast cell stabilizers when tested in acute animal models [50]. Friedl et al. demonstrated that the pathogenesis of burn edema in the skin of rats appears to be related to the interaction of histamine with xanthine oxidase and oxygen radicals [51]. Histamine and its metabolic derivatives increased the catalytic activity of xanthine oxidase (but not xanthine dehydrogenase) in rat plasma and in rat pulmonary artery endothelial cells. In thermally injured rats, levels of plasma histamine and xanthine oxidase rose in parallel, in association with the uric acid increase. Burn edema was greatly attenuated by treating rats with the mast cell stabilizer, cromolyn, complement depletion or the H2 receptor antagonist, cimetidine; but was unaffected by neutrophil depletion [52–54]. Despite encouraging results in animals, beneficial antihistamine treatment of human burn injury has not been demonstrated, although antihistamines are administered to reduce risk of gastric ulcers.
Prostaglandins: Prostaglandins are potent vasoactive autocoids synthesized from the arachidonic acid released from burned tissue and inflammatory cells and contribute to the inflammatory response of
burn injury [55, 56]. Macrophages and neutrophils are activated through the body; infiltrate the wound and release prostaglandin as well as thromboxanes, leukotrienes and interleukin-1. These wound mediators have both local and systemic effects. Prostaglandin E2 (PGE2) and leukotrienes LB4 and LD4 directly and indirectly increase microvascular permeability [57]. Prostacyclin (PGI2) is produced in burn injury and is also a vasodilator, but also may cause direct increases in capillary permeability. PGE2 appears to be one of the more potent inflammatory prostaglandins, causing the postburn vasodilation in wounds, which, when coupled with the increased microvascular permeability amplifies edema formation [58, 59].
Thromboxane: Thromboxane A2 (TXA2) and its metabolite, thromboxane B2 (TXB2) are produced locally in the burn wound by platelets [50]. Vasoconstrictor thromboxanes may be less important in edema formation, however, by decreasing blood flow they can contribute to a growing zone of ischemia under the burn wound and can cause the conversion of a partial-thickness wound to a deeper full-thick- ness wound. The serum level of TXA, and TXA2/PGI2 ratios are increased significantly in burn patients [60]. Heggers showed the release of TXB2 at the burn wound was associated with local tissue ischemia, and that thromboxane inhibitors prevented the progressive dermal ischemia associated with thermal injury and thromboxane release [61, 62]. The TXA2 synthesis inhibitor anisodamine also showed beneficial macrocirculatory effects by restoring the hemodynamic and rheological disturbances towards normal. Demling showed that topically applied ibuprofen (which inhibits the synthesis of prostaglandins and thromboxanes) decreases both local edema and prostanoid production in burned tissue without altering systemic production [63]. On the other hand, systemic administration of ibuprofen did not modify early edema, but did attenuate the post-burn vasoconstriction that impaired adequate oxygen delivery to tissue in burned sheep [64]. Although cyclooxgenase inhibitors have been used after burn-injury, neither their convincing benefit, nor their routine clinical use has been reported.
Kinins: Bradykinin is a local mediator of inflammation that increases venular permeability. It is likely that bradykinin production is increased after burn injury, but its detection in blood or lymph can be dif-
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ficult owing to the simultaneous increase in kininase activity and the rapid inactivation of free kinins. The generalized inflammatory response after burn injury favors the release of bradykinin [65]. Pretreatment of burn-injured animals with aprotinin, a general protease inhibitor, should have decreased the release of free kinin, but no effect on edema was noted [66]. On the other hand, pretreatment with a specific bradykinin receptor antagonist reduced edema in full thickness burn wound in rabbits [8].
Serotonin: Serotonin is released early after burn injury [67]. This agent is a smooth-muscle constrictor of large blood vessels. Antiserotonin agents such as ketanserin have been found to decrease peripheral vascular resistance after burn injury, but have not been reported to decrease edema [67]. On the other hand, the pretreatment effect of methysergide, a serotonin antagonist, reduces hyperemic or increased blood flow response in the burn wounds of rabbits, along with reducing the burn edema [8]. Methysergide did not prevent increases in the capillary reflection coefficient or permeability [68]. Ferrara and collegues found a dose dependent reduction of burn edema when methysergide was given preburn to dogs, but claimed that this was not attributable to blunting of the regional vasodilator response (68). Zhang et al. reported a reduction in nonnutritive skin blood flow after methysergide administration to burned rabbits [69].
Catecholamines: Circulating catecholamines epinephrine and norepinephrine are released in massive amounts after burn injury [17, 70, 71]. On the arteriolar side of the microvessels these agents cause vasoconstriction via alpha 1 receptor activation, which tends to reduce capillary pressure, particularly when combined with the hypovolemia and the reduced venous pressure of burn shock [50]. Reduced capillary pressure may limit edema and induce interstitial fluid to reabsorb from nonburned skin, skeletal muscle, and visceral organs in nonresuscitated burn shock. Further, catecholamines, via ß-agonist activity, may also partially inhibit increased capillary permeability induced by histamine and bradykinin [50]. These potentially beneficial effects of catecholamines may not be operative in directly injured tissue and may also be offset in nonburned tissue by the deleterious vasoconstrictor and ischemic effects. The hemodynamic effects
of catecholamines will be discussed later in the chapter.
Oxygen radicals: Oxygen radicals play an important inflammatory role in all types of shock, including burn. These short-lived elements are highly unstable reactive metabolites of oxygen; each one has an unpaired electron, creating them into strong oxidizing agents [72]. Superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroxyl ion (OH-) are produced and released by activated neutrophils after any inflammatory reaction or reperfusion of ischemic tissue. The hydroxyl ion is believed to be the most potent and damaging of the three. The formation of the hydroxyl radical requires free ferrous iron (Fe2) and H2O2. Evidence that these agents are formed after burn injury is the increased lipid peroxidation found in circulating red blood cells and biopsied tissue [53, 72, 73]. Demling showed that large doses of deferoxamine (DFO), an iron chelator, when used for resuscitation of 40% TBSA in sheep, prevented systemic lipid peroxidation and decreased the vascular leak in nonburned tissue while also increasing oxygen utilization [74]. However, DFO may have accentuated burned tissue edema, possibly by increasing the perfusion of burned tissue.
Nitric oxide (NO) simultaneously generated with the superoxide anion can lead to the formation of peroxynitrite (ONOO-). The presence of nitrotyrosine in burn skin found in the first few hours after injury suggests that peroxynitrite may play a deleterious role in burn edema [75]. On the other hand, the blockade of NO synthase did not reduce burn edema, while treatment with the NO precursor arginine reduces burn edema [76]. NO may be important for maintaining perfusion and limiting the zone of stasis in burn skin [77]. Although the proand anti-inflam- matory roles of NO remain controversial, it would appear that the acute beneficial effects of NO generation out-weigh any deleterious effect in burn shock.
Antioxidants, namely agents that either directly bind to the oxygen radicals (scavengers) or cause their further metabolism, have been evaluated in several experimental studies [78, 79]. Catalase, which removes H2O2 and superoxide dismutase (SOD), which removes radical O2-, have been reported to decrease the vascular loss of plasma after burn injury in dogs and rats [53, 78].
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