Burn injuries with cutaneous loss result in a severe systemic response when profound injuries exceed 20% of the total body surface area. The management of severely burned patients is a complex and dynamic process. Timely and safe operative interventions are critical components of multidisciplinary care. Effective management of severely burned patients, their cutaneous injuries, and the associated systemic disease requires a comprehensive understanding of the pathophysiologic response to trauma, objective indicators of patient status, and an appreciation for the dynamic nature of these parameters.
Our innate immune system has the capacity to detect and respond to a variety of critical stimuli such as 'non-self' molecules derived from pathogens and other insults. Burn eschar, a reservoir of damaged and dying cells release endogenous host-derived molecules termed damage-associated molecular patterns DAMPs which bind to receptors expressed on innate immune cells, notably Toll-like receptors (TLRs) promoting an inflammatory response [58,59,60] . In cases of significant burn injury the collective DAMP associated response, as introduced above, results in a cascade of deleterious systemic effects, specifically a dysregulated sterile inflammatory state which when severe culminates in a profound state of immunosuppression. In the last century Allgöwer et al. [61,62] identified burn tissue derived toxins responsible for severe immunosuppression and mortality. An elegant set of experiments by Hansbrough et al. [63] demonstrated that burn tissue was at least one causal source for the detrimental immunological effects observed in burn injury. These clinicians and others strongly advocated elimination of burn toxins from the skin either by primary excision of the burns [64,65,66] or local application of a protein-complex-binding substance such as cerium nitrate [67,68,69,70]. In concert with this direction, clinical evidence has repeatedly demonstrated that patients with extensive burns (>30% TBSA), whose eschars were excised early, showed reductions in circulating cytokines, hypermetabolism, and mortality. Data derived from a variety of early versus late (> day 6) eschar removal performed in animal studies concluded that early debridement prevented the often seen profound inflammatory state and immunologic dysfunction associated with such injuries, as well as promoting an accelerated reepithelialization and reduction in scarring. A 2006 meta-analysis [46] reviewed prospective studies comparing early excision and grafting with delayed grafting after eschar separation (historical approach) in burn patients without inhalation injury. In this meta-analysis survival was improved in the early excision group with a shortened length of stay (LOS). Of particular note, early excision was reported as spanning a period of as early as < 24 hrs post burn to the 6th post burn day making a recommendation on exact timing difficult. In contrast, a very recent review on regrouped data [71] described that mortality was lower in late excision (>7 days) compared to early excision (<6 days), while early excision reduced septic episodes and LOS. In an experimental burn model we were able to demonstrate that very early debridement of the burn wound led to an exaggerated sequestration of polymorphonuclear leucocytes (PMNs) in the lung [72] . The impact or “second hit” of surgical debridement may explain the subsequent cascade of effects resulting from early excision of the burn eschar. In line with this assumption, data from the German Burn Registry [73] confirmed the negative impact of full thickness burns on survival possibly indicating that the impact of surgical intervention may have a negative effect on outcome. These results underscore the relevance and importance of a second hit phenomenon and ask for an individualized damage control surgical approach in order to reduce DAMP and improve outcome.Our innate immune system has the capacity to detect and respond to a variety of critical stimuli such as 'non-self' molecules derived from pathogens and other insults. Burn eschar, a reservoir of damaged and dying cells release endogenous host-derived molecules termed damage-associated molecular patterns DAMPs which bind to receptors expressed on innate immune cells, notably Toll-like receptors (TLRs) promoting an inflammatory response [22][23][24] . In cases of significant burn injury the collective DAMP associated response, as introduced above, results in a cascade of deleterious systemic effects, specifically a dysregulated sterile inflammatory state which when severe culminates in a profound state of immunosuppression. In the last century Allgöwer et al. [25][26] identified burn tissue derived toxins responsible for severe immunosuppression and mortality. An elegant set of experiments by Hansbrough et al. [27] demonstrated that burn tissue was at least one causal source for the detrimental immunological effects observed in burn injury. These clinicians and others strongly advocated elimination of burn toxins from the skin either by primary excision of the burns [28][29][30] or local application of a protein-complex-binding substance such as cerium nitrate [31][32][33][34]. In concert with this direction, clinical evidence has repeatedly demonstrated that patients with extensive burns (>30% TBSA), whose eschars were excised early, showed reductions in circulating cytokines, hypermetabolism, and mortality. Data derived from a variety of early versus late (> day 6) eschar removal performed in animal studies concluded that early debridement prevented the often seen profound inflammatory state and immunologic dysfunction associated with such injuries, as well as promoting an accelerated reepithelialization and reduction in scarring. A 2006 meta-analysis [35] reviewed prospective studies comparing early excision and grafting with delayed grafting after eschar separation (historical approach) in burn patients without inhalation injury. In this meta-analysis survival was improved in the early excision group with a shortened length of stay (LOS). Of particular note, early excision was reported as spanning a period of as early as < 24 hrs post burn to the 6th post burn day making a recommendation on exact timing difficult. In contrast, a very recent review on regrouped data [36] described that mortality was lower in late excision (>7 days) compared to early excision (<6 days), while early excision reduced septic episodes and LOS. In an experimental burn model, very early debridement of the burn wound led to an exaggerated sequestration of polymorphonuclear leucocytes (PMNs) in the lung [37] . The impact or “second hit” of surgical debridement may explain the subsequent cascade of effects resulting from early excision of the burn eschar. In line with this assumption, data from the German Burn Registry [38] confirmed the negative impact of full thickness burns on survival possibly indicating that the impact of surgical intervention may have a negative effect on outcome. These results underscore the relevance and importance of a second hit phenomenon and ask for an individualized damage control surgical approach in order to reduce DAMP and improve outcome.
Allogenic blood transfusion is well recognized as an independent factor for immunosuppression in trauma patients [74,75]. It is extremely important to appreciate that in the aforementioned metanalysis [46], early excision was accompanied by increase blood transfusion requirements. In order to achieve a timely debridement with reduced blood transfusion requirements, enzymatic debridement has been advocated [76,77]. Several forms of enzymatic debriding agents have been developed and promoted expressing differing potencies and efficiencies. At least one randomized controlled clinical study has demonstrated that enzymatic debridement of up to 15% TBSA can safely be performed accompanied by a reduced blood transfusion rate in the enzymatically debrided group as compared to the conventional surgically debrided burn patients [78, 79]. It is hypothesized that in severely burned patients this evolving technique may reduce the second hit. At present further study and proof is needed, still timely debridement remains the clinical standard for full thickness burns. Allogenic blood transfusion is well recognized as an independent factor for immunosuppression in trauma patients [39][40]. It is extremely important to appreciate that in the aforementioned metanalysis [35], early excision was accompanied by increase blood transfusion requirements. In order to achieve a timely debridement with reduced blood transfusion requirements, enzymatic debridement has been advocated [41][42]. Several forms of enzymatic debriding agents have been developed and promoted expressing differing potencies and efficiencies. At least one randomized controlled clinical study has demonstrated that enzymatic debridement of up to 15% TBSA can safely be performed accompanied by a reduced blood transfusion rate in the enzymatically debrided group as compared to the conventional surgically debrided burn patients [43][44]. It is hypothesized that in severely burned patients this evolving technique may reduce the second hit. At present further study and proof is needed, still timely debridement remains the clinical standard for full thickness burns.
The burn eschar is at considerable risk of becoming a nidus for pathogenic bacterial and fungal growth with subsequent systemic complications such as sepsis, particularly as tissue and cellular integrity and vitality are compromised. Further complicating the clinical challenge of caring for severely injured patients and particularly burn injured patients is the contribution of their premorbid and morbid medical status which may not always allow for safe, early surgical debridement. A very recent report described the binding of DAMPs from eschar by topical cerium nitrate, leading to a reduced systemic inflammatory response and modulating over-activation of PMNs and immunologic dysfunction [37] . Interestingly, as early as 1976 [80], topically applied cerium nitrate, a potent antiseptic was clinically reported to reduce mortality in burn patients. Dutch burn surgeons have shown that the introduction of topical cerium nitrate may allow for safe serial surgical debridement in the compromised burn patient [69]. Further studies will have to show the precise role of topical cerium nitrate in damage control burn treatment. The burn eschar is at considerable risk of becoming a nidus for pathogenic bacterial and fungal growth with subsequent systemic complications such as sepsis, particularly as tissue and cellular integrity and vitality are compromised. Further complicating the clinical challenge of caring for severely injured patients and particularly burn injured patients is the contribution of their premorbid and morbid medical status which may not always allow for safe, early surgical debridement. A very recent report described the binding of DAMPs from eschar by topical cerium nitrate, leading to a reduced systemic inflammatory response and modulating over-activation of PMNs and immunologic dysfunction [45] . Interestingly, as early as 1976 [80], topically applied cerium nitrate, a potent antiseptic was clinically reported to reduce mortality in burn patients. Dutch burn surgeons have shown that the introduction of topical cerium nitrate may allow for safe serial surgical debridement in the compromised burn patient [69]. Further studies will have to show the precise role of topical cerium nitrate in damage control burn treatment.