Intact organ function is essential for positive outcome of burn patients; however, burn injury affects the structure and function of almost every organ.¹ Therefore, organ failure (whether single or multiple) is a significant contributor to postburn morbidity and mortality. The hyper-metabolic and inflammatory postburn response is associated with vast catabolism, protein and amino acid degradation, insulin resistance and hyperglycemia, as well as lipolysis, all of which can contribute to organ failure, especially the liver.^1–3 Inhalation injury impairs the respiratory function by damaging the alveolar epithelium; however, is not the exclusive cause of respiratory failure.^4–6 Renal failure can result from trauma, and inappropriate fluid resuscitation.^7–9 Cardiac failure postburn can be a result of cardio-myocyte apoptosis, dilative cardiomyopathy due to over-resuscitation, or cardio-toxic agents.^{1, 10–12} As previously emphasized, intact organ function is essential to recovery from severe thermal injury. Therefore, a discrepancy between demand and function exist that impairs postburn morbidity and mortality.

Besides the challenge of treating organ failure, at times, it can be very difficult to detect or monitor single- or multiple-organ failure (MOF). Several attempts have been made in the past to validate established scoring systems such as the DENVER2 criteria in the burn patient population.¹³ This patient population is at a high risk of developing organ failure and would benefit from accurate assessment of organ functions. The DENVER2 score monitors the cardiac, respiratory, renal, and liver function of the body.¹⁴ Unlike other scoring systems, it can be applied to patients of any age and weight, as the quantified parameters are consistent in all patient populations. The validity and predictive value of the assessment of organ function with other scoring systems has been controversial especially in the burn patient population. Due to the physiologic changes in the body and treatment requirements such as high-fluid resuscitation, the accuracy of the scoring assessment has been questioned by several studies. However, others and we¹⁵ hypothesize that the DENVER2 score represents an adequate method for screening and monitoring organ failure.

Despite the need to monitor and detect organ failure in burns, to date, there are only few studies looking at the incidence of single or MOF. Therefore, the first aim of this study was to determine the incidence of organ failure and to identify the critical time points for organ specific disorders following severe burn injury during acute hospitalization. Secondly, we analyzed the incidence of organ failure and correlated organ failure with the outcome of each organ failure or the combination of multiple organs.

Eight-hundred twenty-one pediatric patients with burns over 30% total burn surface area (TBSA) admitted to our burn center were included in the study. Organ function or MOF was and is one of the main outcomes of our studies. Therefore, this study is not a retrospective analysis; it is a prospective ongoing study with prospective analysis.

In a first assignment, patients were grouped according the incidence of MOF in non-MOF and MOF groups using the DENVER2 criteria as described below. To determine the effects of specific organ failure, patients were assigned to groups according the occurrence of specific organ failures utilizing the same score system. Organ failure was determined in patients having a score according the DENVER2 definitions greater than two for each organ.

On admission, patients were resuscitated according to the Galveston formula with 5000 cc/m² TBSA burned+2000 cc/m² TBSA lactated Ringer’s solution given in increments over the first 24 hours. Within 48 hours of admission, all patients underwent total burn wound excision and the wounds were covered with autograft. Any remaining open areas were covered with homograft. This was repeated until all open wound areas were covered with autologous skin.

All patients underwent the same nutritional treatment according to a standardized protocol as previously published.^{1, 16, 17} The nutritional route of choice in our patient population was enteral nutrition via a naso-duodenal or naso-gastric tube. Parenteral nutrition was only given in rare instances if the patient could not tolerate enteral feeds.

Patient demographics (age, date of burn and admission, sex, burn size, and depth of burn) and concomitant injuries such as inhalation injury, sepsis, morbidity, and mortality were recorded. Sepsis was defined as previously published.^{1, 16, 17}

Organ failure was assessed using the DENVER2 definitions (Supplemental Tables S1, S2) prospectively during the entire acute hospital stay. Organ-specific functions were assessed continuously during the hospitalization. MOF was set as a total score >3 out of 12 maximum points for two or more organs for a minimum of two consecutive days. The worst daily score was used to assess the organ failure. Severe organ failure for a single organ was set at >2 points out of three maximum points of the daily average of the assessed organ DENVER2 score (Supplemental Tables S1, S2). We further determined time between operations as a measure for wound healing/re-epithelization.

Severe burn injury is associated with profound hypermetabolic and catabolic responses. Protein catabolism leads not only to a failure of the skin barrier but also to impaired organ functions.¹ Impaired organ function can result in organ failure or even in MOF, which is one of the leading causes of death in the thermally injured patient.¹⁸ Despite the common occurrence of organ failure in this patient population, there’s incomplete understanding of single/MOF. The underlying causes leading to organ failure are not clear but have been associated infections and sepsis, open burn wounds, inadequate oxygen delivery and extraction, protein degradation, insulin resistance and hyperglycemia, lipolysis, and impaired gastrointestinal function with increased bacterial translocation. It thus appears that single/MOF in the thermally injured patient is very complex, involving a multi-factorial cascade of postburn pathophysiologic sequelae.^{1, 12, 19}

Aims of this study were to determine the incidence of single-organ failure, MOF, the time course for organ failure, and the outcomes. We found that 19% of our 821 patients had MOF as captured by the DENVER2 score. To our surprise the highest incidence of organ failure was pulmonary followed by cardiac, liver, and kidney. The worst outcome was in patients with profound kidney or liver failure. The best outcome was in burn patients with pulmonary failure. We also found that burn patients with 3 or more organ failure have an extremely poor prognosis. There were no survivors in the group with three organ failures. The poorest outcome again is associated with kidney and liver and an additional organ failure. These data clearly indicate that single/MOF is important contributors to mortality. The results of our study now necessitate investigations to determine which patients are at high risk to develop organ failure to individualize patient treatment. We believe that early detection of patients at high risk for MOF is important and would result in improved outcomes, as interventions would be implemented early in course of treatment. To our knowledge, there are several studies that are currently investigating the effect of biomarkers on the early detection of MOF.

Manifest and severe renal failure was associated with a high mortality despite recent studies showing that renal failure is usually associated with a good outcome.^9,20 We found that renal failure in association with liver failure resulted in very poor outcomes. The reasons for these results are not entirely clear; however, possible explanation is that DENVER2 may only detect severe non-reversible renal failure and the milder cases of renal dysfunction/failure cannot be determined using this score. This surely leads to the question whether DENVER2 is a valid and applicable score. The discussion remains about the best score to use in burn patients. Our choice of the use of the DENVER2 score was based on its application in various multicenter trials indicating applicability and validity in burn patients.

One expects that patients with liver failure would have a very poor prognosis, which was confirmed in the present study. Several studies have demonstrated that a bilirubin level above 4 mg/dl is an indicator of poor prognosis with associated high morbidity and mortality.^{1, 21} The livers metabolic, inflammatory, acute phase and immune functions play a pivotal role in recovery from injury in multiple modulating pleiotropic pathways.^{1, 2, 21, 22} The hepatic acute phase response is characterized by an increased production of acute phase proteins with a failure to produce constitutive proteins. The shift in hepatic protein synthesis leads to physiologic alterations of transport, metabolic and immune functions.^{1, 2, 22} Our data shows that the liver is markedly affected postburn and that the shift of the expression of hepatic derived proteins is associated with organ failure. Animal studies have shown that burn injury causes a vast alteration in the endoplasmic reticulum (ER) and mitochondria with depletion of ER calcium stores leading to hepatocyte apoptosis and intracellular inflammation.^{23, 24} Novel treatments to attenuate these responses may improve liver function postburn preventing hepatomegaly and impaired protein synthesis improving postburn morbidity and consecutively mortality.

Burn injury induces dramatic cardiac stress indicated by increased cardiac output, stroke volume, oxygen consumption, and cardiac index.^{18, 25, 26} In a recent study by Pereira et al.,²⁵ cardiac dysfunction was the main contributor to mortality in patients under four years of age. We have further shown that the only physiologic difference between burn sizes 20 to 40, 40 to 60, 60 to 80, and 80 to 100% TBSA was caused by cardiac dysfunction, which increased in proportion to burn size.¹² Williams et al.²⁶ have recently shown that these alterations do not only persist for a short period of time but that cardiac stress continues to be present for up to two to three years postburn. All of this data together along with our findings show that cardiac stress is present immediately postburn and persists throughout acute hospitalization and up to three years.²⁶ Despite the early and high incidence of cardiac failure, cardiac dysfunction is associated with the best outcome; and we further propose that attenuating cardiac stress (by for example administration of beta adrenergic antagonists such as non-selective β1 and β2 blockers) will improve postburn cardiac oxygenation, reduces tachycardia, improves cardiac filling, and pressure leading to an attenuated cardiac stress response and cardiac work.

Postburn pulmonary complications are not only present after inhalation injury. Patients with severe burns have inflammatory processes causing acute respiratory distress syndrome and pneumonia, which are augmented if inhalation injury is present.^{4, 6, 27, 28} Our data demonstrates that lung injury has one of the best survival probabilities postburn indicating that current treatment regimens such as low-tidal volume ventilation, administration of nebulized heparin, albuterol, cortisol, epinephrine (if needed), and chest physiotherapy as well as mucolysis improve pulmonary ventilation and function. We see this as an example of how early intervention for organ failure can successfully change hospital course. We fail to do so for kidney, liver, probably pancreas, and the gastrointestinal system.

Newer studies looking at proteomic and genomic profiles can help to determine which patients are at risk of developing single/MOF (Glue Grant unpublished findings). We believe that once protein(s) or gene(s) are identified, which can direct the treating physicians in identifying the patients at risk of developing organ failure; their outcomes can be dramatically improved. These novel approaches could shorten hospital length of stay and possibly decrease postburn morbidity and mortality. To test whether some biomarkers can differentiate MOF from non-MOF, we measured glucose and several cytokines and CRP. We found that MOF had significantly higher glucose levels, serum IL-6, MCP-1, TNF, and CRP at almost all time points. These markers were not predictive, however, were significantly different during hospital course.

The present study is the first large-scale study demonstrating the incidence of single or MOF. The general incidence of single or MOF is around 20%. Liver and renal failure had the worst outcome, while pulmonary and cardiac have a good prognosis. A combination of three or more organ failures is always fatal with no therapeutic success. We hypothesize that it is now imperative to develop markers to predict patients at high risk for MOF to improve postburn outcomes. We, therefore, would like to emphasize that early detection of organ failure and intervention are needed to improve postburn outcomes.