In critically ill burn patients, humoral mediators have been shown to be of crucial importance causing MOF, and studies are deciphering these humoral factors using modern molecular techniques.

Sood et al. used early leukocyte mRNA genomics to correlate transcriptome changes with outcomes in 324 severe burn patients. In many ways their mortality findings were as expected. Patients older than age 60 years had a relative risk of death (RR) of 4.53, burns greater than 40% TBSA carried an RR of 4.24, and inhalation carried an RR of 2.08, all independently associated with mortality. They found 39 gene signatures within the leukocyte transcriptome inherent in the genomic storm associated with platelet activation and degranulation, cellular proliferation, and downregulation of proinflammatory cytokines (see Fig. 24.1 ). Jeschke et al. differentiated burn survivors from nonsurvivors based on trajectories in inflammatory and hypermetabolic responses. Nonsurvivors had significantly higher IL-6, IL-8, granulocyte colony-stimulating factor, monocyte chemotactic protein 1, C-reactive protein, glucose, insulin, blood urea nitrogen, creatinine and bilirubin, and hypermetabolic response. IL-8 is a major mediator for inflammation and parallels %TBSA burnt and incidence of MOF. High levels of IL-8 were associated with sepsis, MOF, and mortality suggesting that IL-8 may provide a valid biomarker for monitoring sepsis, infections, and mortality in burn patients.

The humoral inflammatory mediators believed to underlie MOF in burn injury are the same factors and cascades governing the fundamental human responses to severe injury and have been discussed for decades: endotoxin, arachidonic acid (AA) metabolites, cytokines, platelet-activating factor (PAF), activated neutrophils and adherence molecules, nitric oxide, complement, and oxygen-free radicals.

Endotoxin, a lipopolysaccharide component of Gram-negative bacteria in outer cell walls, induces many of the symptoms associated with sepsis: fever, hypotension, release of acute-phase proteins, and production of multiple cytokines, including tumor necrosis factor (TNF) and IL-1 via interaction with TLRs. Endotoxin injection alone causes the same changes in the leukocyte transcriptome as severe burn injury. It also activates complement and the coagulation cascade and results in the release of PAF. Potential sources of endotoxin include Gram-negative bacteria in foci of infections as well as within the gut when the gut barrier fails.

AA makes up approximately 20% of cell membranes and is released from these membranes in response to a multitude of stimuli, which activate phospholipases A ₂ and C, and is then metabolized by active mediators. The cyclooxygenase (COX) pathway yields prostaglandins and thromboxanes, whereas the lipoxygenase pathway results in the production of leukotrienes. Prostaglandins and leukotrienes interact with other mediators in a complex fashion and are later degraded. COX products, such as prostacyclin, inhibit platelet aggregation, thrombus formation, and gastric secretion, whereas other products, such as thromboxane A ₂ (TXA ₂ ), cause platelet aggregation, have profound vasoconstricting effects on both the splanchnic and pulmonary microvasculature, and induce bronchoconstriction and increased membrane permeability. Aspirin irreversibly inhibits COX, driving AA down the lipoxygenase pathway. The lipoxygenase pathway results in the formation of leukotrienes. There are two types based on their metabolism after the action of 5-lipoxygenase: leukotrienes C ₄ , D ₄ , and E ₄ (the sulfidopeptide group) and leukotriene B ₄ . Various cell types, including neutrophils, macrophages, and monocytes, can provide the stimuli to generate leukotrienes. In addition, vessel walls are capable of generating leukotrienes. Leukotrienes C ₄ , D ₄ , and E ₄ have variable actions on vascular tone dependent on the presence or absence of other mediators, including COX products. In addition to their variable effects in redirecting blood flow, leukotrienes C ₄ , D ₄ , and E ₄ increase vascular permeability and are elevated immediately prior to the development of pulmonary failure. The principal effect of leukotriene B ₄ is enhancement of neutrophil chemotaxis. Thus leukotrienes as a group are involved in the formation of edema and pulmonary and systemic vascular changes seen in MOF.

Cytokines are regulatory proteins secreted by immune cells and have multiple paracrine and endocrine effects. There are six major classes: interleukins, TNF, interferons, colony-stimulating factors, chemotactic factors, and growth factors. Those most extensively characterized in sepsis are IL-1, IL-6, and TNF.

IL-1 and IL-6 are elevated in sepsis, and high levels are associated with fatal outcomes and predict systemic infection. IL-1β causes hypotension and decreased systemic vascular resistance, which may be synergistic with the effects of TNF. TNF causes hypotension, cardiac depression, and pulmonary dysfunction in animals. ^, When administered to humans, TNF causes fever, hypotension, decreased systemic vascular resistance, increased protein turnover, elevation of stress hormone levels, ^, and activation of the coagulation cascade.

PAF is a nonprotein phospholipid secreted by many cells, including platelets, endothelial cells, and inflammatory cells, and it is a major mediator of the effects of endotoxin seen in the patient’s pulmonary system. In addition, the effects of PAF on the patient’s hemodynamic state are characterized by vasodilation, cardiac depression, and enhancement of capillary leak. Its complex interactions with other mediators remain poorly understood.

Although tissue injury can occur in the absence of neutrophils, the inflammatory process results in local accumulation of activated inflammatory cells that release various local toxins (e.g., oxygen radicals, proteases, eicosanoids, PAF). When unregulated, such accumulations of activated cells can cause tissue injury. The initial attachment of neutrophils to the vascular endothelium at an inflammatory site is facilitated by the interaction of adherence molecules on the neutrophil and endothelial cell surfaces.

Induced by numerous stimuli, these neutrophil adherence receptors are, intriguingly, reduced after major thermal and nonthermal injury, perhaps explaining in part the increased incidence of infection. The importance of this adherence mechanism can be seen in patients deficient in one integrin class of neutrophil adherence receptors, CD18, who suffer from frequent bacterial infections. The biology of the transmembrane polypeptides governing these complex cell-to-cell interactions is an active area of research and holds promise for therapeutic interventions.

Oxygen radicals, such as hydrogen peroxide and superoxide anion, are released by activated neutrophils in response to a variety of stimuli and when xanthine oxidase is activated after reperfusion in ischemia-reperfusion models. These highly reactive products cause cell membrane dysfunction, increase vascular permeability, and release eicosanoids.

Nitric oxide, released when citrulline is formed from arginine, was identified as an endothelial product in the mid-1980s. Its half-life is merely a few seconds because it is quickly oxidized, but it has profound local microvascular effects. Nitric oxide synthesis is stimulated by various cytokines, endotoxins, thrombin, and injury to the vascular endothelium. It is a potent vasodilator, but its actions vary depending on the vascular bed and presence of other mediators. Nitric oxide is one of the major mediators leading to hypotension in septic shock. ^,

Antigen-antibody complexes activate the complement cascade, and complement fragments thus generated interact with other cytokines to propagate the inflammatory response. Diminished levels of the natural inhibitor of C5a have been demonstrated in patients with acute respiratory distress syndrome (ARDS). In animal models of endotoxemia, the administration of anti-C5a antibody has been shown to diminish hypotension.

Severe injury is associated with the hypermetabolic response, marked by increased oxygen consumption and carbon dioxide production, hyperdynamic circulation, increased minute ventilation, altered immune responses, and catabolism. Persistently higher metabolic rates are seen in nonsurvivors. An essential component of modern burn management is attenuating the hypermetabolic response. Reducing the patient’s metabolic demand via management of the external environment has been an indispensable component of burn care for decades. Presently, β-adrenergic blockade with propranolol is one of the most efficacious pharmacologic interventions. While the effects of growth hormone can be beneficial, its administration was associated with adverse outcomes. Insulin-like growth factor, intensive insulin therapy, and oxandrolone have also been studied.

Anabolic steroids, such as oxandrolone, have been used to reduce postburn catabolism and help shift patients to an anabolic state. Sousse et al. (2015) demonstrated that long-term administration of oxandrolone significantly reduced hypermetabolism and increased height percentile, bone mineralization, lean body mass, and strength. They showed improved pulmonary functions with greater maximum expired ventilation and higher maximum voluntary ventilation. Inhalation injury did not increase burn-induced hypermetabolic stress. Promising investigations continue into the use of anabolic agents to treat severe burn injury, and they are rapidly becoming a standard of care in centers around the world.

In the immediate 2 to 8 hours following burn injury, a shock state can develop due to decreased preload secondary to the shift of intravascular fluid to the interstitium leading to burn edema. Additionally, in the postburn ebb phase, cardiac function is depressed secondary to IL-1β and TNF-α, which can be blocked with a CD14 knockout or halted with nuclear factor κB blockers. By 48 hours following burn injury, the patient becomes hyperdynamic with observed tachycardia and increased cardiac output through β-adrenergy. The decrease in right ventricular ejection fraction seen after endotoxemia can be alleviated by blockade of thromboxane. Initially, systemic vascular resistance is increased; however, as systemic inflammation and sepsis emerge during the flow phase, vasoplegia ensues and exacerbates the distributive shock state that leads to MOF.

By 24 to 48 hours postinjury, the ebb phase ends, and the patient enters the flow phase, marked by elevated cardiac output. The pathophysiology of this phase of cardiac dysfunction has been thoroughly described. Two primary drivers are prolonged elevated levels of catecholamines and sepsis. Sepsis can continue to produce myocardial dysfunction in a cytokine-mediated process. Persistent β-adrenergic receptor activation causes uncoupling from G proteins, decreases cyclic adenosine monophosphate production and altered phosphorylation down the mitogen-activated protein kinase and Akt (protein kinase B) pathways away from the target of rapamycin (mTOR), and reduces sarcoplasmic reticulum calcium ATPase 2 (SERCA2) and ryanodine receptor (RyR). Collectively, these make the myocardium less responsive to catecholamines and perturb calcium homeostasis. Further, nitric oxide secretion from inflamed and burned tissue alters mitochondrial respiration and competes with calcium for binding sites on myosin, thus furthering calcium dysregulation. The prolonged leakage of calcium from the sarcoplasmic reticulum depletes calcium stores and depresses contractility leading to cardiomyocyte apoptosis.

Additionally, pulmonary hypertension and right ventricular failure occur, which are associated with high mortality. This occurs in burn patients due to sepsis-related myocardial effects or acute fluid overload secondary to overresuscitation and/or edema mobilization. Other common causes have been noted: left heart failure, acute pulmonary embolism, sepsis, acute lung injury, and perioperative state. Previously, Jeschke et al. reported nonsurvivors have a 30% higher cardiac index at 29 to 34 days and 91 to 180 days postburn than survivors, thus demonstrating the increased cardiac demand required in the persistent hyperdynamic state typifying MOF. The data suggest that these patients may need a supraphysiologic cardiac index to meet their hypermetabolic needs, although no definitive studies currently exist. Effective and expeditious management of cardiovascular failure is important to prevent or ameliorate MOF and is a critical component of burn center care.

There is increasing evidence that administration of propranolol can improve cardiac function after burn injury by reducing heart rate and cardiac work, thus dampening hypermetabolism and improving the hypercatabolic state.

Pulmonary failure can be a result of direct injury from inhalation of toxins, fluid overload, heart failure, and pulmonary edema, resulting from resuscitation, injury from inflammatory and septic mediators, pneumonia, and iatrogenic ventilator injury. Prevention of the pulmonary component of MOF is based on infection prevention measures (early ventilator weaning/daily spontaneous breathing trials, suctioning, oral hygiene, chest physiotherapy, elevating head of bed) and limiting factors that exacerbate pulmonary injury. Current treatments, such as administration of nebulized heparin, albuterol, cortisol, and epinephrine and chest physiotherapy, as well as mucolysis, improve pulmonary ventilation, function, and outcomes. Cox et al. investigated the integrity of airway epithelium in autopsy specimens of 72 severely burned children, finding airway epithelial loss corresponded to inhalation injury and age. Mortality from inhalation injury was 16.4% and was associated with increased length of mechanical ventilation and length of stay.

Lopez and Enkhbaatar both demonstrated that nebulized epinephrine limited pulmonary vascular hyperpermeability to water and protein flux in an ovine burn model with smoke inhalation. This preserved dynamic compliance, mean airway pressure, and PaO ₂ /FiO ₂ ratio. In their ovine burn with inhalation injury model, Traber et al. administered γ-tocopherol, a reactive oxygen species scavenger. They found decreases in arginase and collagen, significantly improved diffusion capacity, decreased lung water, reduced pulmonary shunt fraction, and reduced peak pressures and bronchiolar obstruction, indicating that free-radical scavengers may reduce smoke-induced chronic pulmonary dysfunction.

In an ovine model of inhalation injury with Pseudomonas infection, there was severe deterioration in pulmonary gas exchange and increased lung lymph flow and protein content, lung water, nitrite/nitrate concentrations, tracheal blood flow, and vascular endothelial growth factor expression. In a different study with this model evaluating microcirculatory changes in response to activated protein C, significant reductions in heart rate and cardiac output were observed, and the changes in microvascular blood flow to the trachea, kidney, and brain were normalized.

For nearly 20 years, the ARDSNet doctrine of limited tidal volumes, pressure-limited ventilation, positive end-expiratory pressure (PEEP), and permissive hypercapnia have dominated the field of pulmonary critical care. Application of these principles to burn care has been limited due to increased CO ₂ production resulting from the hyperdynamic state requiring higher minute ventilation, pulmonary edema from resuscitation increasing the alveolar-arterial gradient, and decreasing compliance and airway injury from inhaled toxins causing increased resistance and mucosal sloughing and plugging. For more than 28 years, Sousse et al. (2016) analyzed pulmonary outcomes in 932 burned pediatric patients with inhalation injury, stratifying for tidal volume. Their findings are staggeringly divergent from ARDSNet data; they determined high tidal volume (15 ± 3 mL/kg) corresponded to significantly decreased ventilator days and maximum PEEP and significantly increased maximum peak inspiratory pressure. ARDS was significantly decreased, but the pneumothorax rate was increased. They concluded that high tidal volumes may interrupt the events leading to lung injury following inhalation injury. Of note, this study was performed in the setting of early spontaneous breathing trials and aggressive discontinuation of mechanical ventilation. It remains unclear whether these data are an aberration or, moreover, point to a fundamental difference in the physiology of inhalation injury. In the setting of severe inhalation injury with hypoxia and hypercapnia, we have seen the remarkable ability of pediatric lungs to heal with eventual normalization of gas exchange several months postinjury; this phenomenon may be attributable to a still-active stem cell population.

Systemic factors beyond sepsis also affect pulmonary failure. For example, inflammation associated with burns leads to hyperglycemia. A threshold of greater than 150 mg/dL leads to overwhelming growth of bacteria in the bronchopulmonary system. The incidence of pneumonia requiring mechanical ventilation and ARDS was higher in patients with average daily glucose greater than 150 mg/dL. These patients also had significantly longer ventilation days and higher incidence of infection and sepsis.

Denver 2 and SOFA scores only address gut failure pertaining to the liver; however, other aspects of gastrointestinal dysfunction also cause significant morbidity and contribute to mortality. Lautenschlager et al. studied isolated rat small intestine perfused with PAF and demonstrated that intestinal circulatory disturbances, atony, ileus, edema, swelling, and loss of mucosal barrier function are engines of MOF. They induced mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen, edema, and the loss of motility seen in intestinal failure and observed that quinidine, a sodium channel blocker, inhibited this pathology whereas dexamethasone did not. Oliveira et al. studied the role of COX-2 inhibitors on gastric and small bowel ileus in prostaglandin-mediated etiology for postburn ileus. Gut mucosal integrity suffers when mesenteric flow is inadequate, and gut blood flow is decreased after burn injury, exacerbated by TXA ₂ release. Support of splanchnic blood flow is an important aspect of MOF prevention, which can be accomplished as part of whole-body hemodynamic support.

In a chronic porcine model of burn injury, burned pigs were given endotoxin bolus, causing a marked decrease in systemic vascular resistance, blood pressure, cardiac index, and mesenteric blood flow. This state increased gut bacterial translocation into mesenteric lymph nodes, spleen, and burn wounds, possibly due to mesenteric ischemia and reperfusion injury.

Enteral feeding has beneficial effects on outcomes compared with parenteral feeding, possibly via an enhancement of gastrointestinal barrier integrity. Enterocytes are principally supported by intraluminal feeding. Intestinal mucosa deprived of intraluminal feedings develops mucosal atrophy. Early enteral feeding is tolerated in burn patients and attenuates their hypermetabolic response. The value of specific nutrients to support the enterocyte is murkier than that of providing adequate mesenteric blood flow and intraluminal nutrition. Glutamine is the preferred fuel of the small bowel enterocyte. Sepsis has been shown to decrease glutamine uptake by the small bowel enterocyte, which may result in barrier failure, and the addition of glutamine to the nutritional regimen is theorized to improve barrier function. Glutamine is not a component of commercial parenteral nutritional formulas because of its short shelf life, although the dipeptide is well tolerated and has a longer shelf life. While supplemental glutamine may improve protein balance in surgical patients and partially reverse mucosal atrophy, it has not been shown to improve intestinal barrier function when given parenterally. For some time, glutamine was thought to be of benefit for critically burned patients. Heyland et al. conducted a large trial to determine a definitive answer and clearly showed that glutamine is not beneficial for burn patients and should not be given in burns.

The large intestinal mucosa is trophic to butyrate, a fatty acid liberated by fiber fermentation. Enteral pectin may help support the colonic mucosa, but the value of such support in the hypermetabolic burn patient remains unclear.

Limited research suggests possible benefits of probiotics for gut barrier support. Probiotics may improve gastrointestinal barrier function, avoiding colonization with pathogenic microorganisms and immunomodulation. They reduce bacterial translocation in the gut of burned rats. Interestingly, they seem to increase diarrhea rates. Accumulating data suggest probiotics may reduce ventilator-associated pneumonia rates. There are some concerns in the current datasets that the control groups have too high an incidence of ventilator-acquired pneumonia, and there have been case reports of sepsis from probiotic organisms in high-risk patients. In a series of 20 severely burned children, probiotics were found to be safe and tended toward fewer surgeries and less time to achieve complete wound closure.

Decontamination of the gut lumen might diminish the impact of gastrointestinal barrier failure. Attempts have been made to assess the impact of selective decontamination of the gut by coating enteric bacteria to inhibit their ability to attach to the intestinal mucosa and translocate. While the rate of pneumonia may decrease by such mechanisms, there is no apparent impact on mortality.

Acute pancreatitis is also notable after severe burn injury, defined as a threefold increase in amylase or lipase with abdominal pain or feeding intolerance. In a pediatric cohort, Rivero et al. reported an incidence of 13/2699 or 0.05% and found pathologic evidence in 11/78 autopsies. This is in contrast to 40% of patients developing hyperamylasemia or hyperlipidemia without symptoms. They postulated that the etiology of these cases was from ischemic injury to the pancreas due to shock. They also noted increased mortality in this cohort.

In a severe burn injury, the liver plays a pivotal role in modulating inflammatory processes, immune functions, metabolic pathways, and the acute-phase response. Thermal injury causes hepatic damage by inducing hepatic edema, fatty infiltration, apoptosis, and the metabolic derangements associated with insulin resistance. Insulin administration decreases the rate of infections and the synthesis of proinflammatory cytokines and improves hepatic structure and function in severely burned and critically ill patients.

Burn injury promotes catabolism and lipolysis in burned children. The resulting free fatty acids are reesterified in the liver to triglycerides where they are not secreted as very low-density lipoprotein due to downregulation of transport proteins, thus leading to progressive fatty liver metamorphosis. Carbohydrates are utilized as a major energy source for critically burned patients. Lee et al. demonstrated that low-fat, high-carbohydrate feeds promote shorter ICU stays per %TBSA, a lower incidence of sepsis, and decreased hepatic steotosis.

Acute liver failure (ALF) is uncommon after burn injury but carries a high mortality. It presents with hepatic encephalopathy, jaundice, and coagulopathy in the absence of chronic liver disease and carries a mortality rate of 40% to 50%. The cause of death is cerebral herniation in 34%, refractory hypotension, and MOF. Henrionet al. studied 142 consecutive cases of ALF in the ICU and found that 70% were due to heart failure, 13% from respiratory failure, and 13% from toxins or sepsis. Most commonly, low flow states cause ALF. The liver receives most of its blood flow via the portal system, and the dependence on portal supply is increased in critical illness because the arterial supply is reduced while the central lobular oxygen requirements increase due to metabolic and synthetic demands. In the setting of heart failure, high central venous pressures associated with fluid overload, or the need for high preload, there is a decrease in the pressure gradient across the liver, which compromises portal flow (and oxygenation), leading to centrilobular necrosis. Thus most postburn ALF is hypoxemic liver failure, with high hepatic (central) venous pressure a major (unrecognized) cause of reduced hepatic oxygen delivery. Less common causes are toxins and viral infections. In addition, many of the medications used in the burn ICU can cause ALF (e.g., acetaminophen, amoxicillin, moxifloxacin, trimethoprim-sulfamethoxazole, fluconazole, voriconazole, amiodarone, metformin, isoflurane, opiates, phenytoin, ibuprofen, iron, anabolic steroids). Immunosuppression associated with burn injury predisposes the activation of latent hepatitis and viral infections (especially cytomegalovirus), which can lead to ALF. Loss of clotting factors causes coagulopathy, whereas loss of anticoagulants can cause thrombosis, collectively promoting disseminated intravascular coagulation. Burn patients with liver dysfunction become prone to hypoglycemia due to loss of glucose homeostasis. ALF leads to further MOF causing vasoplegia with diminished hepatic clearance of circulating vasoactive compounds, increased nitric oxide production, acute renal failure due to ischemia, and acute tubular necrosis, which may progress to hepatorenal syndromes.

To survive a burn injury, adequate renal clearance is essential; 24 hours following resuscitation, it becomes necessary to clear the excess volume administered. Renal function is also critical to clear the extensive metabolic wastes associated with injury and the hyperdynamic state. Concurrently, the kidney is subjected to prerenal insults, such as hypovolemia and shock, and to direct renal toxins, such as myoglobin and medications. To maintain renal function, there needs to be vigilant treatment of compartment syndrome to prevent rhabdomyolysis leading to myoglobinemia, adequate monitoring of abdominal compartment pressure to prevent compromise of renal blood flow, and avoidance of nephrotoxic medications. Mason et al. prospectively analyzed 330 resuscitations dividing the patients relative to the Parkland formula resuscitation. The groups receiving greater than Parkland resuscitation had a higher APACHE score. Patients resuscitated with less than Parkland resuscitation demonstrated greater probability of acute kidney injury (AKI) (odds ratio 3.25; 95% confidence interval 1.18–8.94) without difference in infectious complications. Maintenance of sufficient renal blood flow with appropriate volume resuscitation is vital to maintaining renal function. In a retrospective review of 41,179 burned Finnish patients, 86 had AKI related to the burn and 43 required renal replacement therapy. In the absence of diuretics, urine output of 0.5 mL/kg/hour generally indicates sufficient renal perfusion. In patients with increasing creatinine or decreased urine output, the finding of granular casts on centrifuged microscopic urinalysis is helpful in promptly differentiating organ damage (tubular necrosis) from appropriate renal response to decreased blood flow (prerenal state) and can promptly guide therapy.