Etiology and Prevention of Multisystem Organ Failure

Introduction

Burn trauma begins via a cutaneous thermal injury with or without an inhalation injury. These local primary injuries initiate a series of pathophysiologic cascades previously discussed. Fluid shifts into thermally damaged tissue as well as global endothelial activation; glycocalyx damage and systemic inflammation cause burn edema. The resultant distributive shock combines with humorally mediated myocardial suppression to induce burn shock requiring fluid resuscitation. Immune hyperactivation, hypermetabolism, and adrenal hyperreactivity exacerbate this primary injury. Concomitantly, host defenses such as intact skin and gastrointestinal mucosa are compromised, resulting in significant microbial insult from commensal and pathologic organisms. Ultimately, the common lethal end point of burn trauma and shock is multisystem organ failure (MOF). In one cohort of 821 severe pediatric burns there was a 19% incidence of MOF with a 100% mortality when involving three or more organ systems.

Many scoring systems are currently used to quantify MOF. The DENVER2 system is widely used in research and clinical care by scoring pulmonary, renal, hepatic, and cardiac function from 0 to 3 with a total of 12 points available ( Table 30.1 ). There is an inflection point after a score of 3 with significantly increased mortality. The Sequential Organ Failure Assessment score is based on scores of six systems from 0 to 4 for pulmonary, coagulation, liver, cardiovascular, central nervous, and renal ( Table 30.2 ). This definition system, popularized in sepsis and shock arenas, is at the core of the SEPSIS3 criteria to define septic shock recently published in the Journal of the American Medical Association .

Regardless of the definition used, the more organ systems fail, the greater the mortality. Currently the best predictive model for burn mortality is proteomics combined with clinical covariates. The time course of these failures and patterns of multiple failures are demonstrated in Fig. 30.1 and Table 30.3 . There are two well-described pathways to MOF in burn patients: early and late. The early clinical sequence is characterized by resuscitation failure leading to adult respiratory distress syndrome (ARDS), hemodynamic failure, renal failure, liver failure, gut failure, and sepsis. In the late cascade seen in patients surviving resuscitation, pulmonary failure, hemodynamic instability, renal failure, gut failure, and liver failure also occur. Vasomotor and cardiac failures are terminal events in both. Survival can be seen in patients with greater than three organ system failures, but mortality increases with more failed systems. Understanding the progression of the syndrome aids in prognostication and simplifies decisions regarding termination of futile efforts. This chapter discusses the etiology and prevention of MOF; management will be covered in the critical care chapter.

Jeschke and Herndon reviewed 573 patients and determined that burn sizes associated with mortality, sepsis, infection, and MOF are 60% total body surface area (TBSA) in children and 40% in adults. Kraft and Jeschke monitored MOF in 821 patients to define its course. Respiratory failure had the highest incidence in the first 5 days. Cardiac failure occurred throughout the hospital stay. Hepatic failure increased with hospitalization length and is associated with high mortality in the late cascade. Renal failure had an unexpectedly low incidence but was associated with high mortality in the first 3 weeks. Three or more organ failures was universally fatal in their cohorts. Overall mortality for patients with MOF was 41% compared to 2% without. The Helsinki Burn Center reported their adult burn mortalities between 1999 and 2005 as 71 burn deaths of 1370 patients with 40% caused by MOF and 40% due to untreatable burn injury. On average, four organ failures were noted in the deaths, with acute renal failure being the most common. Sepsis was associated with MOF in all of their deaths.

Etiology and Cellular Response

Attempts to define the etiology of MOF range from genomic and cellular to systemic and epidemiologic. Inadequate oxidative metabolism secondary to hypoperfusion leads to further organ failure as well as the release of humoral inflammatory mediators causing further cellular dysfunction. In ischemia–reperfusion models, oxygen radicals are generated resulting in peroxidation of cell membrane lipids and accumulation of activated neutrophils, with progressive cellular and whole-organ dysfunction. Critically ill patients suffer from supply-dependent oxygen consumption because of defects in cellular oxygen extraction and utilization. This results in inadequate aerobic metabolism unless supranormal levels of oxygen are supplied. Grossly inadequate delivery of oxygen to cells dependent on aerobic metabolism can lead to cellular dysfunction, and this may be followed by organ failures.

Mitochondrial-specific damage is one of the earliest responses to burn injury. There is tissue-specific damage to mitochondrial DNA, most profoundly in the lungs and hearts of burned mice associated with a time-dependent increase in oxidative stress and neutrophil infiltration. Porter and Herndon investigated postburn mitochondrial dysfunction by measuring mitochondrial respiration in saponin-permeabilized myofiber bundles and noted diminished mitochondrial coupling control persisting at 2 years postburn. Uncoupling protein-1 thermogenesis increases after burn trauma and is a mechanism of hypermetabolism in burn victims. This response is both adrenergic-mediated and responsive to ambient temperature, linking thermal regulation to skeletal muscle metabolism. Jeschke and Herndon described the pathophysiologic response to severe burn injury in 242 children with a mean burn size of 56%. All patients were hypermetabolic with significant muscle protein loss, loss of bone mineral content, and profound alterations of serum proteome. Cardiac function was compromised, insulin resistance appeared in the first week, and patients were hyperinflammatory with marked changes in interleukin (IL)-8, monocyte chemotactic protein-1 (MCP-1), and IL-6. Among 821 severely burned children, 586 never developed organ failure by the DENVER2 criteria. Respiratory failure was the most common organ failure occurring in 230, then cardiac in 77, with renal only occurring in 16 ⁴ ( Fig. 30.1 ).

The Inflammation and Host Response to Injury Large-Scale Collaborative Research Program defined the leukocyte transcriptome after severe trauma and burn injury and found a similar “genomic storm” among different injuries, revealing a fundamental human response to severe inflammatory stress. The transcriptome of leukocytes following burn was linked to their immunologic response and related to outcomes. In their study of 167 subjects over 28 days they defined greater than twofold transcriptome changes in 80% of leukocyte genes (5136) compared to healthy controls. Within the first 12 hours the gene expression favors innate immunity and inflammatory response, including NB1, MMP8 (neutrophil collagenase), lactotransferrin (LTF), and haptoglobin (HP) with a marked downregulation of T-cell function and antigen presentation ( Fig. 30.2 ). They found the genomic response was similar between isolated endotoxin challenge, minor trauma, and severe burn, differing primarily in the magnitude and duration of the response, thus postulating that the persistence of cellular debris in the plasma as a danger-associated molecular pattern (DAMP) continues the nonresolving inflammation ( Fig. 30.3 ). These descriptions of genomic response to burn injury reflect a global response and do not account for complex interplays or subpopulations of different cell types within the total leukocyte populations, the microenvironmental effects within different compartments where the immune cells exert their effects, proteomic or metabolomic effects, nor that certain transcripts in low abundance or with a small change may have profound effects. These data do highlight the complexity and universality of the immunologic response to severe injury or minor endotoxemia.

Tompkin's data demonstrate systemic inflammatory response syndrome (SIRS) underlies cellular events leading to MOF. Although many MOF patients will have different engines, such as sterile burn wounds, sepsis is the most common late initiator of SIRS. One overwhelming infection is not required; small repetitive infections may trigger the cascade, perhaps by priming immune cells and making them react more profoundly to each consecutive stimulus. Endotoxin from Gram-negative bacteria is a major intermediary via Toll-like receptor (TLR) pathways, but Gram-positive bacteria cause similar insults. With the advent of early burn wound excision, infected wounds and wound sepsis are decreasing in incidence; pneumonia rather than wound sepsis causes most infectious deaths in burn patients today. Complete wound closure, without donor sites (e.g., with skin substitutes), decreases oxygen consumption thereby ameliorating the inflammatory response to the open wound. Incomplete wound closure does not have this effect. Increased levels of circulating mediators such as IL-6, IL-8, and tumor necrosis factor (TNF) have been shown to originate from the burn wound and contribute to hypermetabolic and inflammatory states seen in burn patients. IL-8 has been demonstrated to be upregulated in the lung after burn injury. The stimulus for this upregulation, which is associated with pulmonary dysfunction, may come from the wound.

A significant source of endotoxemia and septic load leading to MOF is gut barrier failure. Bacterial densities range from near 0 in the stomach, to 10 ⁴ –10 ⁵ in the distal small bowel, to 10 ¹¹ –10 ¹² /g of stool in the normal colon. Although not seen immediately after trauma, serial insults result in increased translocation of bacteria and their products into the portal and lymphatic circulations. Hemorrhagic shock, endotoxin administration, burns, and burn wound sepsis have each been shown to result in increased translocation of bacteria from the gut. Using polyethylene glycol 3350 as a tracer, increasing burn wound size was demonstrated to increase gut permeability to macromolecules such as endotoxin. Smaller molecules, with lactulose as the tracer, passed more readily through the gastrointestinal membrane after injury. Both intra- and transcellular processes allow transloaction. Consequences of loss of the gastrointestinal barrier are profound. Translocating whole bacteria can be a direct source of sepsis or can activate Kupffer cells and promulgate an inflammatory response in conjunction with bacterial products such as endotoxin.

Organ-Specific Failure and Prevention

MOF reversal is challenging, making prevention paramount. Genomic data have demonstrated that patients with MOF began on the same path as those who recover without complications. Prevention is based on arresting the “engines” that drive and amplify the process: sepsis, gut barrier breakdown, the wound, and inadequate perfusion ( Table 30.4 ). With current surgical and pharmacologic modalities, it is more practical to halt these engines than deal with an inadequately understood complex web of mediators. The interplay between organ systems and engines of MOF in the burned patient are complex. For expedience, we will discuss major organ systems sequentially.