Surgical Infections

In the past, our approach to multiple organ failure in the injured or critically ill surgical patient was driven by attempts to simplify a complex process. Early studies focused on uncontrolled invasive infection (sepsis) as the driving force of multiple organ dysfunction syndrome (MODS). However, some patients with adequately controlled infection and those without sepsis nevertheless develop MODS and signs of systemic inflammation. This discrepancy led to investigations of systemic activation of inflammation by a wider variety of biological modulators than just infection. Despite the apparent involvement of biological modulators such as endotoxin, tumor necrosis factor, and interleukin-1 receptor in MODS, agents that neutralize these modulators have failed to thwart the progression of sepsis, septic shock, and organ failure. A new paradigm suggests that, in the critically ill patient at risk for organ failure, an integrated process propagates an excessive systemic inflammatory response and/or an inadequate compensatory anti-inflammatory response. Future studies should examine the balance between these two processes at the level of the individual patient with organ failure. Careful stratification of individual patient responses to inflammatory stressors may be an essential step for creating better strategies for therapeutic interventions that can restore balance between the pro-inflammatory and anti-inflammatory processes in the critically ill patient and possibly prevent organ failure.

Multiple organ failure (MOF) is currently the most common cause of late death after injury and surgery. The pathogenesis of MOF remains incompletely understood but in all likelihood results from a combination of dysregulated balance between inflammatory response and immune function, maldistribution of microcirculatory blood flow, and ischemia/reperfusion injury. Advances in the understanding of the pathogenesis of MOF have been hampered by a lack of precise animal models, accurate definitions of disease, consistent means to qualitatively and quantitatively diagnose disease, and a definable at-risk group of patients for study. Several recent advances in critical care and proposed new therapies hold promise for improving the outcome of patients with multiple injuries who are at risk for MOF. However, as recent clinical trials have shown, studies demonstrating an improvement in outcome from use of these therapeutic agents are difficult to design. The purpose of this article is to discuss the evolution, clinical course, and pathogenesis of MOF, to attempt to better define and quantitate MOF, and to describe recent studies aimed at identifying an at-risk study population for improved treatment and prevention strategies for MOF.

Multiple organ dysfunction syndrome (MODS) is a major cause of morbidity and mortality in surgical intensive care units (SICUs). Multiple organ dysfunction syndrome remains the most important factor associated with mortality in the SICU. Illness severity scores such as the Acute Physiology and Chronic Health Evaluation-III (APACHE III) and the magnitude of the systemic inflammatory response syndrome (SIRS) at the time of SICU admission are useful in stratifying patients at risk for MODS and subsequent mortality. Assessment of key organ systems shows that mortality correlates with the overall severity of organ dysfunction and the number of involved organ systems, as well as to individual organs that fail. Despite the prognostic utility of SIRS/MODS, definitions of dysfunction of individual organs have shortcomings. The problem with quantitating MODS lies in the inability to adequately define organ dysfunction, especially of the gastrointestinal tract, liver, and central nervous system. Biological indicators of organ dysfunction may prove to be better markers for MODS in the future.

Antibiotic resistance in the hospital setting is continuing to increase, particularly in intensive care units (ICUs) and other areas of the hospital such as oncology units, where the use of empiric broad-spectrum antibiotics is common. The problem of antibiotic resistance is also compounded in the immunocompromised patient. Multi-drug resistance is common among both Gram-positive and -negative bacteria, and becoming more prevalent among fungi (yeast). Two major antibiotic-resistant pathogens include extended-spectrum β-lactamase producing Klebsiella pneumoniae (ESBL-KP) and vancomycin-resistant enterococci (VRE). When infections occur with ESBL-KP, a carbapenem antibiotic is usually the drug of choice. When infection occurs with VRE, specific therapy is bacteriostatic, and the clinician may have to rely on empirically selected antibiotics or combinations of antibiotics to achieve a positive outcome. Two newly-approved agents, linezolid and quinupristin/dalfopristin can be used to treat infections caused by resistant gram-positive cocci, but the latter is approved for use against VR-E. faecium. Risk factors for the development of ESBL-KP include the use of extended-spectrum cephalosporins such as ceftazidime. Risk factors for the development of VRE include inappropriate use of vancomycin, extended-spectrum cephalosporins, and antianaerobic drug therapy such as clindamycin. Several institutions have documented a reduction in one or both of these resistant pathogens following a decrease in the use of extended-spectrum cephalosporins combined with the increased use of extended-spectrum penicillins/β-lactamase inhibitor combinations, such as piperacillin/tazobactam, for the empiric therapy of infections. For VRE, a reduction in the inappropriate use of vancomycin is also an important interventional strategy along with improved infection control practice.

Multiple organ dysfunction syndrome (MODS) is caused by an overwhelming, uncontrolled systemic inflammatory response that is activated by a number of hostile stimuli including sepsis, hypovolemic shock, and severe trauma resulting in massive tissue injury. The indiscriminate activation of the inflammatory response due to these insults causes loss of the host's ability to localize the inflammation to the focus of the problem, leading to systemic inflammation and severe host tissue damage and subsequent MODS. While the major players, namely neutrophils, macrophages, endotoxin, cytokines, and oxidants have been known for some time, the disease processes responsible for the pathogenesis of MODS have only recently been elucidated. Our newly found knowledge has resulted in the development of novel therapeutic strategies to prevent or treat MODS, such as scavenging toxic oxygen species and inhibiting endotoxin, or cytokine production, or cytokine activity. Unfortunately, these strategies have not resulted in improved mortality rates among patients with MODS. The complex nature of the host response to severe insults combined with the fact that the host has multiple, redundant parallel systems to deal with various insults has made it difficult for clinical interventions to adequately ameliorate the disease process among patients at risk for MODS. The purpose of this article is to attempt to "dissect out" several individual components of the inflammatory response that play important roles in the development of MODS and to review some potentially beneficial approaches to combat these harmful processes.

Injury will equal or surpass communicable disease in the year 2020 as the number one cause of lost disability-adjusted life-years worldwide. The major cause of "late death" after trauma is organ dysfunction, commonly as a complication of shock or sepsis. The pathophysiology of injury-induced organ dysfunction is poorly characterized but has been linked to systemic inflammation as a result of infection (either obvious or occult) or massive tissue injury (systemic inflammatory response syndrome, SIRS). Subsequent complications of organ dysfunction, including death, may also stem from immunosuppression characteristic of what has been called the counter-regulatory anti-inflammatory response syndrome (CARS). At the cellular level, injurious stimuli trigger adaptive stress responses that include changes in gene expression. Multiple organ dysfunction syndrome (MODS) is the summation of these stress responses to severe systemic injury, integrated at the cellular, organ, and host levels. We hypothesize that a complete understanding at the molecular level of the stress responses induced by injury will aid in the development of therapeutic strategies for treating MODS in the critically ill surgical patient. This paper reviews recent data from our Cellular Injury and Adaptation Laboratory relevant to our understanding of MODS pathophysiology, particularly as it relates to stress-induced cell death by apoptosis. Our data suggest that inhibition of stress-induced apoptosis may improve survival after severe injury.

Clinical and experimental studies performed over the past several decades have implicated bacterial and endotoxin translocation (BET) from the gut to distant organs in the pathogenesis of multiple organ dysfunction syndrome (MODS). Experimental studies in animals directed at maintaining the integrity of the intestinal mucosa have shown efficacy in preventing BET and the induction of distant inflammatory processes, suggesting that the egress of bacteria and their surface endotoxins might be pivotal in inducing MODS. However, clinical studies have failed to convincingly recapitulate these beneficial effects. Selective digestive decontamination, although it effectively decreases rates of respiratory infection, has failed to reduce MODS in critically ill patients and, except in certain patient subsets, has had no demonstrable effect on mortality. Nevertheless, the gut is an immunologically active organ that, irrespective of BET occurrence, appears to contribute significantly to the development of distant organ dysfunction following ischemia/reperfusion injury. Resuscitation strategies aimed at minimizing the inflammatory effects of gut-derived mediators, such as toxic oxygen species, appear promising in preventing the development of distant organ injury in the critically ill patient.

Gram-negative bacteria commonly cause serious infections in hospitalized patients, and those that lead to bacteremic episodes and sepsis syndrome are associated with the highest mortality rate. Sepsis syndrome frequently progresses to multisystem organ dysfunction and failure, with as many as 400,000 cases occurring annually. Unfortunately, the associated mortality rate remains about 40%. Lipopolysaccharide (LPS, endotoxin), an integral component of the gram-negative bacterial outer membrane, plays a critical role in the pathophysiology of this lethal disease process. It is capable of interacting with host macrophages, a process that leads to the secretion of an increasingly well-characterized array of macrophage cytokines. Several different classes of compounds that bind directly to LPS and thereby neutralize its effects are being examined. These consist of anti-LPS monoclonal antibodies (mAbs), naturally occurring proteins and their derivatives (e.g., bactericidal/permeability-increasing protein [BPI], Limulus anti-LPS factor [LALF]), and certain antibiotics (polymyxin B, taurolidine). The molecular biology of BPI, LALF, and LPS binding protein (LBP, which augments the host response to LPS) is of considerable interest, as each demonstrates considerable genetic sequence homology. Although two anti-LPS monoclonal antibodies (HA-1A, E5) did not demonstrate efficacy during sepsis syndrome, information obtained from these clinical trials provided investigators with the ability to better understand this disease process. However, a detailed understanding of the biology of endotoxin antagonism is beginning to emerge, and the application of this knowledge in the clinical setting provides hope that it may be possible to reduce the mortality of sepsis syndrome caused by these microorganisms to a statistic well below the current 40%.

Postoperative or trauma-induced intra-abdominal infections can result in sepsis and multiple organ dysfunction syndrome (MODS). Enteric bacteria and endotoxin released from the gut into the peritoneal cavity in response to injury can directly stimulate the inflammatory cascade responsible for the development of systemic inflammation and subsequent MODS. Therapeutic strategies, such as biologic modifiers that are aimed at blocking or enhancing specific mediators of the inflammatory response, have been developed and tested in animal models with varying efficacy in preventing mortality. Specific therapies that have shown beneficial effects in animal models have not proved successful in prospective, randomized human studies, and it is as yet unclear whether cytokine-based therapies will ultimately have a role in preventing MODS. Testing novel therapies in appropriate animal models that closely simulate human intra-abdominal infection is crucial in developing drugs that will be beneficial in preventing sepsis-induced mortality in critically ill patients.