Multiple Organ Dysfunction and Sepsis

Sepsis

The term sepsis has been used loosely over the years, but since 1992 a consensus has been established about proper terminology. First, the systemic inflammatory response syndrome (SIRS) is defined as having two or more of the following clinical criteria: (1) temperature greater than 38°C or less than 36°C, (2) heart rate greater than 90 beats/min, (3) respiratory rate greater than 20 breaths/min or Pa co ₂ less than 32 torr, and (4) white blood cell count greater than 12,000 or less than 4000 cells/mm ³ or more than 10% immature (band) forms. SIRS is a pathophysiologic response that arises due to release of overwhelming amounts of circulating proinflammatory cytokines, such as tumor necrosis factor-α and various interleukins. This leads to widespread vasodilation and hypotension. These cytokines also affect function of microvascular endothelial cells with inappropriate activation of their inflammatory and procoagulant functions. This leads to accumulation of inflammatory cells within organs, microvascular leakage, and microvascular obstruction, with worsening hypoperfusion of organs. In addition, parenchymal cells within organs are directly affected by the circulating factors, causing further dysfunction. Activation of coagulation factors in the microvasculature has a positive feedback on endothelium and inflammatory cells, increasing systemic inflammation. SIRS may be caused by noninfectious processes, including acute pancreatitis, pulmonary embolism, transfusion reactions, major trauma, and burns, but in the hospital setting it is usually found in association with significant infection.

Sepsis is then defined as SIRS in response to infection, and most of the clinical features of sepsis are similar regardless of the type of infection. Severe sepsis is defined as sepsis associated with organ dysfunction, hypotension (blood pressure less than 90 mm Hg or reduction greater than 40 mm Hg from baseline), or hypoperfusion abnormalities (including lactic acidosis, oliguria, or altered mental status). Septic shock is defined as sepsis with hypotension refractory to fluid resuscitation and hypoperfusion abnormalities. One exception is that children can be in frank septic shock without hypotension but with severe hypoperfusion abnormalities. Importantly, the diagnosis of sepsis requires an infectious etiology but does not require bacteremia. Sepsis can be from infectious agents other than bacteria or can be from a local bacterial infection without seeding of the blood. In fact, even in rigorous studies, bacteremia was documented in only 17%, 25%, and 69% of patients with sepsis, severe sepsis, and septic shock, respectively. This is one reason autopsy pathologists are asked to look for the possible “source of sepsis” in patients with negative blood cultures. In septic hospitalized patients with positive blood cultures, the causative organisms are Gram-positive (47%), Gram-negative (41%), mixed bacteria (5%), anaerobic bacteria (2%), and fungus (5%).

Multiple Organ Dysfunction

Multiple organ dysfunction syndrome (MODS) was also defined in the 1992 consensus meeting of the American College of Physicians/Society of Critical Care Medicine as the presence of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention. As critical care supportive measures progress, increasing numbers of deaths are largely attributed to the progressive failure of several interdependent organ systems rather than a dominant effect of a single underlying illness. MODS has many acceptable names, such as multiorgan failure and multiple systems organ failure, that refer to the same syndrome defined by clinical criteria. In MODS, dysfunction is present in two or more of the following organ systems: (1) respiratory, (2) cardiovascular, (3) renal, (4) hepatic, (5) hematologic, and (6) neurologic. In many clinical settings, scores have been developed to gauge the severity of MODS, such as the popular Sequential Organ Failure Assessment (SOFA) that combines scores from 0 to 4 in the six organ systems just listed, assessing (1) lowered Pa o ₂ /Fi o ₂ , (2) hypotension or vasopressor requirement, (3) elevated serum creatinine, (4) elevated serum bilirubin, (5) thrombocytopenia, and (6) Glasgow Coma Scale score.

Rarely, MODS may be primary, in which an insult injures multiple organs directly, such as with large-scale physical or chemical injuries or widely disseminated disease. Usually MODS is secondary to a combination of SIRS, accumulated effects of various injurious agents (such as drug or oxygen toxicity), episodes of cardiogenic or hypovolemic hypotension, and the effects of failing organ systems on each other. Intensive care—with mechanical ventilation, vasopressors, cardiovascular support devices, intravenous fluids, transfusions, hemodialysis, nutritional supplementation, and a variety of supportive medications—now sustain high-risk patients into phases of complex interdependent organ dysfunction with compounded insults.

In an increasing percentage of hospital autopsies, pathologists are asked to account for multiple organ dysfunctions, including whether there is an infection causing sepsis. We are often on a hunt for the possible “septic source,” concurrent organ pathologies, and complex interactions. In these cases the pathologist needs to consider much of the available clinical information in addition to the morphologic findings.