Page 33 Complete Your CE Test Online - Click Here ● ● Inflammatory cytokines recruit more inflammatory cells to the site, known as leukocytes. ● ● The innate and acquired immune systems work to neutralize the invader; the complement system is considered to be the bridge between the innate and acquired immune response. ● ● Proinflammatory cytokines, known as IL-1 and TNFa, also trigger the coagulation cascade to help form clots and keep the infection localized. ● ● Anti-inflammatory cytokines, along with the regulatory proteins of the complement system, normally keep the inflammatory process in check. ● ● Homeostasis resumes when the invader is neutralized, debris is removed, and tissue repair and healing are complete. Self-evaluation: Question 1 Betty is a 66-year-old woman with a history of degenerative joint disease and diabetes. She has had several years of increasing hip pain and difficulty ambulating. Recently, she underwent surgery to replace the right hip joint. If Betty’s blood were drawn in the first few hours following surgery, what would be the most likely laboratory findings if she is showing an early response that may progress to sepsis? a. Leukocytosis (elevated WBC). b. Elevated hematocrit. c. Leukopenia (low WBC). d. Elevated hemoglobin. PATHOPHYSIOLOGY OF SEPSIS The pathophysiology behind sepsis is complicated and still widely researched. It is a complex manifestation of an abnormal response by the body’s inflammatory response to an infection. The development of sepsis is thought to depend on a variety of factors, including comorbidities (coexisting or preexisting conditions), the pathogen causing the disease, the virulence or harmfulness of the pathogen, and possibly a genetic predisposition (Neviere, 2017). Sepsis often begins from an infection acquired before hospitalization. Typically, when a person gets an infection, the body responds by initiating an inflammatory response to the infectious agent. There is a balancing of localized proinflammatory and anti-inflammatory mediators, known as cytokines, that results in the destruction of the infectious agent and subsequent tissue healing and repair when the immune response remains localized (Neviere, 2017). If, however, the immune response does not stay localized to the site of infection and the response becomes generalized, sepsis can result (Neviere, 2017). In sepsis, the initial immune response becomes exaggerated and causes an imbalance between what is known as a proinflammatory response and an anti-inflammatory response (Schulte et al., 2013). It is still not known why the immune system response remains localized in some instances and becomes generalized in other instances. It may be because of many factors, including what type of organism is invading and the toxic products it releases, the release of a large amount of proinflammatory cytokines, or genetic predisposition (Neviere, 2017). It is believed that the development of sepsis is mostly related to the dysregulation of the innate immune response rather than dysregulation of the acquired immune response. However, evidence of immune suppression in postmortem ICU patients with sepsis has been shown in the depletion of CD4 and CD8 lymphocytes (specific T cells of the adaptive immune response), suggesting there may be a role in the adaptive immune response in sepsis as well (de Pablo, Monserrat, Prieto, & Alvarez-Mon, 2014). The proinflammatory response involves mediators directed at ridding the body of invading pathogens. Proinflammatory mediators are believed to be responsible for the cause of collateral tissue damage in sepsis (Angus & Van der Poll, 2013). Anti-inflammatory response involves mediators crucial for limiting local and systemic tissue injury. In sepsis, this response by the body is believed to increase susceptibility to secondary infections while sepsis progresses (Angus & Van der Poll, 2013). It is a complex back-and-forth response in which proinflammatory and anti-inflammatory mediators attempt to clear the body of infection and aid in tissue recovery. But, as a result, it also causes organ injury and susceptibility to secondary infections (Angus & Van der Poll, 2013). Proinflammatory mediators Proinflammatory mediators include cytokines, such as tumor necrosis factor alpha (TNFa) and interleukin-1 (IL-1). Both TNFa and IL-1 can cause hypotension, leukocytosis, stimulation of other proinflammatory cytokines, and activation of the coagulation cascade (Neviere, 2017). Proinflammatory mediators lead to the recruitment of more macrophages and polymorphonuclear neutrophils (PMNs) that are present to rid the body of the invading organism. PMNs respond to the site of injury and release mediators that cause the signs of local inflammation (warmth, swelling, and redness). Anti-inflammatory mediators Anti-inflammatory mediators are cytokines that inhibit the production of TNFa and IL-1. The main anti-inflammatory cytokines are IL-10 and IL-13 (Jaffer et al., 2010). These anti-inflammatory cytokines inhibit proinflammatory cytokine production and suppress the immune system (Neviere, 2017). There is evidence of immune suppression in patients with sepsis that has progressed to multiple organ dysfunction syndrome (MODS) (Boomer et al., 2011). This finding has revealed the complex nature of sepsis and the fact that it is not simply an issue with a hyperresponse of the proinflammatory immune response but a dysregulation of both the proinflammatory and the anti-inflammatory response. Patients at particular risk of sepsis are 65 years or older, have weakened immune systems, have had a recent health care service, or have a chronic disease requiring frequent medical care. Complement cascade The complement system is made up of proteins that are activated in the immune response and play an important role in helping the body fight infection. Complement is activated in initial stages of widespread bacterial infections that lead to sepsis and have proinflammatory and antimicrobial actions that protect the host (Markiewski et al., 2008). Regulatory complement proteins normally work with other inflammatory mediators to stop the inflammatory response if the threat has been neutralized (Markiewski et al., 2008). If, however, pathogens escape the immune system response, the infection and inflammatory response continue and spread, leading to more tissue damage and more inflammation as seen in sepsis (Markiewski et al., 2008). In later stages of sepsis, a component of the complement system, known as C5a, along with proinflammatory cytokines, contributes to multiorgan dysfunction and circulatory insufficiency (Markiewski et al., 2008). Key points ● ● The exact pathology of sepsis is still being researched. ● ● Sepsis is a dysregulation of proinflammatory and anti-inflammatory mediators (cytokines) released in response to an infectious agent. ● ● Proinflammatory cytokines are believed to be the cause of collateral tissue damage in sepsis; anti-inflammatory cytokines are believed to contribute to the susceptibility to secondary infections. ● ● When the inflammatory response does not stay localized, but becomes generalized, sepsis results. ● ● Toxicity of the invading agent, genetic predisposition, comorbidities, and the release of a large number of proinflammatory mediators may be causative factors in the development of sepsis. ● ● The complement system, in concert with proinflammatory cytokines, can contribute to the widespread inflammatory response and subsequent organ failure and circulatory insufficiency that occur in sepsis.