Page 130 nursing.elitecme.com Complete Your CE Test Online - Click Here 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). Antiinflammatory 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 antiinflammatory 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). Antiinflammatory mediators Antiinflammatory mediators are cytokines that inhibit the production of TNFa and IL-1. The main antiinflammatory cytokines are IL-10 and IL-13 (Jaffer et al., 2010). These antiinflammatory 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 antiinflammatory 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 antiinflammatory mediators (cytokines) released in response to an infectious agent. ● ● Proinflammatory cytokines are believed to be the cause of collateral tissue damage in sepsis; antiinflammatory 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. Self-evaluation: Question 2 Which of the following statements best fits what is known in the pathophysiology of the development of sepsis? a. Sepsis develops as a result of a hyperresponse of proinflammatory mediators to infection. b. Sepsis is a localized response that occurs in response to a large release of cytokines. c. Sepsis is a dysregulated response of both proinflammatory mediators (cytokines) and antiinflammatory mediators. d. Sepsis is normally caused by an infection but can be attributed to noninfectious etiologies as well. EFFECTS OF SEPSIS ON THE BODY All of the organs of the body are susceptible to damage from sepsis. Sepsis causes cellular injury that may be caused by tissue ischemia (lack of oxygen to tissues), cytopathic injury (injury to cells by proinflammatory mediators), and altered apoptosis (programmed cell death) (Neviere, 2017). Apoptosis is the mechanism in which the body gets rid of dysfunctional cells; it is a normal and necessary function of the body. Proinflammatory cells may delay apoptosis in activated immune cells, such as neutrophils and macrophages, and may speed up apoptosis in other cells, such as gut endothelium, leading to disruption of normal functions and contributing to the injury found in sepsis (Al- Khafaji, 2016). The dysregulation of cytokine release leads to endothelial dysfunction. Endothelial dysfunction causes increased capillary permeability and vasodilation, which ultimately leads to hypotension, hemoconcentration (concentration of red blood cells and other cellular products in blood), and edema (Shulte, Berhagen, & Bucala, 2013). Vasodilation and subsequent hypotension and hypoperfusion occur in the patient with sepsis causing poor oxygen delivery and damage to organs in the body. Eventually, in the case of septic shock, activated neutrophils release nitric oxide, which is a strong vasodilator that leads to hypotension seen in septic shock (LaRosa, 2010). Coagulation dysfunction and disseminated intravascular coagulation Interleukin-1 (IL-1) and tumor necrosis factor (TNFa) are proinflammatory cytokines that are released in response to inflammation. IL-1 and TNFa trigger tissue factor that is the first step in the pathway of coagulation. Tissue factor leads to the production of an inflammatory substance known as thrombin that causes fibrin clots to form. Small blood clots may develop during sepsis and impair circulation, especially in the microvascular system, which includes the capillaries. When the blood clots form in the small vessels,