Kelli Irwin Rough Draft

Sepsis syndrome is a widespread, excessive reaction to infection of what?, bacteria, virus, parasite fungus? in the bloodstream. According to, Morton, et al, sepsis develops in approximately 750,000 patients yearly(world-wide or US?). Also, of these inflicted with the disease, about 200,000 deaths result. In the U.S., the disease is actually the 13th leading cause of death Is this overall, or is it amoung a specific group?. (25) Sepsis may occur in response to gram positive or negative bacteria, fungi, or viruses. However, it most commonly is a systemic response to gram negative bacteria. After the innate immune cells react to the microbe, a series of dramatic immune events follows. (14) In the end, organ disruption and death are the results of imbalances in pro-inflammatory and anti-inflammatory cytokines that cannot be clinically reversed. (15)
Add topic sentence because you have a lot going on in this paragraph Gram negative bacteria are comprised of an outer membrane with containing or comprised of??? lipopolysaccharide (LPS). This LPS is considered non-toxic to the body when it remains on the outer membrane. (16) However, when bacterial cells expel LPS, it releases lipid A, the inner area and conserved part of the LPS. Lipid A is released into the bloodstream and causes the activation of the inflammatory response. COMBINE LPS is transferred to CD14 via LPS-binding protein. (27) This transfer allows for the interaction between LPS and Toll-like receptors which ones specifically?(TLRs). (22) In gram positive bacteria, peptidoglycan and lipoteichoic acid actually work together in a similar way as LPS does in gram negative.Not quite sure what this sentence is actually saying, i don't think you really defined what LPS does in gram negative so it's hard to say that LTA and pepidoglycan work together in a similar way as LPS when you haven't showed what LPS does They also have the ability to activate cytokine release, such as TNF, IL-1, and IL-6. (7) TLR2 has actually been shown to detect peptidoglycan, however, it is not able to detect peptidoglycan that is highly purified what is purified peptidoglycan. Carbon dioxide has, interestingly, been proven to cause TLR initiation. (2) Nod (Does Nod need to be all capitals?)proteins have also been shown to detect peptidoglycan on on or in?bacteria, with Nod 1 being specified to gram negative and Nod 2 able to detect all types of bacteria.change this last sentence to make more parralel (28) Neutrophils are excessively released after the initiation of cytokines into the serum. However, the study of neutrophils is difficult to evaluate because their life-cycle still poses many questions.what about their life-cycle poses questions? (4) Infiltrated neutrophils are known to have the ability to generate free radicals. As a result of these free radicals, oxidative stress increases the inflammatory response within the body. how? (3) Yet another way the body causes increased inflammatory response is through the triggering receptor expressed on myeloid cells (TREM-1). TREM-1 actually causes TLRs to increase inflammation. how? TREM-1 and CD14 are co-expressed at a higher rate when a greater level of LPS is involved. (6)
The complement cascade can take place in either the classical, lectin, or alternative pathway. The classical pathway begins with C1 cleaving C4 into C4a and C4b. C4b then binds to C2 via C1 and the result of C4b and C2b bound together equals C3 convertase. doesn't C2 have to be cleaved somewhere to give C2a and C2b? C3 convertase allows for the cleaving of C3 into C3a and C3b. C3b then works collaboratively with C3 convertase to cleave C5 into?, while C3a promotes inflammation. The alternative pathway occurs at the microbial surface when B What is B? is bound to C3b. D what is D? then cleaves this combination into Bb and Ba. C3 convertase is formed by C3b and Bb. Finally, the lectin pathway occurs when MASP-2 define MASP-2 cleaves C4 and allows C2 to bind with the result of C4b. The result is once again, C3 convertase. Once C3 convertase is formed, the rest of the complement cascade in is similar for all three pathways, eventually leading to the membrane attack complex. maybe explain this process(22) The activation of a complement pathway results in the release of C3a and C5a you never showed in the above explanation where C5a comes from which causes the increased level of histamine in the blood. Histamine is released from basophils or mast cells and result in the accumulation of more leukocytes within the serum. (32) It has been noted, however that complement activation may not be proved from having terminal complement complex present in the serum. Last sentence is confusing(10)
Apoptosis is thought to be significant in tissue damage, leading to excessive organ dysfunction. TNF alpha and Fas ligand (FasL) are two initiators of apoptosis that leads to the damaging affects seen in severe sepsis or septic shock. (31). It has also been determined that an increased level of apoptosis in the autonomic centers of the brain is related to the severity of the disease. This autonomic system is responsible for cardiovascular control, so when these cells begin to die off by apoptosis, the heart will start to suffer the consequences could you give a specific exmaple here. (23) Apoptosis occurs in the body through a regulated process that is considered physiologically normal.that last sentence is really wordy Conversely, necrotic cell death is unplanned and unexpected in the body. combine last two sentences In the case of sepsis both apoptopic and necrotic cell death have been shown to occur. Interestingly, there have been substantial amount of epithelial cells of the gastrointestinal tract and lymphocytes observed in sepsis involved in mice, posing many questions as to why this is happening.-confusing However, there is a significant amount of lymphocytes in the gastrointestinal system, which may be indicative of why these cells are commonly killed off. (29)
This systemic inflammatory response leads to an excessive coagulation response within the body. When these inflammatory mediators what inflamitory mediators?are continually fired off in response to the microbe located systemically in the bloodstream, the result is catastrophic. In an ironic manner, the increase in clotting ability which inflammatory mediators can prevail, also causes inflammation from platelets or activated cells. (8) Within the body, inflammation increases the serum concentration of C reactive protein. This issue puts the septic patient at an increased risk of myocardial infarction. Inflammation can also result in the expression of tissue factor on leukocytes. When tissue factor is exposed to phospholipids on activated monocytes, a procoagulant reaction is initiated. On the reversal side, platelets have the ability to release cytokines IL-6 and IL-8. The result is yet more inflammation due to the release of these inflammatory cytokines.
All of these events occurring in the body account for the clinical presentation of septic individuals. Patients with sepsis may present with signs and symptoms of: hypotension with a systolic blood pressure of lower than 90 mmHg or a significant drop of greater than 40mmHg, hypoperfusion, tachycardia, tachypnea, oliguria, lactic acidosis, altered mental status, white blood cell count either greater than 12,000 cells/mm^3, less than 4000 cells/mm^3, or greater than 10% immature. There will be an inadequate amount of blood in the arterial tree. While cardiac output may actually be high, it is not able to provide perfusion to the tissues. Depressed myocardial performance occurs, more than likely related to the activation of TNF, IL-1, and possibly lactic acidosis. The sympathetic nervous system will kick in its response and cause bronchodilation. However, soon after, the activation of cytokines results in bronchoconstriction. Increased vasodilation allows the capillary beds to leak in response to neutrophils and inflammatory mediators. Interstitial edema will occur because of the leaky capillaries, ultimately leading to poor perfusion and impaired gas exchange. Hematologically, platelet abnormalities can arise in septic patients because of an endotoxin which results in their aggregation. Sepsis causes the release of catecholamines which then results in insulin resistance. At this point, cells can no longer depend on fat, protein, or glucose as sources of energy. (34) Protein in muscle is broken down to try and make up for the lack of energy. According to, Brealey, ATP concentrations were extensively lower in sepsis patients who died rather than in surviving patients’ skeletal muscle. Ultimately, this lack of ATP will lead to organ failure and death. (34)
Is this the right place for a new paragraph or should it be a little earlier?Before ATP is halted is ATP halted or is it the production that is halted completely in severe sepsis, a pathway dependent on ATP which involves intracellular proteolysis is shown to be occurring at a higher frequency in septic patients. Therefore, drug therapy is trying to determine if a proteasome inhibitor is effective effective at what? in sepsis. By administering MG-132, a proteasome inhibitor, in vivo, a marked decrease in TNF alpha, IL-10, and IL-1 beta was found. Likewise, the production of IL-6 has also been found to decrease with the use of proteasome inhibitors. (5) These drugs may be a remarkable intervention for regulating the inflammatory response due to sepsis. Studies are continuously being done to try and find ways of an anti-apoptopic treatment. Luckily, the process of apoptosis is fairly orderly and easy to understand so developing pharmacological measures to inhibit apoptosis may be possible. (19) By preventing the process of apoptosis in severe sepsis, the immune system will remain at a functioning level.
Of course antibiotic treatment remains an old, but essential intervention when dealing with sepsis. The course of antibiotics varies by what kind of microbe is causing the infection and the individual’s health condition. Single-drug therapy may involve Cefepime hcl, Cefotaxime sodium, Primaxin (Imipenem/Cilastin), Zosyn (Piperacillin sodium/Tazobactam sodium), or Metropenem. A combined therapy of Levofloxacin, Gentamicin sulfate, and Vancomycin hcl is another common antibiotic regime. (17) While antibiotic treatment is essential, the rate of microbes that become resistant to antibiotics is increasing. The two most common of bacterial resistance are methicillin-resistant staphylococcus aureus and vancomycin-resistant enterococcus faccium. When a patient contracts a drug-resistant microbe, their mortality rate is doubled in sepsis. (26) Therefore, it is important to weigh out the pros and cons to each antibiotic as it is ordered to determine its effectiveness. Another issue with antibiotics is there initiation. If patients are delayed the start of antibiotics, mortality rates are severe. (20) Likewise, the drug therapy should be goal-directed to yield the best results in patients presenting in the emergency room of hospitals. (12)
REWORD The issues between coagulation and inflammation in dealing with sepsis lead to the use of the drug Drotrecogin Alfa. This medication, also known as Xigris, performs with an antithrombotic action in the body. It allows for limitation on inflammatory responses related to thrombin. maybe explain what thrombin is (21) Using the drug also contains profibrinolytic, anti-inflammatory, and anti-apoptotic properties. Activated protein C has the capacity to interact with white blood cells by decreasing their endothelial rolling and adhesion. Ultimately, the drug is able to raise blood pressure and therefore allow for better tissue and organ perfusion. A few contraindications associated with Xigris administration include: hypersensitivity, a cerebrovascular accident within the past 3 months, an increased risk of bleeding, cerebral herniation, presence of an epidural catheter, intraspinal or intracranial or severe head injury within the past 2 months, chronic dialysis, or a patient with HIV who shows a CD-4 count lower than 500/mm^3. (1) While a huge side effect of using this medication is bleeding, it has been found that the benefits of using activated protein C outweigh this risk. (24) Administration of Xigris is recommended in adults at 24mcg/kg/hr over a 96 hour time frame. (1) Also, it is typically only recommended when there is a high-risk of death associated with the sepsis. (8) When the level of activated protein is dramatically decreased in septic conditions, serious side effects can result. Because of the expense and sometimes lack of availability of activated protein C for infusion, it has been found that plasma exchange provides somewhat of a backup opportunity for the patient to receive an amount of the necessary protein C.
Another medication commonly ordered in the presence of severe sepsis is albumin. Albumin is a medication that has the ability expand plasma volume. It therapeutically results in cardiac output maintenance and increasing plasma volume. It is given in sepsis when there is a substantial amount of fluid deficit. Albumin acts in the body by providing colloidal pressure. In doing so, albumin allows fluid to move from the interstitial space back into intravascular space. The administration of albumin is given with crystalloid fluids that are appropriately ordered. Human albumin administration is contraindicated in allergies to albumin, congestive heart failure, increased or simply normal levels of intravascular volume, and anemia. Some of the more common side effects that can result from albumin administration include tachycardia and pulmonary edema. The appropriate dose for adult patients in shock varies independently, but with a standard of 500 mlL’s of 5% albumin given initially. If the patient’s condition is not improving, an additional dose may be given within 30 minutes. (1) In a study done on 104 patients with sepsis, there was a marked decrease in pulmonary edema. Albumin also showed the ability to reduce platelet count in these trials. (35) The medication is recommended to be used cautiously in the septic patient because of the possibility of fluid accumulating in the lungs. However, one study has shown that albumin helped to decrease the amount of pulmonary edema and also improve the function of the lungs. Still, another study found that the degradation of albumin within the body actually could be related to the prevalence of shock associated with meningoccal sepsis. Urine samples were tested in children that were positive for meningitis disease and a postulation was formed. The study is not giving a definitive answer that albumin actually increases these risks.: Rather, it proves that all of the medications associated with sepsis need to be decided upon in on an individualized basis, because what benefits one case of sepsis may not be effective in another. (11)
While there are many pharmaceutical options being tested for sepsis, the mechanisim of using peptides for treatment has recently been evaluated. Temporin A has been studied for therapeutic use alone or in combination with the antibiotic Imipenem. Temporin A is a synthetic peptide found on the skin of the Rana temporaria, or the European red frog. Temporins are about ten to thirteen residue-long peptides that have the ability to work against methicillin resistant staphylococcus aureus and vancomycin resistant enterococcus faccium. They are found to be the shortest peptides with antibacterial properties. (33) Imipenem is a broad-spectrum antibiotic that has the ability to change bacteria into round cells that stop the release of lipoteichoic acid. In this way, the inflammatory response is decreased. Results found that with the use of temporin A, either alone or in combination with Imipenem, the amount of TNF and IL-6 showed a marked decrease. (7) This is important because it presents the possibility for another therapeutic action for sepsis that does not have to involve antibiotics. With the use of temporin A, the rate of antibiotic resistance may therefore decrease.
(In this paragraph, I feel like its more describing the symptons and treatments than relating back to immune response) The crashing blood pressure and decreased cardiac output associated with sepsis are critical measures for intervention. Fluid administration is crucial in septic patients because it is a mechanism for increasing blood pressure. It is a rather simplified attempt at increasing the hypotensive state that these individuals are commonly in. If fluid administration does not reverse the hypotensive state associated with septic patients, other options are available. In order to assist in reversal of these critical events of hypotension and decreased cardiac output associated with sepsis, inotropic and/or vasopressive medications are commonly given. Dopamine is a very common agent that actually possesses both inotropic and vasopressive action together. In doses of 2-10 mcg/kg/min, what is considered a large dose, dopamine acts to stimulate beta-adrenergic and dopaminergic receptors. This then produces renal vasodilation and cardiac stimulation. Therapeutically, dopamine increases blood pressure, improves renal flow, and increases cardiac output. The drug is contraindicated in pheochromocytoma, tachyarrhythmias, and bisulfite hypersensitivity. The major side effects associated with its administration include: arrhythmias, angina, nausea and vomiting, hypotension, and changes in ECG readings. (1)
Dobutamine is another common medication given to septic patients. Unlike dopamine, however, dobutamine depicts only an inotropic action. Therapeutically, dobutamine is beneficial in increasing the cardiac output without resulting in a significant heart rate increase. This is extremely beneficial to septic patients that portray tachycardia along with their hypertensive and decreased cardiac output states. Dobutamine is contraindicated in idiopathic hypertrophic subaortic stenosis and hypersensitivity to either dobutamine or bisulfites. Some of the most common and serious side effects associated with dobutamine administration include hypertension, premature ventricular contractions, and tachycardia. (1)
Sepsis is a severe and life-threatening systemic response to a microbe. While there are many available treatments or therapeutic interventions already being done in hospitals, the rate of mortality is continually increasing. In order to make a difference in this negative trend, it is essential that other treatments and opportunities are brought up. The inclusion of non-pharmaceutical therapy is beneficial to add into the course of drugs because of the high incidence of bacteria becoming resisitant.resistant Many attempts have successfully shown poor results in patients with sepsis. contradicting sentence-if they showed poor results how were they successful? I feel like this inclusion of non-pharmaceutical therapy is not needed here, it sounds awkward Treatment needs to remain individualized. It should be focused on the host factor, the most common pathogens for the infected site, and community susceptibility to particular microbes. (9) Even in cases with the administration of packed red blood cells, antibiotics, and fresh plasma, mortality in septicemia is still a huge issue in healthcare. (18) While this paper focuses on bacterial-induced sepsis, gram negative bacteria in particular, it is important to note that sepsis can occur from a variety of microbes. With new technology and expanding research being done, maybe someday healthcare will find the answers to curing sepsis in a standardized way.

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