Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many advances have improved the care of critically ill patients, but only a few have been through the use of pharmaceutical agents. Recently, the US Food and Drug Administration (FDA) approved drotrecogin alfa (activated), or recombinant human activated protein C, for the treatment of patients with a high risk of death from severe sepsis. Drotrecogin alfa (activated) has antiinflammatory, antithrombotic and fibrinolytic properties. When given as a continuous intravenous infusion, recombinant human activated protein C decreases absolute mortality of severely septic patients by 6.1%, resulting in a 19.4% relative reduction in mortality. The absolute reduction in mortality increases to 13% if the population treated is restricted to patients with an APACHE II score greater than 24, as suggested by the FDA. The most frequent and serious side effect is bleeding. Severe bleeds increased from 2% in patients given placebo to 3.5% in patients receiving drotrecogin alfa (activated). The risk of bleeding was only increased during the actual infusion time of the drug, and the bleeding risk returned to placebo levels 24 hours after the infusion was discontinued. Patients treated in the intensive care unit frequently develop anemia, usually severe enough to require at least one transfusion of red blood cells. With the recent discovery of the harmful effects of allogeneic red blood cell transfusions and the increasing shortage of available red blood cell products, emphasis has been placed on minimizing transfusions. Patients who receive exogenous recombinant human erythropoietin maintain higher hemoglobin levels, in spite of requiring fewer transfusions during their stay in the intensive care unit. Recombinant human erythropoietin appears to be effective whether it is given as 300 units/kg of body weight subcutaneously every other day or as 40,000 units subcutaneously every week. Differences in hemoglobin values were not apparent until at least one week of therapy, but they continued to diverge after that initial week. Furthermore, the incidence of adverse events was similar to that of patients receiving placebo and there was no difference in mortality, suggesting that avoidance of blood transfusions did not translate into increased survival. Thus, recombinant human erythropoietin appears to be both safe and effective in treating the anemia found in critically ill patients, but it is less clear that such treatment is cost effective, especially in the higher dose regimens. Hypotension in patients with septic shock is often difficult to correct. Despite enormous dosages of catecholamines, many of these patients continue to have inadequate blood pressures. Inadequate levels of vasopressin have been identified in patients with septic shock, as well as in other patients with hypotension secondary to refractory vasodilatation. Vasopressin is a peptide hormone secreted from the posterior pituitary in response to hyperosmolality, hypovolemia or hypotension. Levels of vasopressin initially rise in patients with septic shock, but as hypotension persists, vasopressin levels fall below normal. Administration of exogenous vasopressin in physiologic dosages significantly increases blood pressure in patients with shock associated with sepsis and other vasodilatory states. This rise in blood pressure is often significant enough that endogenous catecholamines can be decreased and frequently discontinued entirely. Early withdrawal of the vasopressin replacement infusion results in recurrent hypotension. Unfortunately, randomized, blinded, placebo-controlled trials showing improvement in long-term outcomes such as mortality and length of stay are still lacking.
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PMID:New additions to the intensive care armamentarium. 1504 37

The medical consultant should have a high index of suspicion for sepsis. Early goal-directed therapy is recommended and includes early, aggressive fluid resuscitation, antibiotics, and vasoactive agents, if needed. CVO2 may be helpful in guiding therapy, but targeting supranormal levels of oxygen delivery is not necessary. Empiric use of steroids and early use of activated protein C also need to be considered. Vasopressin should be considered if hypotension persists or if the situation requires escalating doses of norepinephrine.
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PMID:Septic shock in the postoperative patient: three important management decisions. 1684 72

This is a review of the management of septic shock that suggests an approach to treatment (ABCDEF: Airway, Breathing, Circulation, Drugs, Evaluate the source of sepsis, Fix the source of sepsis) for clinicians. The incidence of septic shock is increasing and mortality ranges from 30% to 70%. The commonest sources of infection are lung (25%), abdomen (25%), and other sources. Septic shock occurs because of highly complex interactions between the infecting microorganism(s) and the responses of the human host. The innate immune response is rapidly followed by the more specific adaptive immune response. Septic shock is characterized by alterations in the coagulant/anticoagulant balance such that there is a more pro-coagulant phenotype. Lung protective ventilation (which means the use of relatively low tidal volumes of 4 -6 mL/kg ideal body weight) is recommended for treatment of patients who have septic shock. Rivers early goal-directed therapy is recommended because it showed a significant increase in survival. Surviving Sepsis guidelines recommend resuscitation of septic shock with either crystalloid or colloid. Patients who have septic shock should be treated with intravenous broad-spectrum antibiotics as rapidly as possible and certainly within one hour. Activated protein C (APC) is a vitamin K dependent serine protease that is an anticoagulant and is also cytoprotective and anti-inflammatory. APC (24 mg/kg/hour infusion for 96 hours) decreased mortality (APC 25% vs placebo 31%, relative risk 0.81P=0.005) and improved organ dysfunction in patients at high risk of death (e.g. APACHE II >25 [APC 31% vs placebo 44%]). APC is not recommended to treat surgical patients who have one organ system dysfunction. In 2006, the European regulatory authority indicated that there must be another randomized placebo-controlled trial of APC to further establish efficacy as assessed by mortality reduction. Vasopressin is a key stress hormone in response to hypotension. The VASST study was a randomized trial of vasopressin versus norepinephrine in septic shock. There was no difference in mortality between vasopressin versus norepinephrine-treated patients (35% versus 39% respectively). In patients who had less severe septic shock, patients treated with vasopressin may have lowered mortality compared with norepinephrine (26% vs 36%). Annane et al. found that hydrocortisone plus fludrocortisone (compared to placebo) was associated with lower mortality in patients who had an inadequate response to corticotropin stimulation test (mortality 53% vs 63% respectively). Sprung et al. did a randomized controlled trial of hydrocortisone (50 mg intravenously every 6 hours) compared to placebo (CORTICUS) to address lingering questions regarding the Annane trial. There was no difference in mortality (39.2% hydrocortisone vs 36.1%) or organ dysfunction. Several randomized controlled trials of intensive insulin versus conventional insulin in the critically ill have yielded conflicting results and do not support the routine use of intensive insulin in the ancillary management of septic shock. A recent randomized controlled trial of intensive versus less intensive renal support in patients who had acute kidney injury found no difference in mortality (53.6% vs 51.5% respectively), duration of renal support, or rates of recovery of renal and non-renal organ dysfunction.
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PMID:The current management of septic shock. 1897 11

The hemodynamics of septic shock is characterized by a primary reduction of vascular tone, which defines vasoplegia. Septic vasoplegia is due to reduced endogenous production of vasopressin, as well as to the overproduction of vasodilating molecules (nitric oxide, prostacyclin, peroxynitrite and kynurenine) and the opening of ATP-sensitive potassium channels. Treatment is supportive and includes primarily alpha-adrenergic catecholamines. Vasopressin may also be useful, although its place is still controversial. Further agents can improve the vascular responsiveness to catecholamines, most notably low doses hydrocortisone, and, to a lesser extent, activated protein C. Further, innovative therapies, based on recent understanding of pathophysiological mechanisms, might become useful agents to treat septic vasoplegia in the future.
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PMID:[Pathophysiological mechanisms and treatment of septic shock-induced vasoplegia]. 2227 61