Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Septic shock is a major cause of death following trauma and a persistent problem in surgical patients. It is a challenge to the critical care medicine specialist and carries an unacceptably high mortality rate, despite adequate antibiotic and vasopressor therapy. The prevalent hypothesis regarding its mechanism is that the syndrome is caused by an excessive defensive and inflammatory response. During the acute phase some signalling mechanisms are activated, particularly hormone release, which function to restore the host homeostasis that has been disturbed by the infection. Since the neuroendocrine and immune systems are functionally related, so the exposure to antigens induces a synchronized response, which allows the organism to successfully endure immunology changes. An important characteristic of this communication includes the appearance of proteins released into the circulation by activated immune cells. These proteins, called cytokines can enter the circulation and reach neuroendocrine organs, where they act either themselves or through the release of intermediates such as prostaglandin, catecholamines and nitric oxide. The synthesis of nitric oxide may be induced in brain as a consequence of infection and may alter the function of the hypothalamic-pituitary axis. In this review we discuss the physiologic roles of the nitric oxide in central nervous system controlling the regulation of vasopressin and oxytocin during the pathophysiology of sepsis.
 ...
PMID:Neuro-immune-endocrine mechanisms during septic shock: role for nitric oxide in vasopressin and oxytocin release. 1678 87

Vasopressin, a neurohypophyseal peptide hormone, is the endogenous agonist at V1a, V1b and V2 receptors. The most important physiological function of vasopressin is the maintenance of water homeostasis through interaction with V2 receptors in the kidney. Vasopressin and related compounds are used in various clinical settings such as acute variceal bleeding associated with portal hypertension, septic shock, diabetes insipidus and coagulation disorders. The effect in the former two indications relates to the V1a receptor, and in the two latter indications the effect relates to the V2 receptor. Vasopressin and related compounds have demonstrated activity in animal models of portal hypertension, sepsis and septic shock, diabetes insipidus and coagulation disorders. The use of the compounds in animal models is reviewed. Generally, the effect of vasopressin and related compounds in animal models reflect the activity in the clinical setting, but in some cases important species differences exist.
 ...
PMID:The effect of vasopressin and related compounds at V1a and V2 receptors in animal models relevant to human disease. 1691 9

Vasopressin, synthesized in the hypothalamus, is released by increased plasma osmolality, decreased arterial pressure, and reductions in cardiac volume. Three subtypes of vasopressin receptors, V1, V2, and V3, have been identified, mediating vasoconstriction, water reabsorption, and central nervous system effects, respectively. Vasopressin and its analogs have been studied intensively for the treatment of states of "relative vasopressin deficiency," such as sepsis, vasodilatory shock, intraoperative hypotension, and cardiopulmonary resuscitation. Infusion of vasopressin (0.01-0.04 U/min) decreases catecholamine requirements in patients with sepsis and other types of vasodilatory shock. Bolus application of 1 mg terlipressin, the V1 agonist, reverses refractory hypotension in anesthetized patients and has been studied in patients with septic shock and chronic liver failure. During cardiopulmonary resuscitation, a 40-U bolus dose of vasopressin may be considered to replace the first or second bolus of epinephrine regardless of the initial rhythm. The side effects of vasopressin and its analogs must be further characterized.
 ...
PMID:The vasopressin system: physiology and clinical strategies. 1741 42

Current therapy of septic/vasodilatory cardiovascular failure includes volume resuscitation and infusion of inotropic and vasopressor agents. Norepinephrine is the first-line vasoconstrictor, and can stabilize hemodynamic variables in most patients. Nonetheless, irreversible cardiovascular failure which is resistant to conventional hemodynamic therapies still is the main cause of death in patients with severe sepsis and septic shock. In such advanced, catecholamine-resistant shock states, arginine-vasopressin (AVP) has repeatedly caused an increase in mean arterial blood pressure, a decrease in toxic norepinephrine-dosages, as well as further beneficial hemodynamic, endocrinologic and renal effects. Although AVP exerted negative inotropic effects in previous clinical trials and in selected animal experiments, a continuous low-dose AVP infusion during advanced septic/vasodilatory shock caused a decrease in cardiac index only in patients with a hyperdynamic circulation. Adverse effects on gastrointestinal circulation and the systemic microcirculation can not be excluded, but have not yet been confirmed in clinical prospective trials. Negative side effects of a supplementary AVP therapy are an increase in total bilirubin concentrations, and a decrease in platelet count. A transient increase in hepatic transaminases during AVP infusion is most likely related to preceding hypotensive episodes. Important points which must be considered when using AVP as a "rescue vasopressor" in septic/vasodilatory shock states are: 1) AVP infusion only in advanced shock states that can not be adequately reversed by conventional hemodynamic therapy (e.g. norepinephrine >0,5-0,6 mug/kg/min), 2) presence of normovolemia, 3) AVP infusion only in combination with norepinephrine, 4) strict avoidance of bolus injections and dosages >4 IU/h. Effects of a supplementary AVP infusion in advanced vasodilatory shock on survival are currently examined in a large, prospective multicenter trial in North America and Australia.
 ...
PMID:[Arginine-vasopressin in septic and vasodilatorial shock]. 1715 83

Clinical and experimental studies with LPS injection have shown an increase in vasopressin (AVP) secretion in the early phase of severe sepsis, which is subsequently reduced despite persistent hypotension. The aim of this study was to evaluate the role of inducible nitric oxide synthase (iNOS)-derived NO in hypothalamic activation and in AVP release during severe sepsis induced by cecal ligation and puncture (CLP). Male Wistar rats received i.p. injections of aminoguanidine, an iNOS inhibitor, or saline 30 min before CLP or sham surgeries (controls). CLP led to increased plasma nitrate levels, protein leakage and hypotension and caused mortality of 80% by 24 h. Expression of c-fos in paraventricular (PVN), supraoptic (SON) and organum vasculosum of lamina terminalis (OVLT) nuclei, as well as plasma AVP concentration were increased at 6 h but reduced to basal levels 24 h after CLP. Aminoguanidine pre-treatment prevented the increase in plasma nitrate levels and hypotension in the first 6 h. It also reduced AVP secretion and hypothalamic c-fos expression. After 24 h, the pre-treatment reduced plasma nitrate levels, protein leakage and caused a partial recovery of c-fos expression in SON and OVLT but did not affect AVP release. Furthermore, mortality was reduced to 43%. We conclude that during the early phase of severe sepsis hypotension caused by the iNOS-derived NO is partially responsible for the hypothalamic activation and AVP release. In the late phase, however, the iNOS-derived NO prevents brain activation blunting AVP secretion contributing to hypotension, irreversible shock and animal death.
 ...
PMID:Participation of iNOS-derived NO in hypothalamic activation and vasopressin release during polymicrobial sepsis. 1717 80

The use of catecholamines to defend and resuscitate patients with septic shock remains a cornerstone of intensive care medicine. The pharmacological support of the failing circulation during sepsis and septic shock should be directed at augmenting perfusion of vital organs and facilitating venous return, rather than peripheral arterial vasoconstriction. There appears to be a teleological rationale for primary use of catecholamines to augment failing endogenous neurohumoral and neuroendocrine cardiovascular systems. To this end, it seems intuitive to use the predominant naturally occurring catecholamine, noradrenaline, as the first-line agent for circulatory failure, although there are no definitive clinical trials to support this. Adrenaline has an established place in many parts of the world, particularly low-income countries, and appears to be equivalent to noradrenaline for reversing septic shock. There is increasing evidence for adverse neuroendocrine and immunological effects of dopamine, warranting circumspection about its use. The use of synthetic inotropes and vasopressors for septic shock remains limited, with little biological rationale. Clinicians should wait for definitive outcome-based trials of these expensive agents before incorporating them into practice. Supplemental endocrine replacement therapy with low-dose corticosteroids and vasopressin appears biologically plausible and has an emerging role. Results of large-scale, high-quality trials of endogenous catecholamines for sepsis and septic shock are awaited. These may provide additional, important information for evidence-based guidelines, which currently remain of limited clinical utility.
 ...
PMID:An appraisal of selection and use of catecholamines in septic shock - old becomes new again. 1722 75

The severe impairment of the microcirculation plays a substantial role in the pathogenesis of severe sepsis and septic shock, and leads to multiple organ failure and death. Therapeutic strategies to resuscitate the microcirculatory blood flow and to improve the functional capillar density are therefore essential to surmount the microcirculatory pathology and to avoid tissue hypoxia. Based on reasonable scientific evidence, early fluid resuscitation directed by defined haemodynamic and metabolic goals (EGDT) as well as the application of activated protein C (rhAPC) according to the guidelines could be recommended. Dobutamine is the first choice to improve cardiac output and to overcome myocardial depression in septic shock whereas phosphodiesterase-III-inhibitors and levosimendane are still experimental options. Furthermore selective inhibitors of iNOS, nitroglycerol, as well as vasopressin have to be investigated relating to their specific effects on the microcirculation and their influence on survival in seevere sepsis and septic shock.
 ...
PMID:[Therapeutic options to improve the microcirculation in sepsis and septic shock]. 1727 78

Severely septic patients continue to experience excessive morbidity and mortality despite recent advances in critical care. Although significant resources have been invested in new treatments, almost all have failed to improve outcomes. An improved understanding of sepsis pathophysiology, including the complex interactions between inflammatory, coagulation, and fibrinolytic systems, has accelerated the development of novel treatments. Recombinant human activated protein C (rhAPC), or drotrecogin alfa (activated) (DAA), is currently the only US Food and Drug Administration (FDA)-approved medicine for the treatment of severe sepsis, and only in patients with a high risk of death. This review will discuss the treatment of severe sepsis, focusing on recent discoveries and unresolved questions about DAA's optimal use. Increasing pharmacological experience has generated enthusiasm for investigating medicines already approved for other indications as treatments for severe sepsis. Replacement doses of hydrocortisone and vasopressin may reduce mortality and improve hypotension, respectively, in a subgroup of patients with catecholamine-refractory septic shock. In addition to discussing these new indications, this review will detail the provocative preliminary data from four promising treatments, including two novel modalities: antagonizing high mobility group box protein and inhibiting tissue factor (TF). Observational data from the uncontrolled administration of heparin or statins in septic patients will also be reviewed.
 ...
PMID:Treatment of severe sepsis: where next? Current and future treatment approaches after the introduction of drotrecogin alfa. 1731 65

At present, the clinical management inflammatory vasoplegia associated to sepsis or anaphylaxis is symptomatic. Volume is expanded by means of administration of fluids, and low blood pressure is managed by means of administration of positive inotropes and vasoconstrictors. This therapeutic approach is mainly associated to the cyclic AMP (cAMP) and, many times the circulatory shock is refractory to high amines concentrations. However, beside of cAMP-dependent vasoreactivity mechanisms there are other two known vasoplegia involved mechanisms: cyclic GMP (cGMP) and hyperpolarization that is less clinically considered. Also, it is possible to speculate about 'probable vasopressin deficiency'. Methylene blue (MB) is the most useful and clinically safe cGMP blocker. We propose a decision tree for diagnosis and institution of this therapeutical approach many times underestimate by intensive care and emergency teams.
 ...
PMID:Is the cyclic GMP system underestimated by intensive care and emergency teams? 1736 82

Arginine vasopressin (AVP) levels are increased in hemorrhagic and septic shock. Measurement of AVP levels has limitations due to its short half-life and cumbersome detection method. Copeptin is a more stable peptide derived from the same precursor molecule. We evaluated the plasma copeptin concentration in two independent studies: first, in an experimental baboon model of hemorrhagic shock, and second, in a prospective observational study of 101 consecutive critically ill patients at a university hospital. Copeptin was measured with a newly developed sandwich immunoassay using two polyclonal antibodies to the C-terminal region (amino acid sequence 132-164) of pre-pro-AVP. Copeptin concentrations in hemorrhagic shock increased markedly from median (range) of 7.5 [2.7-13) to 269 pM (241-456 pM). After reperfusion, copeptin levels dropped within hours to a plateau of 27 pM (15-78 pM). In the critically ill patient cohort, copeptin values increased significantly with the severity of the disease and were in patients without sepsis [27.6 pM [2.3-297 pM]), in sepsis [50.0 pM [8.5-268 pM]), in severe sepsis [73.6 pM [15.3-317 pM]), and in septic shock [171.5 pM (35.1-504 pM] compared with 4.1 pM (1.0-13.8 pM) in healthy controls (P for all vs. controls <0.001). On admission, circulating copeptin levels were higher in nonsurvivors (171.5 pM, 46.5-504.0 pM) as compared with survivors (86.8 pM, 8.5-386.0 pM; P = 0.01). Copeptin levels correlated with basal cortisol levels (r = 0.42; P < 0.001) and osmolality (r = 0.42; P < 0.001). In a logistic regression model including other covariates besides copeptin (e.g., determinants of fluid status) on survival, serum copeptin levels were the only independent significant predictor of outcome (P = 0.03). Copeptin concentrations are elevated in hemorrhagic and septic shock. Copeptin was higher on admission in nonsurvivors as compared with survivors, suggesting copeptin as a prognostic marker in sepsis. The availability of a reliable assay for the measurement of AVP release can also prove useful for the assessment of fluid and osmosis status in various diseases.
 ...
PMID:Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. 1751 50


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>