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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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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.
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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.
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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.
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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.
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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.
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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.
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PMID:Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. 1751 50

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng.kg-1.min-1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.
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PMID:Continuous versus bolus infusion of terlipressin in ovine endotoxemia. 1758 82

Acute renal failure during human sepsis is often nonoliguric. To study the underlying mechanisms, renal function was assessed in endotoxic and control male Wistar rats during and after saline loading and treatment with the selective V2 receptor agonist desmopressin. Escherichia coli endotoxin (dose, 8 mg/kg) was administered from time (t)=0 to t=60 min; saline loading (rate, 5 mL/100 g per hour) was administered from t=0 to t=120 min. Thereafter, half of each group received desmopressin (dose, 10 microg) for 1 h. The inner medullary (IM) osmolality, hematocrit, plasma, and urinary concentrations of sodium, potassium, urea, and osmolality were measured; then, aquaporin 2 (AQP2) immunohistochemistry was performed. Plasma vasopressin concentrations were measured at t=180 min. Saline loading increased urine volume in all rats. In the endotoxic group, mean arterial pressure decreased when saline loading was stopped. Despite increased hematocrit and vasopressin levels (>16 pg/mL), the endotoxin group had a low IM osmolality (mean +/- SEM, 412+/-0.04 mOsm/kg H2O) in comparison with the control group (mean +/- SEM, 1,094+/-0.17 mOsm/kg H2O) and was not able to either decrease urine volume or raise urine osmolality. Desmopressin treatment in endotoxin-treated rats maintained mean arterial pressure, increased sodium reabsorption, IM osmolality, and urine osmolality, and decreased urine flow. The AQP2 intensity decreased in the endotoxin group, and the apical localization disappeared; both were not affected by desmopressin. Our results indicate that endotoxemia in rats acutely diminishes renal urinary concentration capacity and is associated with a decreased IM osmolality and diminished apical AQP2 localization. These findings may help to explain nonoliguric acute renal failure in human septic shock.
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PMID:Mechanisms of the urinary concentration defect and effect of desmopressin during endotoxemia in rats. 1769 23

Volatile anesthetics such as isoflurane have been shown to offer anti-inflammatory effects during experimental endotoxemia whereas the alpha-adrenergic vasopressor norepinephrine exhibits proinflammatory properties on systemic cytokine release under the same conditions. However, during major surgery and in patients with systemic inflammatory response syndrome or sepsis both agents are frequently administered concurrently. We therefore aimed to investigate the influence of preexisting i.v. administration of noradrenaline or vasopressin on the anti-inflammatory effects of isoflurane during experimental endotoxemia. Anesthetized, ventilated Sprague-Dawley rats (n=7 per group) were randomly treated. In the LPS-only group, animals received lipopolysaccharide (LPS, 5 mg/kg, i.v.) with no further specific treatment. In the LPS-isoflurane group, isoflurane inhalation at 1 MAC was initiated simultaneously with induction of endotoxemia (LPS 5 mg/kg, i.v.). Animals in the LPS-isoflurane-norepinephrine group received norepinephrine infusion at 50 microg/kg/h 10 min prior to injection of LPS and inhalation of isoflurane. In the LPS-isoflurane-vasopressin group, vasopressin was administered at 0.5 IE/kg/h 10 min prior to LPS and isoflurane. In the LPS-norepinephrine and the LPS-vasopressin groups the infusion of each vasopressor was started prior to LPS injection without any application of isoflurane. A Sham group served as the control. After 4 h of endotoxemia, plasma levels of TNFalpha, IL-1beta and IL-10 were measured. Alveolar macrophages (AM) were cultured ex vivo for nitrite assay. Induction of endotoxemia resulted in a significant rise in measured plasma cytokines and nitrite production from cultured AM. Inhalation of isoflurane significantly attenuated plasma levels of TNFalpha (-65%) and IL-1beta (-53%) compared to the LPS-only group whereas it had no effect on nitrite production from cultured AM. Preexisting infusions of norepinephrine or vasopressin abolished the anti-inflammatory effects of isoflurane. The data demonstrate that the administration of norepinephrine or vasopressin both counteracted the anti-inflammatory effects of inhaled isoflurane on proinflammatory cytokine release during experimental endotoxemia in rats.
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PMID:Norepinephrine and vasopressin counteract anti-inflammatory effects of isoflurane in endotoxemic rats. 1778 93


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