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James A Russell - One of the best experts on this subject based on the ideXlab platform.
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selepressin a novel selective vasopressin v1a agonist is an effective substitute for Norepinephrine in a phase iia randomized placebo controlled trial in septic shock patients
Critical Care, 2017Co-Authors: James A Russell, Jean Louis Vince, Anne Louise Kjolbye, Haka Olsso, Alla Lemings, Herbe D Spape, Pede Carl, Pierrefrancois Laterre, Lars GrundemaAbstract:Vasopressin is widely used for vasopressor support in septic shock patients, but experimental evidence suggests that selective V1A agonists are superior. The initial pharmacodynamic effects, pharmacokinetics, and safety of selepressin, a novel V1A-selective vasopressin analogue, was examined in a phase IIa trial in septic shock patients. This was a randomized, double-blind, placebo-controlled multicenter trial in 53 patients in early septic shock (aged ≥18 years, fluid resuscitation, requiring vasopressor support) who received selepressin 1.25 ng/kg/minute (n = 10), 2.5 ng/kg/minute (n = 19), 3.75 ng/kg/minute (n = 2), or placebo (n = 21) until shock resolution or a maximum of 7 days. If mean arterial pressure (MAP) ≥65 mmHg was not maintained, open-label Norepinephrine was added. Co-primary endpoints were maintenance of MAP >60 mmHg without Norepinephrine, Norepinephrine dose, and proportion of patients maintaining MAP >60 mmHg with or without Norepinephrine over 7 days. Secondary endpoints included cumulative fluid balance, organ dysfunction, pharmacokinetics, and safety. A higher proportion of the patients receiving 2.5 ng/kg/minute selepressin maintained MAP >60 mmHg without Norepinephrine (about 50% and 70% at 12 and 24 h, respectively) vs. 1.25 ng/kg/minute selepressin and placebo (p < 0.01). The 7-day cumulative doses of Norepinephrine were 761, 659, and 249 μg/kg (placebo 1.25 ng/kg/minute and 2.5 ng/kg/minute, respectively; 2.5 ng/kg/minute vs. placebo; p < 0.01). Norepinephrine infusion was weaned more rapidly in selepressin 2.5 ng/kg/minute vs. placebo (0.04 vs. 0.18 μg/kg/minute at 24 h, p < 0.001), successfully maintaining target MAP and reducing Norepinephrine dose vs. placebo (first 24 h, p < 0.001). Cumulative net fluid balance was lower from day 5 onward in the selepressin 2.5 ng/kg/minute group vs. placebo (p < 0.05). The selepressin 2.5 ng/kg/minute group had a greater proportion of days alive and free of ventilation vs. placebo (p < 0.02). Selepressin (2.5 ng/kg/minute) was well tolerated, with a similar frequency of treatment-emergent adverse events for selepressin 2.5 ng/kg/minute and placebo. Two patients were infused at 3.75 ng/kg/minute, one of whom had the study drug infusion discontinued for possible safety reasons, with subsequent discontinuation of this dose group. In septic shock patients, selepressin 2.5 ng/kg/minute was able to rapidly replace Norepinephrine while maintaining adequate MAP, and it may improve fluid balance and shorten the time of mechanical ventilation. ClinicalTrials.gov, NCT01000649 . Registered on September 30, 2009.
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vasopressin compared with Norepinephrine augments the decline of plasma cytokine levels in septic shock
American Journal of Respiratory and Critical Care Medicine, 2013Co-Authors: James A Russell, Chris Fjell, Joe L Hsu, Terry Lee, Joh H Oyd, Simone Thai, Joel Singe, Andrew J Patterso, Keith R WalleyAbstract:Rationale: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus Norepinephrine) could change plasma cytokine levels in early septic shock. Objectives: Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and Norepinephrine on plasma cytokine levels in septic shock. Methods:Westudied394patientsinarandomized,controlledtrialof vasopressin versus Norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus Norepinephrine-induced changes in cytokine levels over 24 hours. Measurements and Main Results: A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P , 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with Norepinephrine (P ¼ 0.037). In less
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vasopressin versus Norepinephrine infusion in patients with septic shock
The New England Journal of Medicine, 2008Co-Authors: James A Russell, Joel Singe, Keith R Walley, Anthony C Gordo, Paul C Hebe, James D Coope, Cheryl L Holmes, Sangeeta Mehta, Joh T Granto, Michelle StormsAbstract:Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with Norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. Methods In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 μg of Norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or Norepinephrine (5 to 15 μg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions. Results A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 Norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and Norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P = 0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P = 0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P = 1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the Norepinephrine group at 28 days (26.5% vs. 35.7%, P = 0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P = 0.76). A test for heterogeneity between these two study strata was not significant (P = 0.10). Conclusions Low-dose vasopressin did not reduce mortality rates as compared with Norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869.)
Keith R Walley - One of the best experts on this subject based on the ideXlab platform.
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vasopressin compared with Norepinephrine augments the decline of plasma cytokine levels in septic shock
American Journal of Respiratory and Critical Care Medicine, 2013Co-Authors: James A Russell, Chris Fjell, Joe L Hsu, Terry Lee, Joh H Oyd, Simone Thai, Joel Singe, Andrew J Patterso, Keith R WalleyAbstract:Rationale: Changes in plasma cytokine levels may predict mortality, and therapies (vasopressin versus Norepinephrine) could change plasma cytokine levels in early septic shock. Objectives: Our hypotheses were that changes in plasma cytokine levels over 24 hours differ between survivors and nonsurvivors, and that there are different effects of vasopressin and Norepinephrine on plasma cytokine levels in septic shock. Methods:Westudied394patientsinarandomized,controlledtrialof vasopressin versus Norepinephrine in septic shock. We used hierarchical clustering and principal components analysis of the baseline cytokine concentrations to subgroup cytokines; we then compared survivors to nonsurvivors (28 d) and compared vasopressin- versus Norepinephrine-induced changes in cytokine levels over 24 hours. Measurements and Main Results: A total of 39 plasma cytokines were measured at baseline and at 24 hours. Hierarchical clustering and principal components analysis grouped cytokines similarly. Survivors (versus nonsurvivors) had greater decreases of overall cytokine levels (P , 0.001). Vasopressin decreased overall 24-hour cytokine concentration compared with Norepinephrine (P ¼ 0.037). In less
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vasopressin versus Norepinephrine infusion in patients with septic shock
The New England Journal of Medicine, 2008Co-Authors: James A Russell, Joel Singe, Keith R Walley, Anthony C Gordo, Paul C Hebe, James D Coope, Cheryl L Holmes, Sangeeta Mehta, Joh T Granto, Michelle StormsAbstract:Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with Norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. Methods In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 μg of Norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or Norepinephrine (5 to 15 μg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions. Results A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 Norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and Norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P = 0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P = 0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P = 1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the Norepinephrine group at 28 days (26.5% vs. 35.7%, P = 0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P = 0.76). A test for heterogeneity between these two study strata was not significant (P = 0.10). Conclusions Low-dose vasopressin did not reduce mortality rates as compared with Norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869.)
Xavie Monne - One of the best experts on this subject based on the ideXlab platform.
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effects of Norepinephrine on mean systemic pressure and venous return in human septic shock
Critical Care Medicine, 2012Co-Authors: Romai Persichini, Serena Silva, Jeanlouis Teboul, Mathieu Jozwiak, Denis Chemla, Christia Richard, Xavie MonneAbstract:Objectives: Norepinephrine exerts venoconstriction that could increase both the mean systemic pressure and the resistance to venous return, but this has not yet been investigated in human septic shock. We examined the relative importance of both effects and the resulting effect on venous return when decreasing the dose of Norepinephrine. Setting: Intensive care unit. Patients: Sixteen septic shock patients. Measurements: For estimating the venous return curve, we constructed the regression line between the pairs of cardiac index (pulse contour analysis) and central venous pressure values. These values were measured during 15-sec end-inspiratory and end-expiratory ventilatory occlusions performed at two levels of positive end-expiratory pressure, in view of widening the range of cardiac index:central venous pressure measurements and increasing the accuracy of the regression line. The x-axis intercept of the regression line was used to estimate the mean systemic pressure and the inverse of the slope of the regression line to quantify resistance to venous return. These measurements were obtained before and after decreasing the dose of Norepinephrine. Passive leg raising was performed before and after decreasing the dose of Norepinephrine. Main Results: Decreasing the dose of Norepinephrine from 0.30 (0.10–1.40) to 0.19 (0.08–1.15) µg/kg/min decreased the mean systemic pressure from 33 ± 12 mm Hg to 26 ± 10 mm Hg (p = .0003). The slope of the multipoint cardiac index:central venous pressure relationship increased (p = .02). The resistance to venous return decreased, i.e., 1/slope decreased. Simultaneously, cardiac index decreased from 3.47 ± 0.86 L/min/m2 to 3.28 ± 0.76 L/min/m2 (p = .04), indicating a decrease in venous return. Passive leg raising increased cardiac index to a larger extent after (8% ± 4%) than before (1% ± 4%) decreasing Norepinephrine (p = .001), suggesting an increase in unstressed blood volume at the lowest dose of Norepinephrine. Conclusions: In septic shock patients, decreasing the dose of Norepinephrine decreased the mean systemic pressure and, to a lesser extent, the resistance to venous return. As a result, venous return decreased.
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third generation flotrac vigileo does not reliably track changes in cardiac output induced by Norepinephrine in critically ill patients
BJA: British Journal of Anaesthesia, 2012Co-Authors: Xavie Monne, Christia Richard, Mathieu Jozwiak, Nadia Anguel, Jeanlouis TeboulAbstract:Background The ability of the third-generation FloTrac/Vigileo software to track changes in cardiac index (CI) induced by volume expansion and Norepinephrine in critically ill patients is unknown. Methods In subjects with circulatory failure, we administered volume expansion (20 subjects) and increased (20 subjects) or decreased (20 subjects) the dose of Norepinephrine. We measured arterial pressure waveform-derived CI provided by the third-generation FloTrac/Vigileo device (CIpw) and transpulmonary thermodilution CI (CItd) before and after therapeutic interventions. Results Considering the pairs of measurements performed before and after all therapeutic interventions (n=60), a bias between the absolute values of CIpw and CItd was 0.26 (0.94) litre min−1 m−2 and the percentage error was 54%. Changes in CIpw tracked changes in CItd induced by volume expansion with moderate accuracy [n=20, bias=−0.11 (0.54) litre min−1 m−2, r2=0.26, P=0.02]. When changes in CItd were induced by Norepinephrine (n=40), a bias between CIpw and CItd was 0.01 (0.41) litre min−1 m−2 (r2=0.11, P=0.04). The concordance rates between changes in CIpw and CItd induced by volume expansion and Norepinephrine were 73% and 60%, respectively. The bias between changes in CIpw and CItd significantly correlated with changes in total systemic vascular resistance (r2=0.41, P Conclusions The third-generation FloTrac/Vigileo device was moderately reliable for tracking changes in CI induced by volume expansion and poorly reliable for tracking changes in CI induced by Norepinephrine.
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early administration of Norepinephrine increases cardiac preload and cardiac output in septic patients with life threatening hypotension
Critical Care, 2010Co-Authors: Olfa Hamzaoui, Christia Richard, Xavie Monne, Jeanfrancois George, Hatem Ksouri, Julie Maizel, Jeanlouis TeboulAbstract:Introduction: We sought to examine the cardiac consequences of early administration of Norepinephrine in severely hypotensive sepsis patients hospitalized in a medical intensive care unit of a university hospital. Methods: We included 105 septic-shock patients who already had received volume resuscitation. All received Norepinephrine early because of life-threatening hypotension and the need to achieve a sufficient perfusion pressure rapidly and to maintain adequate flow. We analyzed the changes in transpulmonary thermodilution variables associated with the increase in mean arterial pressure (MAP) induced by Norepinephrine when the achieved MAP was ≥65 mm Hg. Results: Norepinephrine significantly increased MAP from 54 ± 8 to 76 ± 9 mm Hg, cardiac index (CI) from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m 2 , stroke volume index (SVI) from 34 ± 12 to 39 ± 13 ml/m 2 , global end-diastolic volume index (GEDVI) from 694 ± 148 to 742 ± 168 ml/m 2 , and cardiac function index (CFI) from 4.7 ± 1.5 to 5.0 ± 1.6 per min. Beneficial hemodynamic effects on CI, SVI, GEDVI, and CFI were observed in the group of 71 patients with a baseline echocardiographic left ventricular ejection fraction (LVEF) >45%, as well as in the group of 34 patients with a baseline LVEF ≤45%. No change in CI, SVI, GEDVI, or CFI was observed in the 17 patients with baseline LVEF ≤45% for whom values of MAP ≥75 mm Hg were achieved with Norepinephrine. Conclusions: Early administration of Norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility. This effect remained in patients with poor cardiac contractility except when values of MAP ≥75 mm Hg were achieved.
Kim S Khaw - One of the best experts on this subject based on the ideXlab platform.
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randomized double blinded comparison of Norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for cesarean delivery
Anesthesiology, 2015Co-Authors: Warwick Nga D Kee, Shara W Y Lee, Kim S KhawAbstract:Background During spinal anesthesia for cesarean delivery, phenylephrine can cause reflexive decreases in maternal heart rate and cardiac output. Norepinephrine has weak β-adrenergic receptor agonist activity in addition to potent α-adrenergic receptor activity and therefore may be suitable for maintaining blood pressure with less negative effects on heart rate and cardiac output compared with phenylephrine. Methods In a randomized, double-blinded study, 104 healthy patients having cesarean delivery under spinal anesthesia were randomized to have systolic blood pressure maintained with a computer-controlled infusion of Norepinephrine 5 μg/ml or phenylephrine 100 μg/ml. The primary outcome compared was cardiac output. Blood pressure heart rate and neonatal outcome were also compared. Results Normalized cardiac output 5 min after induction was greater in the Norepinephrine group versus the phenylephrine group (median 102.7% [interquartile range, 94.3 to 116.7%] versus 93.8% [85.0 to 103.1%], P = 0.004, median difference 9.8%, 95% CI of difference between medians 2.8 to 16.1%). From induction until uterine incision, for Norepinephrine versus phenylephrine, systolic blood pressure and stroke volume were similar, heart rate and cardiac output were greater, systemic vascular resistance was lower, and the incidence of bradycardia was smaller. Neonatal outcome was similar between groups. Conclusions When given by computer-controlled infusion during spinal anesthesia for cesarean delivery, Norepinephrine was effective for maintaining blood pressure and was associated with greater heart rate and cardiac output compared with phenylephrine. Further work would be of interest to confirm the safety and efficacy of Norepinephrine as a vasopressor in obstetric patients.
David Robertso - One of the best experts on this subject based on the ideXlab platform.
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orthostatic intolerance and tachycardia associated with Norepinephrine transporter deficiency
The New England Journal of Medicine, 2000Co-Authors: Joh R Shanno, Nancy Flattem, Giris Jacob, Jens Jorda, Onnie K Lack, Italo Iaggioni, Randy D Lakely, David RobertsoAbstract:Background Orthostatic intolerance is a syndrome characterized by lightheadedness, fatigue, altered mentation, and syncope and associated with postural tachycardia and plasma Norepinephrine concentrations that are disproportionately high in relation to sympathetic outflow. We tested the hypothesis that impaired functioning of the Norepinephrine transporter contributes to the pathophysiologic mechanism of orthostatic intolerance. Methods In a patient with orthostatic intolerance and her relatives, we measured postural blood pressure, heart rate, plasma catecholamines, and systemic Norepinephrine spillover and clearance, and we sequenced the Norepinephrine-transporter gene and evaluated its function. Results The patient had a high mean plasma Norepinephrine concentration while standing, as compared with the mean (±SD) concentration in normal subjects (923 vs. 439±129 pg per milliliter [5.46 vs. 2.59±0.76 nmol per liter]), reduced systemic Norepinephrine clearance (1.56 vs. 2.42±0.71 liters per minute), impa...
