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Robert S. Sheldon - One of the best experts on this subject based on the ideXlab platform.

  • Fludrocortisone for the Prevention of Vasovagal Syncope: A Randomized, Placebo-Controlled Trial.
    Journal of the American College of Cardiology, 2016
    Co-Authors: Robert S. Sheldon, Satish R. Raj, M. Sarah Rose, Carlos A. Morillo, Andrew D. Krahn, Eduardo Medina, Mario Talajic, Teresa Kus, Colette M. Seifer, Małgorzata Lelonek
    Abstract:

    Abstract Background There is limited evidence whether being on Fludrocortisone prevents vasovagal syncope. Objectives The authors sought to determine whether treatment with Fludrocortisone reduces the proportion of patients with recurrent vasovagal syncope by at least 40%, representing a pre-specified minimal clinically important relative risk reduction. Methods The multicenter POST 2 (Prevention of Syncope Trial 2) was a randomized, placebo-controlled, double-blind trial that assessed the effects of Fludrocortisone in vasovagal syncope over a 1-year treatment period. All patients had >2 syncopal spells and a Calgary Syncope Symptom Score >−3. Patients received either Fludrocortisone or matching placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily. The main outcome measure was the first recurrence of syncope. Results The authors randomized 210 patients (71% female, median age 30 years) with a median 15 syncopal spells over a median of 9 years equally to Fludrocortisone or placebo. Of these, 96 patients had ≥1 syncope recurrences, and only 14 patients were lost to follow-up before syncope recurrence. There was a marginally nonsignificant reduction in syncope in the Fludrocortisone group (hazard ratio [HR]: 0.69: 95% confidence interval [CI]: 0.46 to 1.03; p = 0.069). In a multivariable model, Fludrocortisone significantly reduced the likelihood of syncope (HR: 0.63; 95% CI: 0.42 to 0.94; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to Fludrocortisone (HR: 0.51; 95% CI: 0.28 to 0.89; p = 0.019). Conclusions The study did not meet its primary objective of demonstrating that Fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%. The study demonstrated a significant effect after dose stabilization, and there were significant findings in post hoc multivariable and on-treatment analyses. (A randomised clinical trial of Fludrocortisone for the prevention of vasovagal syncope; ISRCTN51802652 ; Prevention of Syncope Trial 2 [POST 2]; NCT00118482 )

  • the second prevention of syncope trial post ii a randomized clinical trial of Fludrocortisone for the prevention of neurally mediated syncope rationale and study design
    American Heart Journal, 2006
    Co-Authors: Satish R. Raj, Sarah Rose, Deborah Ritchie, Robert S. Sheldon
    Abstract:

    Background Neurally mediated syncope is a common and frequently distressing problem. It is associated with a poor quality of life, which improves when the frequency of syncope is reduced. Few therapies for neurally mediated syncope have been proven effective. Fludrocortisone is commonly used to prevent recurrences of syncope but with little evidence to support its use. A placebo-controlled clinical trial of Fludrocortisone for the prevention of neurally mediated syncope is needed. Structure of Study POST II is a multicenter, international, randomized, placebo-controlled study of Fludrocortisone in the prevention of neurally mediated syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive Fludrocortisone 0.05 to 0.2 mg or matching placebo and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. Power Calculations Assuming a 40% risk of syncope in the control arm, a relative reduction of 40% by Fludrocortisone, and a dropout rate of 20%, the enrollment of 310 patients will give an 80% power of reaching a positive conclusion about Fludrocortisone therapy, with P = .05. Registration POST II is registered with both www.controlled-trials.com (ISRCTN 51802652) and www.clinicaltrials.gov (NCT00118482). Implications This study will be the first adequately powered trial to determine whether Fludrocortisone is effective in preventing neurally mediated syncope. If it is effective, then Fludrocortisone may become the first-line medical therapy for this condition.

  • The Second Prevention of Syncope Trial (POST II)—a randomized clinical trial of Fludrocortisone for the prevention of neurally mediated syncope: Rationale and study design
    American Heart Journal, 2006
    Co-Authors: Satish R. Raj, Sarah Rose, Deborah Ritchie, Robert S. Sheldon
    Abstract:

    Background Neurally mediated syncope is a common and frequently distressing problem. It is associated with a poor quality of life, which improves when the frequency of syncope is reduced. Few therapies for neurally mediated syncope have been proven effective. Fludrocortisone is commonly used to prevent recurrences of syncope but with little evidence to support its use. A placebo-controlled clinical trial of Fludrocortisone for the prevention of neurally mediated syncope is needed. Structure of Study POST II is a multicenter, international, randomized, placebo-controlled study of Fludrocortisone in the prevention of neurally mediated syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive Fludrocortisone 0.05 to 0.2 mg or matching placebo and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. Power Calculations Assuming a 40% risk of syncope in the control arm, a relative reduction of 40% by Fludrocortisone, and a dropout rate of 20%, the enrollment of 310 patients will give an 80% power of reaching a positive conclusion about Fludrocortisone therapy, with P = .05. Registration POST II is registered with both www.controlled-trials.com (ISRCTN 51802652) and www.clinicaltrials.gov (NCT00118482). Implications This study will be the first adequately powered trial to determine whether Fludrocortisone is effective in preventing neurally mediated syncope. If it is effective, then Fludrocortisone may become the first-line medical therapy for this condition.

Satish R. Raj - One of the best experts on this subject based on the ideXlab platform.

  • Fludrocortisone for the Prevention of Vasovagal Syncope: A Randomized, Placebo-Controlled Trial.
    Journal of the American College of Cardiology, 2016
    Co-Authors: Robert S. Sheldon, Satish R. Raj, M. Sarah Rose, Carlos A. Morillo, Andrew D. Krahn, Eduardo Medina, Mario Talajic, Teresa Kus, Colette M. Seifer, Małgorzata Lelonek
    Abstract:

    Abstract Background There is limited evidence whether being on Fludrocortisone prevents vasovagal syncope. Objectives The authors sought to determine whether treatment with Fludrocortisone reduces the proportion of patients with recurrent vasovagal syncope by at least 40%, representing a pre-specified minimal clinically important relative risk reduction. Methods The multicenter POST 2 (Prevention of Syncope Trial 2) was a randomized, placebo-controlled, double-blind trial that assessed the effects of Fludrocortisone in vasovagal syncope over a 1-year treatment period. All patients had >2 syncopal spells and a Calgary Syncope Symptom Score >−3. Patients received either Fludrocortisone or matching placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily. The main outcome measure was the first recurrence of syncope. Results The authors randomized 210 patients (71% female, median age 30 years) with a median 15 syncopal spells over a median of 9 years equally to Fludrocortisone or placebo. Of these, 96 patients had ≥1 syncope recurrences, and only 14 patients were lost to follow-up before syncope recurrence. There was a marginally nonsignificant reduction in syncope in the Fludrocortisone group (hazard ratio [HR]: 0.69: 95% confidence interval [CI]: 0.46 to 1.03; p = 0.069). In a multivariable model, Fludrocortisone significantly reduced the likelihood of syncope (HR: 0.63; 95% CI: 0.42 to 0.94; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to Fludrocortisone (HR: 0.51; 95% CI: 0.28 to 0.89; p = 0.019). Conclusions The study did not meet its primary objective of demonstrating that Fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%. The study demonstrated a significant effect after dose stabilization, and there were significant findings in post hoc multivariable and on-treatment analyses. (A randomised clinical trial of Fludrocortisone for the prevention of vasovagal syncope; ISRCTN51802652 ; Prevention of Syncope Trial 2 [POST 2]; NCT00118482 )

  • the second prevention of syncope trial post ii a randomized clinical trial of Fludrocortisone for the prevention of neurally mediated syncope rationale and study design
    American Heart Journal, 2006
    Co-Authors: Satish R. Raj, Sarah Rose, Deborah Ritchie, Robert S. Sheldon
    Abstract:

    Background Neurally mediated syncope is a common and frequently distressing problem. It is associated with a poor quality of life, which improves when the frequency of syncope is reduced. Few therapies for neurally mediated syncope have been proven effective. Fludrocortisone is commonly used to prevent recurrences of syncope but with little evidence to support its use. A placebo-controlled clinical trial of Fludrocortisone for the prevention of neurally mediated syncope is needed. Structure of Study POST II is a multicenter, international, randomized, placebo-controlled study of Fludrocortisone in the prevention of neurally mediated syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive Fludrocortisone 0.05 to 0.2 mg or matching placebo and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. Power Calculations Assuming a 40% risk of syncope in the control arm, a relative reduction of 40% by Fludrocortisone, and a dropout rate of 20%, the enrollment of 310 patients will give an 80% power of reaching a positive conclusion about Fludrocortisone therapy, with P = .05. Registration POST II is registered with both www.controlled-trials.com (ISRCTN 51802652) and www.clinicaltrials.gov (NCT00118482). Implications This study will be the first adequately powered trial to determine whether Fludrocortisone is effective in preventing neurally mediated syncope. If it is effective, then Fludrocortisone may become the first-line medical therapy for this condition.

  • The Second Prevention of Syncope Trial (POST II)—a randomized clinical trial of Fludrocortisone for the prevention of neurally mediated syncope: Rationale and study design
    American Heart Journal, 2006
    Co-Authors: Satish R. Raj, Sarah Rose, Deborah Ritchie, Robert S. Sheldon
    Abstract:

    Background Neurally mediated syncope is a common and frequently distressing problem. It is associated with a poor quality of life, which improves when the frequency of syncope is reduced. Few therapies for neurally mediated syncope have been proven effective. Fludrocortisone is commonly used to prevent recurrences of syncope but with little evidence to support its use. A placebo-controlled clinical trial of Fludrocortisone for the prevention of neurally mediated syncope is needed. Structure of Study POST II is a multicenter, international, randomized, placebo-controlled study of Fludrocortisone in the prevention of neurally mediated syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive Fludrocortisone 0.05 to 0.2 mg or matching placebo and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. Power Calculations Assuming a 40% risk of syncope in the control arm, a relative reduction of 40% by Fludrocortisone, and a dropout rate of 20%, the enrollment of 310 patients will give an 80% power of reaching a positive conclusion about Fludrocortisone therapy, with P = .05. Registration POST II is registered with both www.controlled-trials.com (ISRCTN 51802652) and www.clinicaltrials.gov (NCT00118482). Implications This study will be the first adequately powered trial to determine whether Fludrocortisone is effective in preventing neurally mediated syncope. If it is effective, then Fludrocortisone may become the first-line medical therapy for this condition.

Daniel Guido Fuster - One of the best experts on this subject based on the ideXlab platform.

  • furosemide Fludrocortisone test and clinical parameters to diagnose incomplete distal renal tubular acidosis in kidney stone formers
    Clinical Journal of The American Society of Nephrology, 2017
    Co-Authors: Nasser Dhayat, Michael W. Gradwell, Ganesh Pathare, Manuel Anderegg, Lisa Schneider, David Luethi, Cedric Mattmann, Orson W. Moe, Bruno Vogt, Daniel Guido Fuster
    Abstract:

    Background and objectives Incomplete distal renal tubular acidosis is a well known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/Fludrocortisone test was recently proposed as an alternative. Because of the lack of rigorous comparative studies, the validity of the furosemide/Fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, nonprovocative parameters in predicting incomplete distal renal tubular acidosis has not been studied. Design, setting, participants, & measurements We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/Fludrocortisone testing. Results Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 8%. Sensitivity and specificity of the furosemide/Fludrocortisone test were 77% and 85%, respectively, yielding a positive predictive value of 30% and a negative predictive value of 98%. Testing of several nonprovocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH 3.8 mEq/L yielded a negative predictive value of 98% with a sensitivity of 85% and a specificity of 77% for the diagnosis of incomplete distal renal tubular acidosis. Conclusions The furosemide/Fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/Fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of nonprovocative clinical parameters.

  • Incomplete dRTA in kidney stone formers: diagnostic performance of furosemide/Fludrocortisone testing and non-provocative clinical parameters
    2017
    Co-Authors: Nasser Dhayat, Ganesh Pathare, Manuel Anderegg, Bruno Vogt, Daniel Guido Fuster
    Abstract:

    Background and objectives: Incomplete distal renal tubular acidosis is a well-known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/Fludrocortisone test was recently proposed as an alternative. Due to the lack of rigorous comparative studies, the validity of the furosemide/Fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, non-provocative parameters in predicting incomplete distal renal tubular acidosis has not been studied. Design, setting, participants, and measurements: We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/Fludrocortisone testing. Results: Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 7.78 %. Sensitivity and specificity of the furosemide/Fludrocortisone test FF test were 77 % and 85 %, respectively, yielding a positive predictive value of 30 % and a negative predictive value of 98 %. Testing of several non-provocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH 3.8 mmolmEq/l yielded a negative predictive value of 98 % with a sensitivity of 85 % and a specificity of 77 % for the diagnosis of incomplete distal renal tubular acidosis. Conclusions: The furosemide/Fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/Fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of non-provocative clinical parameters.

  • incomplete drta in kidney stone formers diagnostic performance of furosemide Fludrocortisone testing and non provocative clinical parameters
    2017
    Co-Authors: Nasser Dhayat, Ganesh Pathare, Manuel Anderegg, Bruno Vogt, Daniel Guido Fuster
    Abstract:

    Background and objectives: Incomplete distal renal tubular acidosis is a well-known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/Fludrocortisone test was recently proposed as an alternative. Due to the lack of rigorous comparative studies, the validity of the furosemide/Fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, non-provocative parameters in predicting incomplete distal renal tubular acidosis has not been studied. Design, setting, participants, and measurements: We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/Fludrocortisone testing. Results: Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 7.78 %. Sensitivity and specificity of the furosemide/Fludrocortisone test FF test were 77 % and 85 %, respectively, yielding a positive predictive value of 30 % and a negative predictive value of 98 %. Testing of several non-provocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH <5.3 with a plasma potassium threshold >3.8 mmolmEq/l yielded a negative predictive value of 98 % with a sensitivity of 85 % and a specificity of 77 % for the diagnosis of incomplete distal renal tubular acidosis. Conclusions: The furosemide/Fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/Fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of non-provocative clinical parameters.

  • Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers.
    Clinical Journal of the American Society of Nephrology, 2017
    Co-Authors: Nasser Dhayat, Michael W. Gradwell, Ganesh Pathare, Manuel Anderegg, Lisa Schneider, David Luethi, Cedric Mattmann, Orson W. Moe, Bruno Vogt, Daniel Guido Fuster
    Abstract:

    Background and objectives Incomplete distal renal tubular acidosis is a well known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/Fludrocortisone test was recently proposed as an alternative. Because of the lack of rigorous comparative studies, the validity of the furosemide/Fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, nonprovocative parameters in predicting incomplete distal renal tubular acidosis has not been studied. Design, setting, participants, & measurements We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/Fludrocortisone testing. Results Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 8%. Sensitivity and specificity of the furosemide/Fludrocortisone test were 77% and 85%, respectively, yielding a positive predictive value of 30% and a negative predictive value of 98%. Testing of several nonprovocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH 3.8 mEq/L yielded a negative predictive value of 98% with a sensitivity of 85% and a specificity of 77% for the diagnosis of incomplete distal renal tubular acidosis. Conclusions The furosemide/Fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/Fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of nonprovocative clinical parameters.

Eric Bellissant - One of the best experts on this subject based on the ideXlab platform.

  • Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers
    AAPS Journal, 2017
    Co-Authors: Noureddine Hamitouche, Emmanuelle Comets, Mégane Ribot, Jean-claude Alvarez, Eric Bellissant, Bruno Laviolle
    Abstract:

    This study aimed at describing the pharmacokinetics and the concentration-effect relationships of Fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral Fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe Fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for Fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for Fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with Fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC50) was about 200 times lower for Fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady Fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of Fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of Fludrocortisone should be reconsidered.

  • Pharmacokinetics of oral Fludrocortisone in septic shock.
    British Journal of Clinical Pharmacology, 2016
    Co-Authors: Andrea Polito, Noureddine Hamitouche, Mégane Ribot, Eric Bellissant, Bruno Laviolle, Djillali Annane, Angelo Polito, Jean-claude Alvarez
    Abstract:

    Aim: The combination of hydrocortisone and Fludrocortisone improved outcomes in septic shock. However, the specific role of Fludrocortisone remains controversial and its pharmacokinetics (PK) has never been investigated in septic shock. This study aimed at characterizing the PK of Fludrocortisone in septic shock. Methods: This was a single-centre ancillary PK study of a large multinational trial of crystalloids versus colloids for acute hypovolemia in intensive care unit (ICU) patients. In 21 adults with septic shock, Fludrocortisone plasma concentrations were measured by liquid chromatography-mass spectrometry tandem analysis, before and repeatedly until 18 h after an oral dose of 50 μg. PK parameters were estimated using a nonlinear mixed-effects modelling. Results: Undetectable plasma concentrations were observed in 7 out of 21 patients. In the remaining 14 patients, plasma Fludrocortisone concentrations were best described by a one-compartmental model with first-order absorption, a lag time (Tlag ) before the absorption phase, and first-order elimination. Severity of illness, as quantified by Simplified Acute Physiology Score II, significantly increased Tlag and apparent clearance. There was a large inter-individual variability in PK parameters. The population estimates of PK parameters (inter-individual variability) were: Tlag 0.65 h (98%), apparent clearance 40 l h-1 (49%) and apparent volume of distribution 78 l (75%). Plasma half-life was estimated at 1.35 h (95% CI, 0.84-2.03) and area under the curve of plasma concentrations was estimated at 1.25 μg h l-1 (95% CI, 1.09-1.46). Conclusions: A single oral dose of Fludrocortisone yielded undetectable plasma concentrations in one-third of adults with septic shock. Fludrocortisone PK showed a short plasma elimination half-life and a large inter-individual variability.

  • Fludrocortisone and hydrocortisone, alone or in combination, on in vivo hemodynamics and in vitro vascular reactivity in normal and endotoxemic rats: a randomized factorial design study
    Journal of Cardiovascular Pharmacology, 2014
    Co-Authors: Bruno Laviolle, Nicolas Nesseler, Catherine Massart, Eric Bellissant
    Abstract:

    Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for Fludrocortisone. We assessed the effects of single administrations of Fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous Fludrocortisone (5 and 20 μg/kg) and hydrocortisone (4 and 20 mg/kg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P \textless 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P = 0.039 and P = 0.007, respectively). At dose 1, Fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both Fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of Fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

  • Fludrocortisone and hydrocortisone, alone or in combination, on in vivo hemodynamics and in vitro vascular reactivity in normal and endotoxemic rats: a randomized factorial design study.
    Journal of Cardiovascular Pharmacology, 2014
    Co-Authors: Bruno Laviolle, Nicolas Nesseler, Catherine Massart, Eric Bellissant
    Abstract:

    Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for Fludrocortisone. We assessed the effects of single administrations of Fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous Fludrocortisone (5 and 20 μg/kg) and hydrocortisone (4 and 20 mg/kg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P < 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P = 0.039 and P = 0.007, respectively). At dose 1, Fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both Fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of Fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

  • Low doses of Fludrocortisone and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers
    British Journal of Clinical Pharmacology, 2013
    Co-Authors: Bruno Laviolle, Erwan Donal, Pascale Le Maguet, Fabrice Lainé, Eric Bellissant
    Abstract:

    AIMS: A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for Fludrocortisone. Since there continues to be disagreement about the utility of Fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and Fludrocortisone (50 μg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose-response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. METHODS: This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 × 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then Fludrocortisone 50 μg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 μg kg(-1) min(-1)), each dose being infused during 5 min. RESULTS: Both Fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (Fludrocortisone × hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. CONCLUSIONS: Single administrations of Fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo-aldosteronism. These similar effects of hydrocortisone and Fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading.

Bruno Laviolle - One of the best experts on this subject based on the ideXlab platform.

  • Population Pharmacokinetic-Pharmacodynamic Model of Oral Fludrocortisone and Intravenous Hydrocortisone in Healthy Volunteers
    AAPS Journal, 2017
    Co-Authors: Noureddine Hamitouche, Emmanuelle Comets, Mégane Ribot, Jean-claude Alvarez, Eric Bellissant, Bruno Laviolle
    Abstract:

    This study aimed at describing the pharmacokinetics and the concentration-effect relationships of Fludrocortisone and hydrocortisone on urinary sodium/potassium excretion in healthy volunteers. This was a placebo-controlled, randomized, double blind, crossover study, of oral Fludrocortisone and intravenous hydrocortisone, given alone or in combination, in 12 healthy male volunteers. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships on urinary sodium/potassium ratio for each drug. A one-compartment model was used to describe Fludrocortisone and hydrocortisone pharmacokinetics. Mean plasma half-life was 1.40 h (95%CI [0.80;2.10]) for Fludrocortisone and 2.10 h (95%CI [1.78;2.40]) for hydrocortisone. Clearance was 40.8 L/h (95%CI [33.6;48]) for Fludrocortisone and 30 L/h (95%CI [25.3;34.7]) for hydrocortisone. An indirect response model was used to describe effects on urinary sodium/potassium ratio. Fludrocortisone plasma concentrations showed a wider inter-individual dispersion than hydrocortisone plasma concentrations. Urinary sodium/potassium ratio variability was also higher with Fludrocortisone as compared to hydrocortisone. The plasma concentration of drug producing 50% of maximal inhibition of urinary sodium/potassium (IC50) was about 200 times lower for Fludrocortisone (0.08 μg/L, 95%CI [0.035;0.125]) than for hydrocortisone (16.7 μg/L, 95%CI [10.5;22.9]). Simulations showed that a 4-time per day administration regimen allow to achieve steady Fludrocortisone plasma concentrations with stable decrease in urinary sodium/potassium ratio after the second administration of Fludrocortisone. Fludrocortisone and hydrocortisone have short and similar plasma elimination half-lives in healthy subjects. Fludrocortisone plasma concentrations and effect on urinary sodium/potassium ratio had a higher inter-individual variability as compared to hydrocortisone. The administration regimen of Fludrocortisone should be reconsidered.

  • Pharmacokinetics of oral Fludrocortisone in septic shock.
    British Journal of Clinical Pharmacology, 2016
    Co-Authors: Andrea Polito, Noureddine Hamitouche, Mégane Ribot, Eric Bellissant, Bruno Laviolle, Djillali Annane, Angelo Polito, Jean-claude Alvarez
    Abstract:

    Aim: The combination of hydrocortisone and Fludrocortisone improved outcomes in septic shock. However, the specific role of Fludrocortisone remains controversial and its pharmacokinetics (PK) has never been investigated in septic shock. This study aimed at characterizing the PK of Fludrocortisone in septic shock. Methods: This was a single-centre ancillary PK study of a large multinational trial of crystalloids versus colloids for acute hypovolemia in intensive care unit (ICU) patients. In 21 adults with septic shock, Fludrocortisone plasma concentrations were measured by liquid chromatography-mass spectrometry tandem analysis, before and repeatedly until 18 h after an oral dose of 50 μg. PK parameters were estimated using a nonlinear mixed-effects modelling. Results: Undetectable plasma concentrations were observed in 7 out of 21 patients. In the remaining 14 patients, plasma Fludrocortisone concentrations were best described by a one-compartmental model with first-order absorption, a lag time (Tlag ) before the absorption phase, and first-order elimination. Severity of illness, as quantified by Simplified Acute Physiology Score II, significantly increased Tlag and apparent clearance. There was a large inter-individual variability in PK parameters. The population estimates of PK parameters (inter-individual variability) were: Tlag 0.65 h (98%), apparent clearance 40 l h-1 (49%) and apparent volume of distribution 78 l (75%). Plasma half-life was estimated at 1.35 h (95% CI, 0.84-2.03) and area under the curve of plasma concentrations was estimated at 1.25 μg h l-1 (95% CI, 1.09-1.46). Conclusions: A single oral dose of Fludrocortisone yielded undetectable plasma concentrations in one-third of adults with septic shock. Fludrocortisone PK showed a short plasma elimination half-life and a large inter-individual variability.

  • Fludrocortisone and hydrocortisone, alone or in combination, on in vivo hemodynamics and in vitro vascular reactivity in normal and endotoxemic rats: a randomized factorial design study
    Journal of Cardiovascular Pharmacology, 2014
    Co-Authors: Bruno Laviolle, Nicolas Nesseler, Catherine Massart, Eric Bellissant
    Abstract:

    Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for Fludrocortisone. We assessed the effects of single administrations of Fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous Fludrocortisone (5 and 20 μg/kg) and hydrocortisone (4 and 20 mg/kg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P \textless 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P = 0.039 and P = 0.007, respectively). At dose 1, Fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both Fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of Fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

  • Fludrocortisone and hydrocortisone, alone or in combination, on in vivo hemodynamics and in vitro vascular reactivity in normal and endotoxemic rats: a randomized factorial design study.
    Journal of Cardiovascular Pharmacology, 2014
    Co-Authors: Bruno Laviolle, Nicolas Nesseler, Catherine Massart, Eric Bellissant
    Abstract:

    Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for Fludrocortisone. We assessed the effects of single administrations of Fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous Fludrocortisone (5 and 20 μg/kg) and hydrocortisone (4 and 20 mg/kg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P < 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P = 0.039 and P = 0.007, respectively). At dose 1, Fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both Fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of Fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

  • Low doses of Fludrocortisone and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers
    British Journal of Clinical Pharmacology, 2013
    Co-Authors: Bruno Laviolle, Erwan Donal, Pascale Le Maguet, Fabrice Lainé, Eric Bellissant
    Abstract:

    AIMS: A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for Fludrocortisone. Since there continues to be disagreement about the utility of Fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and Fludrocortisone (50 μg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose-response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. METHODS: This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 × 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then Fludrocortisone 50 μg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 μg kg(-1) min(-1)), each dose being infused during 5 min. RESULTS: Both Fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (Fludrocortisone × hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. CONCLUSIONS: Single administrations of Fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo-aldosteronism. These similar effects of hydrocortisone and Fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading.