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Publication Record


Fludrocortisone Is Associated With a Higher Risk of All-Cause Hospitalizations Compared With Midodrine in Patients With Orthostatic Hypotension.
Grijalva CG, Biaggioni I, Griffin MR, Shibao CA
(2017) J Am Heart Assoc 6:
MeSH Terms: Adrenergic alpha-1 Receptor Agonists, Aged, Blood Pressure, Databases, Factual, Female, Fludrocortisone, Heart Failure, Hospitalization, Humans, Hypotension, Orthostatic, Incidence, Logistic Models, Male, Medicaid, Middle Aged, Midodrine, Multivariate Analysis, Prevalence, Propensity Score, Retrospective Studies, Risk Factors, Tennessee, Time Factors, Treatment Outcome, United States, Vasoconstrictor Agents
Show Abstract · Added July 27, 2018
BACKGROUND - Orthostatic hypotension causes ≈80 000 hospitalizations per year in the United States. Treatments for orthostatic hypotension include fludrocortisone, a mineralocorticoid analog that promotes sodium reabsorption; and midodrine, an α-1 adrenergic agonist that is a direct vasoconstrictor. Although both medications are used to treat orthostatic hypotension, few studies have compared their relative safety.
METHODS AND RESULTS - We compared incidence rates of hospitalizations for all causes, and for congestive heart failure between users of fludrocortisone and users of midodrine in a retrospective cohort study of Tennessee Medicaid adult enrollees (1995-2009). Adjusted incidence rate ratios were calculated using negative binomial regression models. Subgroup analyses based on history of congestive heart failure were conducted. We studied 1324 patients initiating fludrocortisone and 797 patients initiating midodrine. Compared with fludrocortisone users, midodrine users had higher prevalence of cardiovascular conditions. Incidence rates of all-cause hospitalizations for fludrocortisone and midodrine users were 1489 and 1330 per 1000 person-years, respectively (adjusted incidence-rate ratio 1.20, 95% confidence interval, 1.02-1.40). The respective rates of heart failure-related hospitalization were 76 and 84 per 1000 person-years (adjusted incidence-rate ratio: 1.33, 95% confidence interval, 0.79-2.56). Among patients with a history of congestive heart failure, the rates of all-cause hospitalization for fludrocortisone and midodrine were 2448 and 1820 per 1000 person-years (adjusted incidence-rate ratio: 1.42, 95% confidence interval, 1.07-1.90), and the respective rates of heart failure exacerbation-related hospitalizations were 297 and 263 per 1000 person-years (adjusted incidence-rate ratio: 1.48, 95% confidence interval, 0.69-3.16).
CONCLUSIONS - Compared with users of midodrine, users of fludrocortisone had higher rates of all-cause hospitalizations, especially among patients with congestive heart failure.
© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
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MeSH Terms
Living with severe orthostatic hypotension.
Jordan J, Diedrich A, Grassi G, Tank J
(2016) J Hypertens 34: 1942-4
MeSH Terms: Blood Pressure, Humans, Hypotension, Orthostatic, Posture
Added October 14, 2016
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4 MeSH Terms
Efficacy of Servo-Controlled Splanchnic Venous Compression in the Treatment of Orthostatic Hypotension: A Randomized Comparison With Midodrine.
Okamoto LE, Diedrich A, Baudenbacher FJ, Harder R, Whitfield JS, Iqbal F, Gamboa A, Shibao CA, Black BK, Raj SR, Robertson D, Biaggioni I
(2016) Hypertension 68: 418-26
MeSH Terms: Aged, Autonomic Nervous System, Blood Pressure, Blood Pressure Determination, Female, Humans, Hypotension, Orthostatic, Intermittent Pneumatic Compression Devices, Male, Midodrine, Monitoring, Physiologic, Splanchnic Circulation, Treatment Outcome, Vasoconstrictor Agents
Show Abstract · Added October 14, 2016
UNLABELLED - Splanchnic venous pooling is a major hemodynamic determinant of orthostatic hypotension, but is not specifically targeted by pressor agents, the mainstay of treatment. We developed an automated inflatable abdominal binder that provides sustained servo-controlled venous compression (40 mm Hg) and can be activated only on standing. We tested the efficacy of this device against placebo and compared it to midodrine in 19 autonomic failure patients randomized to receive either placebo, midodrine (2.5-10 mg), or placebo combined with binder on separate days in a single-blind, crossover study. Systolic blood pressure (SBP) was measured seated and standing before and 1-hour post medication; the binder was inflated immediately before standing. Only midodrine increased seated SBP (31±5 versus 9±4 placebo and 7±5 binder, P=0.003), whereas orthostatic tolerance (defined as area under the curve of upright SBP [AUCSBP]) improved similarly with binder and midodrine (AUCSBP, 195±35 and 197±41 versus 19±38 mm Hg×minute for placebo; P=0.003). Orthostatic symptom burden decreased with the binder (from 21.9±3.6 to 16.3±3.1, P=0.032) and midodrine (from 25.6±3.4 to 14.2±3.3, P<0.001), but not with placebo (from 19.6±3.5 to 20.1±3.3, P=0.756). We also compared the combination of midodrine and binder with midodrine alone. The combination produced a greater increase in orthostatic tolerance (AUCSBP, 326±65 versus 140±53 mm Hg×minute for midodrine alone; P=0.028, n=21) and decreased orthostatic symptoms (from 21.8±3.2 to 12.9±2.9, P<0.001). In conclusion, servo-controlled abdominal venous compression with an automated inflatable binder is as effective as midodrine, the standard of care, in the management of orthostatic hypotension. Combining both therapies produces greater improvement in orthostatic tolerance.
CLINICAL TRIAL REGISTRATION - URL: https://www.clinicaltrials.gov. Unique identifier: NCT00223691.
© 2016 American Heart Association, Inc.
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14 MeSH Terms
Early discontinuation of treatment in patients with orthostatic hypotension.
Shibao C, Grijalva CG, Lipsitz LA, Biaggioni I, Griffin MR
(2013) Auton Neurosci 177: 291-6
MeSH Terms: Adrenergic alpha-1 Receptor Agonists, Aged, Anti-Inflammatory Agents, Cohort Studies, Female, Fludrocortisone, Follow-Up Studies, Humans, Hypotension, Orthostatic, Male, Middle Aged, Midodrine, Retrospective Studies, Withholding Treatment
Show Abstract · Added December 10, 2013
BACKGROUND - Midodrine and fludrocortisone are considered the first-line pharmacologic treatments for orthostatic hypotension (OH). Although OH is thought to require long-term therapy, it is unknown how long patients remain on treatment ("persistence").
METHODS - We assembled a retrospective cohort of patients with OH aged ≥ 50 years enrolled in Tennessee Medicaid (1996-2008), and identified new episodes of midodrine and fludrocortisone use. Follow-up continued from the first medication fill through treatment discontinuation (90 days without medication), change in treatment, death, hospitalization, and loss of enrollment or study end. We compared persistence on treatment using Cox regression models and fludrocortisone as reference. Covariates included demographics, healthcare utilization measurements and co-morbidities.
RESULTS - We identified 1704 OH patients, who initiated 1767 episodes of fludrocortisone (1103) or midodrine (664) use. The median age was 69 years, 53% were female and 80% were white. During 738 person years of follow-up, episodes of use ended because of treatment discontinuation in 467 (27% fludrocortisone, 25% midodrine); treatment change in 72 (3% fludrocortisone, 6% midodrine) and death in 53 (3% fludrocortisone, 2% midodrine). Overall median persistence on fludrocortisone and midodrine was 254 (IQR: 119-783) and 259 (IQR: 119-807) days, respectively. The adjusted hazard ratio (aHR) for overall non-persistence on midodrine compared to fludrocortisone was 1.07 (95% CI: 0.90-1.28).
CONCLUSIONS - Overall duration of OH treatment with first-line medications was short, and similar for fludrocortisone and midodrine. Further research is warranted to determine the causes of this low persistence. (Words#234).
© 2013.
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14 MeSH Terms
Neurogenic orthostatic hypotension: pathophysiology, evaluation, and management.
Metzler M, Duerr S, Granata R, Krismer F, Robertson D, Wenning GK
(2013) J Neurol 260: 2212-9
MeSH Terms: Humans, Hypotension, Orthostatic, Nervous System Diseases
Show Abstract · Added March 7, 2014
Neurogenic orthostatic hypotension is a distinctive and treatable sign of cardiovascular autonomic dysfunction. It is caused by failure of noradrenergic neurotransmission that is associated with a range of primary or secondary autonomic disorders, including pure autonomic failure, Parkinson's disease with autonomic failure, multiple system atrophy as well as diabetic and nondiabetic autonomic neuropathies. Neurogenic orthostatic hypotension is commonly accompanied by autonomic dysregulation involving other organ systems such as the bowel and the bladder. In the present review, we provide an overview of the clinical presentation, pathophysiology, epidemiology, evaluation and management of neurogenic orthostatic hypotension focusing on neurodegenerative disorders.
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3 MeSH Terms
Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium.
Fedorowski A, Franceschini N, Brody J, Liu C, Verwoert GC, Boerwinkle E, Couper D, Rice KM, Rotter JI, Mattace-Raso F, Uitterlinden A, Hofman A, Almgren P, Sjögren M, Hedblad B, Larson MG, Newton-Cheh C, Wang TJ, Rose KM, Psaty BM, Levy D, Witteman J, Melander O
(2012) Eur Heart J 33: 2331-41
MeSH Terms: Aged, Antihypertensive Agents, Atherosclerosis, Blood Pressure, Epidemiologic Methods, Female, Gene Frequency, Heterozygote, Homozygote, Humans, Hypotension, Orthostatic, Male, Middle Aged, Polymorphism, Single Nucleotide
Show Abstract · Added April 15, 2014
AIMS - Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown.
METHODS AND RESULTS - A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥ 20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85-0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75-0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87-0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02-1.24; P = 0.02, rs198358: 1.10, 1.01-1.20; P = 0.04, and rs5068: 1.22, 1.04-1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04).
CONCLUSION - The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.
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14 MeSH Terms
Dysautonomia: perioperative implications.
Mustafa HI, Fessel JP, Barwise J, Shannon JR, Raj SR, Diedrich A, Biaggioni I, Robertson D
(2012) Anesthesiology 116: 205-15
MeSH Terms: Airway Management, Anesthesia, Baroreflex, Drug Interactions, Humans, Hyperventilation, Hypotension, Orthostatic, Infections, Perioperative Care, Postoperative Care, Primary Dysautonomias
Show Abstract · Added May 20, 2014
Severe autonomic failure occurs in approximately 1 in 1,000 people. Such patients are remarkable for the striking and sometimes paradoxic responses they manifest to a variety of physiologic and pharmacologic stimuli. Orthostatic hypotension is often the finding most commonly noted by physicians, but a myriad of additional and less understood findings also occur. These findings include supine hypertension, altered drug sensitivity, hyperresponsiveness of blood pressure to hypo/hyperventilation, sleep apnea, and other neurologic disturbances. In this article the authors will review the clinical pathophysiology that underlies autonomic failure, with a particular emphasis on those aspects most relevant to the care of such patients in the perioperative setting. Strategies used by clinicians in diagnosis and treatment of these patients, and the effect of these interventions on the preoperative, intraoperative, and postoperative care that these patients undergo is a crucial element in the optimized management of care in these patients.
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11 MeSH Terms
Long-term treatment with rituximab of autoimmune autonomic ganglionopathy in a patient with lymphoma.
Hollenbeck R, Black BK, Peltier AC, Biaggioni I, Robertson D, Winton EF, Raj SR
(2011) Arch Neurol 68: 372-5
MeSH Terms: Aged, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents, Autoantibodies, Autoimmune Diseases of the Nervous System, Autonomic Nervous System Diseases, Blood Pressure, Female, Ganglia, Autonomic, Humans, Hypotension, Orthostatic, Lymphoma, B-Cell, Norepinephrine, Plasma Exchange, Receptors, Nicotinic, Rituximab, Sweating
Show Abstract · Added December 10, 2013
OBJECTIVE - To report on the response to therapy in a patient with autoimmune autonomic ganglionopathy with a high titer of an autoantibody directed against the α-3 subunit of the nicotinic acetylcholine receptor (nAChR) of the autonomic ganglia.
DESIGN - Case report.
SETTING - University-based referral center for autonomic dysfunction.
PATIENT - Patient with prior indolent B-cell lymphoma who presented with symptomatic orthostatic hypotension and autonomic failure and was found to have a high titer of nAChR antibody.
INTERVENTION - Plasma exchange and rituximab therapy (both initial 4-week therapy and maintenance therapy).
MAIN OUTCOME MEASURES - Autonomic ganglionic antibody titer; the autonomic assessments were the presence of orthostatic hypotension, the concentration of plasma norepinephrine, and quantitative sweat testing.
RESULTS - Treatment with rituximab followed by plasma exchange significantly decreased the nAChR antibody titers for a short time, and then the titers increased. The titers suppressed to almost undetectable levels once regular maintenance therapy with rituximab was initiated. Reduction in nAChR antibody titer resulted in a decrease in orthostatic hypotension, an increased concentration of upright plasma norepinephrine, improvement in some sweat function, and improvement in symptoms.
CONCLUSIONS - Long-term rituximab therapy suppressed autoantibody production to undetectable levels over the course of 2 years and resulted in sustained clinical improvement in this patient with debilitating autoimmune autonomic ganglionopathy. More data are needed before rituximab therapy can be recommended as routine therapy for this disorder.
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17 MeSH Terms
Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure.
Shibao C, Okamoto LE, Gamboa A, Yu C, Diedrich A, Raj SR, Robertson D, Biaggioni I
(2010) Hypertension 56: 847-51
MeSH Terms: Adrenergic alpha-Antagonists, Aged, Analysis of Variance, Blood Pressure, Cholinesterase Inhibitors, Cross-Over Studies, Female, Heart Rate, Humans, Hypotension, Orthostatic, Male, Middle Aged, Pure Autonomic Failure, Pyridostigmine Bromide, Single-Blind Method, Yohimbine
Show Abstract · Added December 10, 2013
Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the α-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11±3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6±3 mm Hg [95% CI: -5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension.
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16 MeSH Terms
Coexistent autoimmune autonomic ganglionopathy and myasthenia gravis associated with non-small-cell lung cancer.
Peltier AC, Black BK, Raj SR, Donofrio P, Robertson D, Biaggioni I
(2010) Muscle Nerve 41: 416-9
MeSH Terms: Autoimmune Diseases of the Nervous System, Carcinoma, Non-Small-Cell Lung, Electromyography, Ganglia, Autonomic, Humans, Hypotension, Orthostatic, Lung Neoplasms, Male, Middle Aged, Muscle Weakness, Myasthenia Gravis, Norepinephrine, Plasma Exchange, Tachycardia, Treatment Outcome
Show Abstract · Added December 10, 2013
We report the case of a 55-year-old man with non-small-cell lung cancer who underwent radiation, chemotherapy with carbotaxol and paclitaxel, and left upper lobe removal 2 years prior to evaluation. He was referred for disabling orthostatic hypotension (113/69 mm Hg supine and 66/47 mm Hg standing after 10 minutes) without a compensatory heart rate increase (57 to 59 beats per minute), fatigue, and constipation with episodes of ileus. Clinical examination showed mild ptosis bilaterally, fatiguable neck flexor weakness, and hip flexor weakness. Blood pressure response to Valsalva maneuver was abnormal with an absence of phase 4 overshoot and a Valsalva heart rate ratio of 1.04. Plasma norepinephrine level was low (79 pg/ml supine, 330 pg/ml standing). Single-fiber electromyography of the right extensor digitorum communis revealed normal mean consecutive difference (jitter) but several pairs exceeded a jitter of 100 mus. Antibodies against muscle acetylcholine receptor [(AChR) 0.66 nmol/L, normal <0.02 nmol/L] and ganglionic AChR (0.34 nmol/L, normal <0.02 nmol/L) were present. Treatment with plasma exchange normalized responses to standing posture (105/68 supine to 118/82 mm Hg standing, 66 to 79 beats per minute), to Valsalva (normal blood pressure overshoot, hazard ratio 1.47), norepinephrine (194 pg/ml supine, 763 pg/ml standing), and jitter measurements. We conclude that autoimmune autonomic ganglionopathy and myasthenia gravis can coexist and suggest that the latter should be excluded in patients with autoimmune autonomic ganglionopathy who complain of fatigue that shows improvement with non-supine rest.
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15 MeSH Terms