Original Article
Treatment of Orthostatic Hypotension with Erythropoietin
N Engl J Med 1993; 329:611-615August 26, 1993
- Abstract
Background and Methods
Patients with orthostatic hypotension caused by autonomic neuropathy frequently have a decreased red-cell mass. This would be expected to compromise their effective circulating blood volume and aggravate the orthostatic hypotension. We studied the effect of increasing the red-cell mass with erythropoietin, given subcutaneously in a dose of 50 U per kilogram of body weight three times a week for 6 to 10 weeks to eight patients with orthostatic hypotension -- four men, one teenage boy, and three women (age range, 17 to 68 years). Four patients had type I diabetes mellitus and autonomic neuropathy, three patients had pure autonomic failure, and one patient had sympathotonic orthostatic hypotension. Seven patients received fludrocortisone (0.1 or 0.2 mg per day) before, during, and after the trial of erythropoietin. The red-cell volume, plasma volume, and hemodynamic response to orthostatic stress were measured before and after therapy.
Results
Erythropoietin increased the mean (±SD) hematocrit from 0.34 ±0.04 to 0.45 ±0.04 (P<0.005) and increased the red-cell volume from 16.8 ±3.9 to 25.3 ±3.1 ml per kilogram (P<0.005), but had no effect on plasma volume. The systolic blood pressure increased from 81 ±11 to 100 ±24 mm Hg (P<0.01) and the diastolic blood pressure increased from 46 ±10 to 63 ±18 mm Hg (P<0.01) while the patients were standing. The average systolic and diastolic blood pressure while the patients were supine did not increase significantly, although hypertension in the supine position developed in three patients. Orthostatic dizziness improved during treatment in six of the eight patients.
Conclusions
In patients with orthostatic hypotension, increasing the red-cell volume with erythropoietin elevates blood pressure while standing. Possible long-term adverse effects are not known.
Media in This Article
Figure 1
Effect of Erythropoietin on Blood Pressure in Patients with Orthostatic Hypotension.Table 1
Clinical Characteristics of the Patients with Orthostatic Hypotension Who Received Erythropoietin.Article Activity
- Article
Although the autonomic nervous system has a recognized role in the maintenance of sodium and water balance and the regulation of plasma volume, little is known about its role in the regulation of red-cell volume. This question is of interest because some patients with autonomic neuropathy are anemic and have a decreased red-cell mass1-3. A decreased red-cell mass would be expected to compromise effective circulating blood volume and therefore aggravate hypotension in these patients. To address this issue, we determined the effect of increasing the red-cell mass with erythropoietin on the hemodynamic response to orthostatic stress in eight patients with orthostatic hypotension.
Methods
Patients
We studied eight patients with orthostatic hypotension (defined as a decrease in systolic blood pressure of more than 20 mm Hg and a decrease in diastolic blood pressure of more than 10 mm Hg during the first three minutes after the patients changed from the supine to the upright posture) and a documented deficit in red-cell mass. Four patients had type I diabetes mellitus and multiple features of diabetic autonomic neuropathy, including gastroparesis diabeticorum. Three patients had pure autonomic failure, and one patient had sympathotonic orthostatic hypotension (Table 1Table 1
Clinical Characteristics of the Patients with Orthostatic Hypotension Who Received Erythropoietin.). Three patients had mild renal insufficiency, with serum creatinine concentrations between 1.4 and 1.6 mg per deciliter (124 to 142 μmol per liter). All the patients had a history of chronic orthostatic dizziness (from 8 months to 10 years in duration), and six had a history of orthostatic syncope. Seven patients were receiving fludrocortisone (Florinef, Bristol-Meyers Squibb, Evansville, Ind.) therapy when referred to us; Patient 8 had taken it in the past but discontinued it because of ankle edema. The fludrocortisone was continued in the seven patients at a daily dose of 0.1 mg (three patients) or 0.2 mg (four patients). Patients with reversible causes of orthostatic hypotension -- Addison's disease, gastrointestinal bleeding, and dehydration -- were excluded on the basis of history, physical examination, and appropriate laboratory tests, as were patients with hypertension that occurred when they were supine (a blood pressure of 150/100 mm Hg or greater) and patients with a history of congestive heart failure, seizures, liver disease, chronic renal failure, or thromboembolic events. The protocol was approved by the institutional review boards of Temple University, the State University of New York Health Sciences Center at Syracuse, and West Virginia University.We assessed autonomic function by measuring the beat-to-beat variation with deep breathing,4 the heart-rate response to the Valsalva maneuver,4 the plasma norepinephrine response to orthostatic stress,5-7 and autonomic surface potentials8. All assessments, except the plasma norepinephrine measurements, were performed at least twice, and the mean result was calculated.
The beat-to-beat variation with deep breathing was determined by measuring RR intervals electrocardiographically for 2 minutes while the patients breathed deeply according to a 10-second cycle of inspiration and expiration. The variation, calculated by subtracting the minimal heart rate from the maximal, is an index of respiration-induced sinus arrhythmia, which is mediated by the parasympathetic innervation of the heart4. The heart-rate response to the Valsalva maneuver was measured electrocardiographically while the patients blew for 15 seconds into a polyethylene tube connected to a manometer to generate a pressure of 40 mm Hg. The degree of post-Valsalva bradycardia was determined by calculating the Valsalva ratio -- the longest RR interval after the maneuver divided by the shortest interval during the maneuver. This test assesses the integrity of cardiac innervation, the baroreceptor reflex, and the efferent limb of the sympathetic nervous system4. The plasma norepinephrine response to orthostatic stress also tests the efferent limb of the sympathetic nervous system. Autonomic surface potentials were measured from recording electrodes over the palms and soles8. The stimulating electrode was placed over the median nerve, and four stimuli of gradually increasing intensity were delivered. The electrodermal response is a measure of sympathetic sudomotor activity in the extremities. The test is useful in determining whether autonomic dysfunction is focal or diffuse9,10.
Measurement of the Hemodynamic Response to Orthostatic Stress
Blood pressure and heart rate were measured electronically with an Accutorr I Datascope (Paramus, N.J.) or a Dinamap Vital Signs Monitor (Critikon, Tampa, Fla.). All hemodynamic measurements were made in the morning. The patients were instructed to rest quietly for at least five minutes before blood pressure was measured in the supine position and were then asked to stand for five minutes to assess the orthostatic change in blood pressure. In two patients who were unable to stand for five minutes, the blood pressure was measured after two minutes of standing. The results presented generally represent the mean of hemodynamic measurements made on two or three days.
Evaluation of Anemia
The nature of anemia was evaluated by measuring the red-cell indexes and serum iron-binding capacity, serum iron concentrations, and in some patients, serum erythropoietin, ferritin, folic acid, and vitamin B12 concentrations. Serum ferritin was measured by an immunoradiometric assay, folic acid and vitamin B12 were measured by radioimmunoassays, and erythropoietin was measured by a double-antibody immunoassay11.
Study Protocol
Erythropoietin (Ortho Pharmaceuticals, Raritan, N.J.) was given subcutaneously at a dose of 50 U per kilogram of body weight three times a week. A complete blood count was performed every 10 to 14 days until reticulocytosis occurred and the target hematocrit, which was 10 percent above base line, was reached (as it was in seven of the eight patients) (Table 2Table 2
Effects of Erythropoietin on Blood Pressures in the Supine and Standing Positions in Patients with Orthostatic Hypotension.). The duration of treatment ranged from 6 to 10 weeks. Plasma and red-cell volumes and the hemodynamic response to orthostatic stress were measured in Patients 1, 2, 3, 7, and 8 in the hospital and in Patients 4, 5, and 6 while they were outpatients. The trial of erythropoietin was initiated as soon as possible after the orthostatic hypotension and red-cell deficit were documented. The plasma and red-cell volumes were remeasured and hemodynamic measurements were repeated at least 48 hours (but no longer than one week) after the last dose of erythropoietin was given. Patients were given a diet containing 120 to 150 mmol of sodium per day in the hospital and received instructions for maintaining sodium intake in this range at home.Plasma glucose concentrations were measured three or four times daily in the patients with diabetes, and the dose of insulin was adjusted to provide optimal glycemic control.
Measurement of Plasma and Red-Cell Volumes
The plasma volume was determined from the iodine-125 distribution space,12 and the red-cell volume was calculated from the plasma volume and the hematocrit according to the method of Nusynowitz and Blumhardt13. We measured the red-cell mass in some patients with an independent method -- the dilution of endogenous red cells labeled with sodium chromate Cr 5114. The agreement between the two methods was good.
Statistical Analysis
The results are presented as means ±SD. The statistical significance of the differences was assessed with the two-tailed paired t-test.
Results
Most of the patients with orthostatic hypotension performed poorly on at least one vasomotor-reflex test or had other evidence of autonomic neuropathy, such as absent autonomic surface potentials (Table 1). The increase in plasma norepinephrine concentrations with standing (value standing minus value supine) was lower than normal in five patients (less than 140 pg per milliliter [0.83 nmol per liter]).
The mean (±SD) hematocrit before fludrocortisone therapy was 0.35 ±0.04, and it was 0.34 ±0.04 while the patients were receiving fludrocortisone just before erythropoietin treatment was initiated. The mean corpuscular volume averaged 88.9 ±3.1 micrometers3. The serum iron level was normal (86 ±39 μg per deciliter [15.3 ±6.7 μmol per liter]). The serum ferritin level was normal in five of the six patients in whom it was measured, and serum vitamin B12 and folic acid concentrations were normal in all five patients tested. The red-cell volume, as measured indirectly,12,13 was below the lower limits of normal (25 ml per kilogram for men and 20 ml per kilogram for women) in all the patients. The results were confirmed in six patients by measuring the distribution space of 51Cr-labeled endogenous red cells14. The plasma volume, by contrast, was decreased (less than 30 ml per kilogram) in only one patient5. The serum erythropoietin level was within the normal range (5 to 20 mU per milliliter) in six of the seven patients in whom it was measured; one patient (Patient 1) had a markedly elevated value (128 mU per milliliter).
Erythropoietin therapy increased the mean hematocrit from 0.34 ±0.04 to 0.45 ±0.04 (P<0.005) and increased the red-cell volume from 16.8 ±3.9 to 25.3 ±3.1 ml per kilogram (P<0.005). The plasma volume, however, was virtually unchanged (Table 3Table 3
Hematologic Effects of Erythropoietin in Patients with Orthostatic Hypotension.). The mean weight of the patients before and after erythropoietin therapy was 63.4 ±12.3 and 64.1 ±12.2 kg, respectively.The mean systolic blood pressure while the patients were standing increased from 81 ±11 to 100 ±24 mm Hg (P<0.01) and the mean diastolic blood pressure increased from 46 ±10 to 63 ±18 mm Hg (P<0.01) after erythropoietin therapy (Figure 1Figure 1
Effect of Erythropoietin on Blood Pressure in Patients with Orthostatic Hypotension.). Before erythropoietin therapy, the mean heart rate increased from 75 ±11 to 96 ±25 beats per minute when the patients changed from the supine to the upright position; after erythropoietin therapy the heart rates were 76 ±14 and 93 ±25 beats per minute, respectively. The mean blood pressure while supine was not significantly different after erythropoietin therapy from the value before treatment (139 ±31/79 ±12 vs. 126 ±16/74 ±12 mm Hg). However, hypertension while supine developed in three of the eight patients during the administration of erythropoietin (Figure 1). There were no other adverse drug effects. Although there was no correlation between a patient's base-line performance on most autonomic-function tests and the hemodynamic response to erythropoietin, there was a tendency for patients with a blunted response to the Valsalva maneuver at base line to have a greater increase during erythropoietin treatment in blood pressure while supine (r = -0.72, P = 0.07). There was no correlation between the effect of erythropoietin on the red-cell volume and its hemodynamic effects.All patients were asked at the end of the trial to assess the efficacy of erythropoietin; six of the eight stated that their orthostatic dizziness had definitely improved. Four of the patients who described improvement had a recurrence of orthostatic dizziness two or three months after the discontinuation of erythropoietin.
Discussion
We found that the administration of erythropoietin increased blood pressure in the upright posture in patients with orthostatic hypotension. Since autonomic reflexes fail to regulate vascular tone appropriately in patients with orthostatic hypotension, their blood pressure tends to fluctuate widely according to changes in blood volume15. The pressor effect of erythropoietin was probably due to the increased production of red cells and the expansion of red-cell mass, although erythropoietin may have vascular effects as well16-18. The latter may be due to increased hemoglobin concentrations or increased blood viscosity. Hemoglobin binds nitric oxide and may therefore inhibit the action of this endogenous vasodilator19.
The usual approach to the treatment of patients with orthostatic hypotension is to expand the plasma volume by administering fludrocortisone. Many patients with autonomic neuropathy, however, have a normal plasma volume15 and become hypervolemic during long-term therapy with fludrocortisone. Hypertension while supine, edema, or congestive heart failure may ensue, particularly when high doses of fludrocortisone (0.4 mg per day or more) are administered15,20. We postulated that erythropoietin would correct the deficit in red-cell mass without causing hypervolemia. Although our studies of plasma and red-cell volumes indicated that erythropoietin therapy did not overcorrect the red-cell deficit, hypertension while supine nevertheless developed in three patients.
The cause of the decreased red-cell volume that occurs in some patients with autonomic neuropathy is unknown. Although most of our patients had normal serum erythropoietin concentrations, the concentrations probably would have been high if the red-cell deficit had been appropriately recognized by the kidneys. A normal serum erythropoietin level may therefore be inappropriately low. Biaggioni et al. found that the serum erythropoietin level was lower in patients with anemia due to autonomic failure than in patients with iron-deficiency anemia (unpublished data). They postulated that decreased erythropoietin secretion in patients with autonomic neuropathy is a manifestation of renal denervation, perhaps linked to the decrease in renin secretion that also occurs in this disorder1,21.
The only adverse effect of erythropoietin was hypertension in the supine position, which developed in three patients even though we excluded patients with a propensity for such hypertension (a blood pressure greater than 150/100 mm Hg). This restriction limits the usefulness of erythropoietin therapy, since at least 50 percent of patients with autonomic neuropathy already have hypertension while supine or acquire it when given fludrocortisone. We continued to give the patients a low dose of fludrocortisone during the trial of erythropoietin, since we thought it unlikely that erythropoietin, which is expensive and must be taken parenterally, would ever replace fludrocortisone as first-line therapy for patients with orthostatic hypotension. We therefore designed this study to determine whether combined treatment with erythropoietin and fludrocortisone was better than treatment with fludrocortisone alone. Our results indicate that this is the case and suggest that erythropoietin in combination with low-dose fludrocortisone may be preferable to fludrocortisone alone in patients whose red-cell volume is decreased. Most of the patients we studied had definite improvement in their orthostatic symptoms and an improved sense of well-being after the reversal of their red-cell deficit. Similar observations have been made by another group of investigators (Biaggioni I: personal communication). Additional studies of larger numbers of patients are needed to determine whether erythropoietin plus a low dose of fludrocortisone is more beneficial than a higher dose of fludrocortisone. Until such information becomes available, we recommend that fludrocortisone remain the primary mode of treatment and erythropoietin be reserved for patients whose hypotension fails to respond to mineralocorticoid therapy. Moreover, erythropoietin should only be used in patients with anemia or a documented deficit in red-cell volume.
In summary, erythropoietin increases blood pressure in the upright posture in patients with autonomic neuropathy and may be useful therapeutically in patients who have an inadequate response to mineralocorticoid therapy.
Supported by Public Health Service grants (AM-32239 to Dr. Hoeldtke and AG-03055 to Dr. Streeten), General Clinical Research Center grants (RR-00349 and RR-00220), and the C.E. Compton Nutrition Foundation.
We are indebted to the nurses of the General Clinical Research Centers of Temple University Hospital and the State University of New York Health Sciences Center at Syracuse who took care of the patients participating in these studies; to Mrs. Kim Bryner, West Virginia University, who performed the autonomic-function testing; and to Mr. Thomas Scullard, Health Sciences Center at Syracuse, who measured plasma norepinephrine concentrations in Patients 4, 5, and 6.
Source Information
From the Department of Medicine, Temple University, Philadelphia (R.D.H.); the Department of Medicine, West Virginia University, Morgantown (R.D.H.); and the Department of Medicine, State University of New York Health Sciences Center at Syracuse (D.H.P.S.).
- References
References
1
Slaton PE Jr ,Biglieri EG . Reduced aldosterone excretion in patients with autonomic insufficiency. J Clin Endocrinol Metab 1967;27:37-45
CrossRef | Web of Science | Medline2
Chokroverty S ,Barron KD ,Katz FH ,Del Greco F ,Sharp JT . The syndrome of primary orthostatic hypotension. Brain 1969;92:743-768
CrossRef | Web of Science | Medline3
Biaggioni I ,Haile V ,Robertson D . The anemia of primary autonomic failure: evidence for sympathetic modulation of erythropoiesis. Clin Res 1991;39:300-300 abstract.4
Ewing DJ ,Campbell IW ,Clarke BF . Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann Intern Med 1980;92:308-311
Web of Science | Medline5
Hoeldtke RD ,Davis KM . The orthostatic tachycardia syndrome: evaluation of autonomic function and treatment with octreotide and ergot alkaloids. J Clin Endocrinol Metab 1991;73:132-139
CrossRef | Web of Science | Medline6
Peuler JD ,Johnson GA . Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephrine and dopamine. Life Sci 1977;21:625-636
CrossRef | Web of Science | Medline7
Watson E . Liquid chromatography with electrochemical detection for plasma norepinephrine and epinephrine. Life Sci 1981;28:493-497
CrossRef | Web of Science | Medline8
Hoeldtke RD ,Davis KM ,Hshieh PB ,Gaspar SR ,Dworkin GE . Autonomic surface potential analysis: assessment of reproducibility and sensitivity. Muscle Nerve 1992;15:926-931
CrossRef | Web of Science | Medline9
Hoeldtke RD ,Dworkin GE ,Gaspar SR ,Israel BC . Sympathotonic orthostatic hypotension: a report of four cases. Neurology 1989;39:34-40
Web of Science | Medline10
Streeten DH . Pathogenesis of hyperadrenergic orthostatic hypotension: evidence of disordered venous innervation exclusively in the lower limbs. J Clin Invest 1990;86:1582-1588
CrossRef | Web of Science | Medline11
Egrie JC ,Cotes PM ,Lane J ,Gaines Das RE ,Tam RC . Development of radioimmunoassays for erythropoietin using recombinant erythropoietin as tracer and immunogen. J Immunol Methods 1987;99:235-241
CrossRef | Web of Science | Medline12
Berson SA ,Yalow RS ,Schreiber SS ,Post J . Tracer experiments with I131 labeled human serum albumin: distribution and degradation studies. J Clin Invest 1953;32:746-768
CrossRef | Web of Science | Medline13
Nusynowitz ML ,Blumhardt R . Proceedings: estimation of true red cell volume from RISA red cell volume. Am J Roentgenol Radium Ther Nucl Med 1974;120:549-552
Medline14
Standard techniques for the measurement of red-cell and plasma volume: a report by the International Committee for Standardization in Hematology (ICSH): Panel on Diagnostic Applications of Radioisotopes in Haematology
CrossRef | Web of Science | Medline15
Wilcox CS. Body fluids and renal function in autonomic failure. In: Bannister R, ed. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. 1st ed. Oxford, England: Oxford University Press, 1983:115-54.
16
Baskin S ,Lasker N . Erythropoietin-associated hypertension. N Engl J Med 1990;323:999-999
Full Text | Web of Science | Medline17
London GM ,Zins B ,Pannier B , et al. Vascular changes in hemodialysis patients in response to recombinant human erythropoietin. Kidney Int 1989;36:878-882
CrossRef | Web of Science | Medline18
Heidenreich S ,Rahn KH ,Zidek W . Direct vasopressor effect of recombinant human erythropoietin on renal resistance vessels. Kidney Int 1991;39:259-265
CrossRef | Web of Science | Medline19
Martin W ,Smith JA ,White DG . The mechanisms by which haemoglobin inhibits the relaxation of rabbit aorta induced by nitrovasodilators, nitric oxide, or bovine retractor penis inhibitory factor. Br J Pharmacol 1986;89:563-571
Web of Science | Medline20
Chobanian AV ,Volicer L ,Tifft CP ,Gavras H ,Liang C ,Faxon D . Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. N Engl J Med 1979;301:68-73
Full Text | Web of Science | Medline21
Biaggioni I ,Garcia F ,Inagami T ,Haile V . Hyporeninemic normoaldosteronism in severe autonomic failure. J Clin Endocrinol Metab 1993;76:580-586
CrossRef | Web of Science | Medline
- Citing Articles (77)
Citing Articles
1
Italo Biaggioni. 2012. Erythropoietin in Autonomic Failure. , 643-644.
CrossRef2
J Richard G Marigold, Monica Arias, Michael Vassallo, Stephen C. Allen, Joseph SK Kwan. (2011) Autonomic dysfunction in older people. Reviews in Clinical Gerontology 21:01, 28-44
CrossRef3
Nicholas J. Silvestri, Christopher H. Gibbons. 2011. Autonomic Dysfunction in Neuromuscular Disorders. , 61-77.
CrossRef4
H. Lahrmann, P. Cortelli, M. Hilz, C. J. Mathias, W. Struhal, M. Tassinari. 2010. Orthostatic Hypotension. , 469-475.
CrossRef5
Jonathan N. Johnson, Kenneth J. Mack, Nancy L. Kuntz, Chad K. Brands, Coburn J. Porter, Philip R. Fischer. (2010) Postural Orthostatic Tachycardia Syndrome: A Clinical Review. Pediatric Neurology 42:2, 77-85
CrossRef6
Rodica Pop-Busui, Laurel Roberts, Subramaniam Pennathur, Mathias Kretzler, Frank C. Brosius, Eva L. Feldman. (2010) The Management of Diabetic Neuropathy in CKD. American Journal of Kidney Diseases 55:2, 365-385
CrossRef7
Christopher H. Gibbons, Satish R Raj, Heinz Lahrmann, Michael Benatar, Christopher H. Gibbons. 2010. Pharmacological treatments of postural hypotension. .
CrossRef8
Fiona Kearney, Alan Moore. (2009) Pharmacological options in the management of orthostatic hypotension in older adults. Expert Review of Cardiovascular Therapy 7:11, 1395-1400
CrossRef9
S G Carruthers. (2009) A Truncated Erythropoietin Receptor EPOR-T Is Associated With Hypertension Susceptibility. Clinical Pharmacology & Therapeutics 86:2, 134-136
CrossRef10
David G. Benditt, John T. Nguyen. (2009) Syncope. Journal of the American College of Cardiology 53:19, 1741-1751
CrossRef11
O. Blétry. 2009. Hypotension Orthostatique. , 646-647.
CrossRef12
Imad T. Jarjour, Laila K. Jarjour. (2008) Low Iron Storage in Children and Adolescents with Neurally Mediated Syncope. The Journal of Pediatrics 153:1, 40-44.e1
CrossRef13
Roy Freeman. (2008) Current pharmacologic treatment for orthostatic hypotension. Clinical Autonomic Research 18:S1, 14-18
CrossRef14
Freeman, Roy, . (2008) Neurogenic Orthostatic Hypotension. New England Journal of Medicine 358:6, 615-624
Full Text15
Shane Smyth, Daniel L. Menkes. (2008) Coincident membranous glomerulonephritis and chronic inflammatory demyelinating polyradiculoneuropathy: Questioning the autoimmunity hypothesis. Muscle & Nerve 37:1, 130-135
CrossRef16
Marvin S. Medow, Julian M. Stewart, Sanjukta Sanyal, Arif Mumtaz, Domenic Sica, William H. Frishman. (2008) Pathophysiology, Diagnosis, and Treatment of Orthostatic Hypotension and Vasovagal Syncope. Cardiology in Review 16:1, 4-20
CrossRef17
Robert E. Schmidt, Karen G. Green, Dongyan Feng, Denise A. Dorsey, Curtis A. Parvin, Jin-Moo Lee, Qinlgi Xiao, Michael Brines. (2008) Erythropoietin and its carbamylated derivative prevent the development of experimental diabetic autonomic neuropathy in STZ-induced diabetic NOD-SCID mice. Experimental Neurology 209:1, 161-170
CrossRef18
Italo Biaggioni. (2007) The Sympathetic Nervous System and Blood Volume Regulation: Lessons from Autonomic Failure Patients. The American Journal of the Medical Sciences 334:1, 61-64
CrossRef19
Do-Hyoung Kim, Tae-Young Kim, Sun-Min Kim, Soo-Jeong Yoo, Dong-Jin Oh, Suk-Hee Yu. (2007) IGF-1 is an Independent Risk Factor for Anemia in Diabetic Pre-dialysis Patients. The Korean Journal of Internal Medicine 22:3, 186
CrossRef20
N Yamamoto, E Sasaki, K Goda, K Nagata, H Tanaka, J Terasaki, H Yasuda, A Imagawa, T Hanafusa. (2006) Treatment of post-dialytic orthostatic hypotension with an inflatable abdominal band in hemodialysis patients. Kidney International 70:10, 1793-1800
CrossRef21
H. Lahrmann, P. Cortelli, M. Hilz, C. J. Mathias, W. Struhal, M. Tassinari. (2006) EFNS guidelines on the diagnosis and management of orthostatic hypotension. European Journal of Neurology 13:9, 930-936
CrossRef22
Janet B. McGill, David S.H. Bell. (2006) Anemia and the role of erythropoietin in diabetes. Journal of Diabetes and its Complications 20:4, 262-272
CrossRef23
Ehab A Eltahawy, Blair P Grubb. (2006) Neurocardiogenic syncope: mechanisms, evaluation and treatment. Future Cardiology 2:3, 325-334
CrossRef24
Lukasz Iwanczyk, Nancy T. Weintraub, Laurence Z. Rubenstein. (2006) Orthostatic Hypotension in the Nursing Home Setting. Journal of the American Medical Directors Association 7:3, 163-167
CrossRef25
Christopher H. Gibbons, Roy Freeman. (2006) Treatment options for autonomic neuropathies. Current Treatment Options in Neurology 8:2, 119-132
CrossRef26
S Thomas, P E Stevens. (2006) Anaemia in diabetic kidney disease: An area for improvement?. Practical Diabetes International 23:1, 22-26
CrossRef27
Takatoshi Saito, Katsuyoshi Tojo, Aya Morimoto, Naoko Tajima. (2005) Normocytic normochromic anemia due to autonomic neuropathy in type 2 diabetic patients without severe nephropathy. Diabetes Research and Clinical Practice 70:3, 239-247
CrossRef28
Joel Handler. (2005) Symptomatic Orthostatic Hypotension/Supine Hypertension. The Journal of Clinical Hypertension 7:10, 612-616
CrossRef29
Shamil Yusuf, A. John Camm. (2005) Deciphering the sinus tachycardias. Clinical Cardiology 28:6, 267-276
CrossRef30
YOSHIO SHIMIZU, KAZUMI SUZUKAWA, YUKO HIRANO, MASANORI SEKI, KOUICHI HIRAYAMA, KEIGYO YOH, AKI HIRAYAMA, KUNIHIRO YAMAGATA, SOHJI NAGASE, TOSHIRO NAGASAWA, AKIO KOYAMA. (2005) Erythropoietin-resistant anaemia in a predialysis patient with Klinefelter syndrome. Case Report. Nephrology 10:2, 147-150
CrossRef31
Shamil Yusuf, A John Camm. (2005) The sinus tachycardias. Nature Clinical Practice Cardiovascular Medicine 2:1, 44-52
CrossRef32
Atul Pathak, Jean-Michel Senard. (2004) Pharmacology of orthostatic hypotension in Parkinson’s disease: from pathophysiology to management. Expert Review of Cardiovascular Therapy 2:3, 393-403
CrossRef33
Bonnie Sealey, Karen Lui. (2004) Diagnosis and Management of Vasovagal Syncope and Dysautonomia. AACN Clinical Issues: Advanced Practice in Acute and Critical Care 15:3, 462-477
CrossRef34
Andrea S Winkler, Timothy J Peters, Joanne T Marsden, Allan C Deacon, Georgina Chandler, Iain C Macdougall. (2003) Erythropoietin treatment in the neuropsychiatric porphyrias. Clinica Chimica Acta 338:1-2, 61-66
CrossRef35
M. Yousuf Kanjwal, Daniel J. Kosinski, Blair P. Grubb. (2003) Treatment of postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. Current Cardiology Reports 5:5, 402-406
CrossRef36
YOUSUF KANJWAL, DAN KOSINSKI, BLAIR P. GRUBB. (2003) The Postural Orthostatic Tachycardia Syndrome:. Definitions, Diagnosis, and Management. Pacing and Clinical Electrophysiology 26:8, 1747-1757
CrossRef37
AS Winkler, DR Bosman. (2003) Symptomatic postural hypotension in diabetes: aetiology and management. Practical Diabetes International 20:6, 219-225
CrossRef38
BLAIR P. GRUBB, DANIEL J. KOSINSKI, YOUSUF KANJWAL. (2003) Orthostatic Hypotension:. Pacing and Clinical Electrophysiology 26:4p1, 892-901
CrossRef39
Simona Maule, Mirko Tredici, Sara Del Colle, Livio Chiandussi. (2003) Treatment of Patients with Neurogenic Orthostatic Hypotension. High Blood Pressure & Cardiovascular Prevention 10:2, 95-103
CrossRef40
William H. Frishman, Victor Azer, Domenic Sica. (2003) Drug Treatment of Orthostatic Hypotension and Vasovagal Syncope. Heart Disease 5:1, 49-64
CrossRef41
KAZUNOBU KAWAKAMI, HARUHIKO ABE, NOBUYA HARAYAMA, YASUHIDE NAKASHIMA. (2003) Successful Treatment of Severe Orthostatic Hypotension with Erythropoietin. Pacing and Clinical Electrophysiology 26:1p1, 105-107
CrossRef42
Horacio Kaufmann. (2002) Treatment of Patients With Orthostatic Hypotension and Syncope. Clinical Neuropharmacology 25:3, 133-141
CrossRef43
Maxime Lamarre-Cliche. (2002) Drug Treatment of Orthostatic Hypotension Because of Autonomic Failure or Neurocardiogenic Syncope. American Journal of Cardiovascular Drugs 2:1, 23-35
CrossRef44
Peter D. Donofrio, James B. Caress. (2001) AUTONOMIC DISORDERS. The Neurologist 7:4, 220-233
CrossRef45
Andrea S. Winkler, Joanne Marsden, Matthew Parton, Peter J. Watkins, K. Ray Chaudhuri. (2001) Erythropoietin deficiency and anaemia in multiple system atrophy. Movement Disorders 16:2, 233-239
CrossRef46
Blair P. Grubb, Daniel J. Kosinski. (2001) Syncope Resulting from Autonomic Insufficiency Syndromes Associated with Orthostatic Intolerance. Medical Clinics of North America 85:2, 457-472
CrossRef47
Olaf Oldenburg, Anna Mitchell, Jens Nürnberger, Susanne Koeppen, Raimund Erbel, Thomas Philipp, Andreas Kribben. (2001) Ambulatory norepinephrine treatment of severe autonomic orthostatic hypotension. Journal of the American College of Cardiology 37:1, 219-223
CrossRef48
Kathryn E Boehm, Edith J Morris, Katrinka T Kip, Barry Karas, Blair P Grubb. (2001) Diagnosis and management of neurally mediated syncope and related conditions in adolescents. Journal of Adolescent Health 28:1, 2-9
CrossRef49
Daniel J. Kosinski, Blair Grubb. (2000) Vasodepressor syncope. Current Treatment Options in Cardiovascular Medicine 2:4, 309-315
CrossRef50
David H. P. Streeten, Deaver Thomas, David S. Bell. (2000) The Roles of Orthostatic Hypotension, Orthostatic Tachycardia, and Subnormal Erythrocyte Volume in the Pathogenesis of the Chronic Fatigue Syndrome. The American Journal of the Medical Sciences 320:1, 1-8
CrossRef51
Patrizia Cotroneo, Bianca Maria Ricerca, Lucia Todaro, Dario Pitocco, Andrea Manto, Valeria Ruotolo, Sergio Storti, Patrizia Damiani, Salvatore Caputo, Giovanni Ghirlanda. (2000) Blunted erythropoietin response to anemia in patients with Type 1 diabetes. Diabetes/Metabolism Research and Reviews 16:3, 172-176
CrossRef52
BARRY KARAS, BLAIR P. GRUBB, KATHY BOEHM, KATRINKA KIP. (2000) The Postural Orthostatic Tachycardia Syndrome: A Potentially Treatable Cause of Chronic Fatigue, Exercise Intolerance, and Cognitive Impairment in Adolescents. Pacing and Clinical Electrophysiology 23:3, 344-351
CrossRef53
Johannes J. Lieshout, A. Derk Jan Harkel, Wouter Wieling. (2000) Fludrocortisone and sleeping in the head-up position limit the postural decrease in cardiac output in autonomic failure. Clinical Autonomic Research 10:1, 35-42
CrossRef54
Douglas W. Zochodne. (2000) Diabetic neuropathies. Current Treatment Options in Neurology 2:1, 23-29
CrossRef55
A. S. Winkler, J. Marsden, K. R. Chaudhuri, H. Hambley, P. J. Watkins. (1999) Erythropoietin depletion and anaemia in diabetes mellitus. Diabetic Medicine 16:10, 813-819
CrossRef56
BLAIR P. GRUBB, BARRY KARAS. (1999) Clinical Disorders of the Autonomic Nervous System Associated with Orthostatic Intolerance: An Overview of Classification, Clinical Evaluation, and Management. Pacing and Clinical Electrophysiology 22:5, 798-810
CrossRef57
GIRIS JACOB, ITALO BIAGGIONI. (1999) Idiopathic Orthostatic Intolerance and Postural Tachycardia Syndromes. The American Journal of the Medical Sciences 317:2, 88-101
CrossRef58
DAVID H. P. STREETEN. (1999) Orthostatic Intolerance. A Historical Introduction to the Pathophysiological Mechanisms. The American Journal of the Medical Sciences 317:2, 78-87
CrossRef59
Christopher J. Mathias, DPhil, DSc, FRCP, Jeffery R. Kimber, BSc, MB, BS, MRCP. (1999) POSTURAL HYPOTENSION: Causes, Clinical Features, Investigation, and Management. Annual Review of Medicine 50:1, 317-336
CrossRef60
L. Keselbrener, A. Korzets, S. Akselrod. (1997) Failure of erythropoietin treatment in a case with primary autonomic failure. Clinical Autonomic Research 7:6, 333-336
CrossRef61
BLAIR P. GRUBB, DANIEL J. KOSINSKI, KATHY BOEHM, KATRINKA KIP. (1997) The Postural Orthostatic Tachycardia Syndrome: A Neurocardiogenic Variant Identified During Head-Up Tilt Table Testing. Pacing and Clinical Electrophysiology 20:9, 2205-2212
CrossRef62
Horacio Kaufmann. (1997) Neurally Mediated Syncope and Syncope Due to Autonomic Failure: Differences and Similarities. Journal of Clinical Neurophysiology 14:3, 183-196
CrossRef63
B. NAIR, J. LEITCH, A. BLACK. (1996) Erythropoietin treatment for postural hypotension from autonomic dysfunction. Australian and New Zealand Journal of Medicine 26:6, 859-860
CrossRef64
Fernando Valderrábano. (1996) Erythropoietin in chronic renal failure. Kidney International 50:4, 1373-1391
CrossRef65
DAVID BN LEE, ZESONG ZHANG, MING-SHU HU, NORA JAMGOTCHIAN, JACK D BARRETT, HARRY J WARD, PETER EGGENA. (1996) The effect of erythropoietin on the cardiovascular system. Nephrology 2:s1, s199-s202
CrossRef66
JM Senard, JL Montastruc. (1996) Which drug for which orthostatic hypotension?. Fundamental & Clinical Pharmacology 10:3, 225-233
CrossRef67
Alan J. McDougall, James G. McLeod. (1996) Autonomic neuropathy, I. Clinical features, investigation, pathophysiology, and treatment. Journal of the Neurological Sciences 137:2, 79-88
CrossRef68
Mark E Williams. (1995) Management of the diabetic transplant recipient. Kidney International 48:5, 1660-1674
CrossRef69
Vincenza Spallone, Luigi Uccioli, Guido Menzinger. (1995) Diabetic autonomic neuropathy. Diabetes / Metabolism Reviews 11:3, 227-257
CrossRef70
R. Perera, L. Isola, H. Kaufmann. (1995) Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clinical Autonomic Research 5:4, 211-213
CrossRef71
Malcolm F Hand, William G Haynes, Heather A Johnstone, John L Anderton, David J Webb. (1995) Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. Kidney International 48:3, 806-813
CrossRef72
J. L. Ducla-Soares, P. M. Santos. (1995) Energy expenditure and anaemia of autonomic failure. Clinical Autonomic Research 5:3, 179-179
CrossRef73
T.S. Purewal, P.J. Watkins. (1995) Postural Hypotension in Diabetic Autonomic Neuropathy: a Review. Diabetic Medicine 12:3, 192-200
CrossRef74
Roy Freeman, Richard J. Cohen, J. Philip Saul. (1995) Transfer function analysis of respiratory sinus arrhythmia: A measure of autonomic function in diabetic neuropathy. Muscle & Nerve 18:1, 74-84
CrossRef75
Dan Ziegler. (1994) Diabetic cardiovascular autonomic neuropathy: Prognosis, diagnosis and treatment. Diabetes / Metabolism Reviews 10:4, 339-383
CrossRef76
G. Barosi. (1994) Inadequate erythropoietin response to anemia: definition and clinical relevance. Annals of Hematology 68:5, 215-223
CrossRef77
Alan M. Berg, Jennifer J. Anderson, Stuart R. Chipkin, Victor K. Lee, Martha Skinner, Alan S. Cohen, Robert W. Simms. (1994) Autonomic neuropathy in AL (primary) amyloidosis and its effect on survival. Amyloid 1:1, 39-46
CrossRef
