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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.
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 1). 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.
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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 2). 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.
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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 microm3. 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 3). The mean weight of the patients before and after erythropoietin therapy was 63.4 ±12.3 and 64.1 ±12.2 kg, respectively.
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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 well16,17,18. 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
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