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Original Studies |
Department of Medicine (R.D.H., G.G.H., K.D.B.), and Departments of Community Medicine, Biostatistics, and Computer Science (G.R.H.), West Virginia University, Morgantown, West Virginia 26506-9159
Address all correspondence and requests for reprints to: Robert D. Hoeldtke, M.D., Ph.D., Department of Medicine, P.O. Box 9159, Morgantown, West Virginia 26506-9159.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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adrenergic agonist),
and octreotide (an SRIH analogue) to each other and to combination
therapy. Sixteen patients participated. Our hypothesis was that the 2
drugs together would be more effective than either drug alone. The effect of the drugs on the hemodynamic response to food ingestion was evaluated while patients were sitting. Midodrine (5 mg orally, 30 min before breakfast) increased mean blood pressure slightly (5–10 mm Hg, over 30 min) before the patients started eating, but it only partially reversed the hypotensive effect of food ingestion. The nadir in postprandial blood pressure after midodrine was 69 ± 4 mm Hg, not different from placebo (63 ± 5). Nevertheless, midodrine accentuated the response to sc octreotide (0.5 µg/kg). Fifteen minutes after octreotide administration to midodrine-pretreated patients, the average mean blood pressure was 115 ± 9 mm Hg, higher (P = .0095) than after octreotide given alone (102 ± 7).
Drug effects on orthostatic hypotension were assessed by measuring standing time (minutes before symptoms of hypotension or definite hypotension). In the absence of treatment, standing time was 3.5 ± 7 min; 1 h after 10 mg midodrine, 8.4 ± 2.7 min (P = .11); after 1.0 µg/kg octreotide, 13.2 ± 3.9 min (P = .0034 vs. no treatment); and after both drugs, 21.2 ± 5.5 min (P = .0002 vs. no treatment, P = .036 vs. octreotide only).
The combination of midodrine and octreotide is more potent than either drug alone.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A new orally active dihydroergotamine like 1 adrenergic
agonist, midodrine or [1-(2', 5'
dimethoxyphenyl)-2-glycinamidoethanol-hydrochloride], has an excellent
safety record and recently has been approved by the Food and Drug
Administration for the treatment of orthostatic hypotension (6, 7, 8). The
purpose of the present study was to compare octreotide and midodrine
with each other and to combination therapy and to determine whether the
synergism previously described for octreotide and dihydroergotamine
could similarly be demonstrated for octreotide and midodrine.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Sixteen patients with autonomic neuropathy and chronic
orthostatic hypotension participated (Table 1
). All patients complained of
orthostatic dizziness; 8 had experienced orthostatic syncope, 5 had
experienced postprandial syncope, and 7 had lost the confidence to walk
outside their home environment. Reversible causes of orthostatic
hypotension (such as Addison’s Disease, dehydration, gastrointestinal
bleeding, or vasodilator drugs) were excluded, on the basis of the
history and physical and routine laboratory studies.
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) had pure autonomic failure, 4 had diabetic autonomic
neuropathy (patients 11–14), and 1 (patient 15) had multiple system
atrophy. Assessment of autonomic function
The hemodynamic response to standing was assessed in the morning, before breakfast. Blood pressure was measured electronically at 1-min intervals, with an Accutorr III (Datascope, Paramus, New Jersey), before and after the patients stood for 2 min. Blood was drawn for plasma norepinephrine before and after standing. Norepinephrine was measured by high-performance liquid chromatography with Coulochem detection (9) in American Medical Laboratories, Chantilly, VA. Two patients, unable to stand for 2 min, had blood drawn while they were on a tilt table, adjusted to the maximum angle the patient could tolerate (60° for patient 7, 45° for patient 15) for 2 min.
The diagnosis of autonomic neuropathy was confirmed by measuring the
beat-to-beat variation with deep breathing, a test of cardiac
parasympathetic function; and the heart rate response to the Valsalva
maneuver, a measure of cardiac innervation, the baroreceptor reflex,
and the efferent limb of the sympathetic nervous system (10).
Peripheral sympathetic involvement was evaluated by autonomic surface
potential analysis, a measure of the sympathetic sudomotor activity in
the skin (11). All patients had either a decreased plasma
norepinephrine increment with standing or poor performance on at least
one autonomic function test. Eight patients performed poorly on two or
more tests (Table 1).
Experimental design
Most patients (n = 13) were studied while hospitalized at West Virginia University Hospital and while being administered a diet containing 130 meq of sodium daily. Three individuals participated as outpatients. Five of the patients were being treated with fludrocortisone at the time of referral, and this was continued at a fixed daily dose (0.1 mg/day in three patients and 0.2 mg/day in two). Other pressor agents were discontinued at least 1 week before the experiments. Midodrine was supplied by Roberts Pharmaceuticals (Eatontown, NJ). The placebo (Cebocaps) was purchased from Forest Pharmaceuticals, St. Louis, Missouri.
Treatment with midodrine and octreotide was approved by the Institutional Review Board of West Virginia University, and informed written consent was obtained.
Protocol 1
Effect of drug treatment on the hemodynamic response to breakfast. Patients (n = 9) were instructed to sit in a chair at 0800 h, and mean arterial blood pressure was measured every 15 min for 31/2 h. After 30 min, the patients were given a caffeine-free breakfast (425 Cal, 70% from carbohydrate). All patients received, on separate days, each of the four treatments (midodrine, 5 mg orally; octreotide, 0.5 µg/kg sc; midodrine plus octreotide in the stated doses; or a placebo). The midodrine or placebo was given orally 30 min before breakfast to see if its maximal effect at 1–2 h would prevent the postprandial nadir that generally occurs 1–11/2 h after eating. The octreotide was injected 15 min after the beginning of breakfast.
The order in which the drugs (midodrine, octreotide, or placebo) were administered individually was assigned randomly. Because we were concerned about an excessive pressor response to octreotide in midodrine-pretreated patients, we elected not to randomly assign patients to the midodrine octreotide combination until we had established that they were not extremely sensitive to octreotide given alone. Thus, the midodrine octreotide combination was always the last treatment administered.
Protocol 2
Effect of low dose (5 mg) vs. high dose (10 mg) midodrine on blood pressure while patients were sitting, before and after breakfast.Patients (n = 10) were instructed to sit in a chair at 0800 h, and blood pressure was monitored every 15 min, before and after breakfast, for 31/2 h, just as in Protocol 1. All patients received, on separate consecutive days, each of the three treatments (placebo, 5 mg midodrine, or 10 mg midodrine), which were given in random sequence after the first blood pressure measurement, 30 min before breakfast.
Protocol 3
Effect of midodrine (10 mg) or octreotide (1.0 µg/kg), alone and in combination, on standing time and standing blood pressure. Patients (n = 12) selected for this protocol had, on previous days, received octreotide (0.3–0.5 µg/kg) and were known to tolerate these doses. This protocol was performed, after an overnight fast, at 0800 h. Patients were instructed to rest comfortably in the semirecumbent posture with the head of the bed elevated 30 degrees for at least 15 min and then, on separate days, they received (according to a randomized design) either midodrine (10 mg, orally), octreotide (1.0 µg/kg, sc), or no treatment. Patient 2, who was susceptible to the gastrointestinal side effects of octreotide, was given only 0.3 µg/kg. Nine of the 12 participants in this protocol, after receiving each drug individually, agreed to be treated with the combination of midodrine and octreotide, given in the same doses and same time sequence described above for the drugs given alone. Three individuals (patients 10, 14, and 15) did not receive the combination of drugs, because octreotide given alone caused nausea or an excessive pressor response. One hour after the midodrine or 8 min after the octreotide, the patients were instructed to stand by the side of their bed until they developed dizziness, neck pain, blurred vision, the perception that they might lose consciousness, or other symptoms that prevented them from continuing to stand. Blood pressure was monitored every minute, or more frequently if the patient seemed unstable or presyncopal. The protocol was terminated if any of these symptoms developed or if the patient developed hypotension (one systolic blood pressure reading below 60 mm Hg or two consecutive readings below 65). Standing time, to the nearest minute, was recorded as the time the patient was able to maintain the upright posture before the onset of hypotension or symptoms of cerebral hypoperfusion.
Statistical methods
All data presented in the text represents mean ± SE. The effect of midodrine and octreotide on blood pressure, over time, was analyzed by repeated-measures ANOVA, and comparison between treatments was assessed using orthogonal contrasts (12). We assumed there were no between-treatment carryover effects, because the plasma half-life of octreotide after sc administration is 100–130 min; the plasma half-life of midodrine is 130 min.
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Results |
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After placebo treatment, the mean blood pressure deceased
gradually, while the patients were sitting, from 85 ± 6 mm Hg; to
63 ± 5 mm, 75 min after the beginning of breakfast (Fig. 1). On the days that the patients
received midodrine, the baseline blood pressure was 77 ± 6 mm Hg;
and 86 ± 9, 30 min after treatment (P = 0.10).
The hypotensive effect of food ingestion then became evident, and the
blood pressure decreased to a nadir of 69 ± 4 mm Hg, not
different from the nadir after placebo (63 ± 5 mm Hg).
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). No patient had an excessive pressor response to
octreotide or intolerable side effects; therefore, all were given
combination therapy. Administration of octreotide to
midodrine-pretreated patients increased blood pressure from 88 ±
6 mm Hg at 15 min, to 115 ± 9 at 30 min; and the blood pressure
remained about 10–13 mm Hg higher than when octreotide was given alone
from 30–120 min (P < 0.01–0.05, as indicated in Fig. 1). Protocol 2
Low-dose (5 mg) and high-dose (10 mg) midodrine increased sitting
blood pressure while patients were fasting. At the beginning of
breakfast (30 min after drug treatment), the mean blood pressure was
100 ± 10 mm Hg after 10 mg midodrine and 91 ± 8 after 5 mg
midodrine [significantly higher (P < 0.01) for each
dose than after placebo treatment], which resulted in an average mean
blood pressure of 77 ± 5 mm Hg at time zero. The pressor effect
of midodrine, most evident at the beginning of breakfast, persisted
during the postprandial period, despite its attenuation by the
hypotensive effect of food ingestion (Fig. 2). The blood pressure after 10 mg
midodrine was significantly higher (P < 0.05) than
after 5 mg midodrine, at all time points except 90 and 105 min.
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In the absence of treatment, the patients with autonomic
neuropathy were able to stand 3.5 ± .7 min (Fig. 3). After midodrine, standing time was
8.4 ± 2.7 min (P = .11); and after octreotide,
standing time increased to 13.2 ± 3.9 min (P =
.0034). The subset of patients (n = 9), treated with both
midodrine and octreotide, stood for 21.2 ± 5.5 min (different
from no treatment, P = .0002). Combination therapy was
more effective than midodrine only (P = .002) and
octreotide only (P = .036). The synergism between
midodrine and octreotide was striking for certain individuals (patients
2 and 3), who were able to stand for much longer times after
combination therapy than when the drugs were given individually (Fig. 4). In three patients (5, 7, 13),
however, combination therapy failed to reverse the hypotensive effect
of standing.
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Midodrine was well tolerated by most patients, although 6 of 16 patients complained of pruritis of the scalp or a goose-flesh sensation (6, 7). Two patients developed urgency on urination, and three developed supine hypertension, during chronic therapy. Two of three patients with diabetic autonomic neuropathy who received octreotide and six of the nondiabetic patients developed gastrointestinal complaints after octreotide.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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adrenergic agonist and vasoconstrictor. When used
alone, it is relatively ineffective in counteracting the hypotensive
effect of eating, which suggests that, like dihydroergotamine, it has
little or no effect on the splanchnic circulation (1). Postprandial
hypotension is a well-documented, but frequently unrecognized, feature
of autonomic neuropathy (3). It may obscure the therapeutic effect of
pressor drugs and confuse the assessment of their benefit (13, 14).
Hirayama et al. reported that ingestion of breakfast
reversed the pressor effect of midodrine (15). We confirmed that blood
pressure decreases postprandially after midodrine, but the pressure
remains 10–20 mm Hg higher than after placebo (Fig. 2) because the
pressor effect, established while patients are fasting, persists (even
though it is attenuated postprandially). In this series of patients,
midodrine was less effective in counteracting orthostatic hypotension
than has been indicated in other recent reports (6, 7, 8). Our results may
be different because our patients had more severe hypotension. Jankovic
et al. (6) and Low et al. (8) used an inclusion
criterion of an orthostatic decrease in systolic blood pressure of only
15 mm Hg. The average supine and upright blood pressures in our
patients were 133 ± 6/76 ± 3 and 80 ± 3/54 ± 3,
respectively, and the average orthostatic decrease in systolic blood
pressure was 53 ± 6 mm Hg. Moreover, we based our assessment on
the measurement of standing time, as well as standing blood pressure.
Jankovic et al. (6), Fouad-Tarazi et al. (7), and
Low et al. (8) assessed therapy by measuring blood pressure
after the patient stood only 1 min. Improvement in blood pressure after
this inadequate orthostatic stress does not provide rigorous proof of
drug efficacy. Proper documentation of the efficacy of new treatments
of orthostatic hypotension should include the measurement of standing
time (which should be measured in the morning, before breakfast) and
evidence that the putative therapy increases the time the patient can
tolerate the upright posture (16, 17, 18, 19). Improvement in standing time is
a stringent criterion, because motionless standing promotes orthostatic
venous pooling, which the act of walking tends to counteract (17).
Thus, patients who are able to stand for 10 min may be able to walk for
40–60 min, or even longer. We observed only a modest pressor effect of
midodrine and a marginal effect on standing time, yet patients felt
better after therapy (20), especially while walking.
Octreotide’s pressor effect is distinct from that of midodrine and
other agonists in a number of ways. Octreotide acts independently
of the adrenergic nervous system, is a splanchnic (as well as a
systemic vasoconstrictor), and increases cardiac output (1, 21).
Octreotide is more potent than midodrine and is highly effective in
reversing the hypotensive effect of food ingestion; yet, it fails to
reliably prevent the powerful hypotensive effect of standing, shown by
patients disabled from orthostatic hypotension (4, 5). Moreover, its
gastrointestinal side effects frequently prevent the use of therapeutic
doses. Patients with diabetic autonomic neuropathy are more vulnerable
to the gastrointestinal side effects of octreotide than are patients
with idiopathic autonomic neuropathy, and chronic therapy is generally
ineffective in diabetic patients. Approximately half of patients with
pure autonomic failure or multiple system atrophy develop loose bowel
movements or diarrhea after octreotide; but in some instances, this
resolves with reduction in octreotide dose. We recommend starting
patients on a low dose of octreotide (0.1-.15 µg/kg) and then
gradually increasing that to 0.4–1.2 µg/kg as needed or until
gastrointestinal symptoms develop. Because octreotide suppresses
exocrine pancreatic function (22) and, therefore, disrupts digestion
and absorption, pancreatic enzyme supplements should be provided to
patients who develop loose bowel movements (and the dose of octreotide
should be titrated, accordingly). We have observed patients who
experienced gastrointestinal symptoms during the first week of
treatment, but these symptoms subsided with chronic therapy. Others
have similarly reported that gastrointestinal effects of octreotide may
resolve during chronic therapy in patients with acromegaly (23, 24).
Although neither midodrine, octreotide, nor the combination provides ideal therapy for orthostatic hypotension, the two drugs tend to complement each other. Midodrine’s pressor effect is attenuated postprandially, but octreotide compensates for this shortcoming. Midodrine complements octreotide by potentiating its pressor effect, particularly while patients are standing. This may make it possible to use a lower dose of octreotide in those with gastrointestinal side effects. Most patients placed on chronic octreotide therapy should be pretreated with midodrine 1–2 h before each injection of octreotide.
In summary, midodrine and octreotide have synergistic pressor effects, which are therapeutically useful in patients with low blood pressure as a result of autonomic neuropathy. The two drugs act by different mechanisms, affect different vascular beds, and complement each other clinically.
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Footnotes |
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Received May 28, 1997.
Revised October 22, 1997.
Accepted October 27, 1997.
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References |
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1
and ß1 adrenergic agonists. J Auton Nerv Syst. 45:149–154.[CrossRef][Medline]
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, midodrine;
, octreotide; 
, midodrine plus octreotide. Error bars are omitted
for the midodrine treatment, for clarity of presentation. *, Drug
treatment was different from placebo, P < 0.01;
, drug treatment was different from placebo, P <
.05; 
, combination therapy was different from octreotide only and
midodrine only, P < .05; §, combination therapy
was different from octreotide only and midodrine only,
P < 0.025; , combination therapy was different
from octreotide only and midodrine only, P <
0.01.
