Severe Orthostatic Hypotension Research Articles

Beta-adrenergic blood pressure regulation in shy-drager syndrome and pheochromocytoma

Both Shy-Drager syndrome and pheochromocytoma are characterized by an abnormal catecholamine secretion, e.g. a reduced secretion in Shy-Drager syndrome, and an excessive stimulation in pheochromocytoma resulting in adrenergic dysfunction and in adrenergic hyperactivity, respectively. The relationship between extreme variations in circulating catecholamines and beta-adrenergic receptor activity was studied in two patients with severe orthostatic hypotension (Shy-Drager syndrome) and in a patient with pheochromocytoma with excessive spontaneous catecholamine increases using the lymphocyte beta 2-adrenoceptor assay. In both patients with Shy-Drager syndrome, basal plasma concentrations of epinephrine and dopamine were low under resting conditions and could not be stimulated in the upright position. Norepinephrine was low in the first patient, and could not be stimulated; whereas the second patient had a normal basal concentration of norepinephrine, which could be moderately stimulated. There was no beta-adrenoceptor abnormality in the first patient: however, in the second patient, there were no measurable beta-adrenoceptors on membrane fractions, whereas a population of receptors only in the low affinity state could be identified on intact cells. Alpha-adrenoceptor density on thrombocyte membranes was slightly increased in both patients with Shy-Drager syndrome and showed no substantial change during upright posture. Catecholamine increases in the pheochromocytoma patient were accompanied by a rise in blood pressure, bradycardia, and an acute up-regulation of beta-adrenoceptors. Plasma concentrations of cAMP paralleled the increase in receptor density and blood pressure. The findings in pheochromocytoma add support to the theory that an acute catecholamine stimulation gives rise to an acute beta-adrenergic sensitization leading to blood pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis of transient ischemic attacks and stroke in baboons.

We describe a series of experiments in which a subhuman primate model was used to create temporary and permanent cerebral ischemia by three separate mechanisms. In the first group of five baboons, a hemodynamic model was produced by creating unilateral and bilateral carotid stenotic lesions of varying degrees with and without associated reduction in systemic perfusion pressure. Only global ischemic changes and no focal changes resulted. In the second group of three baboons, a macroembolic model was produced by introducing solid particulate material into the extracranial circulation. No reversible contralateral focal neurologic changes resulted. In the third group of 11 baboons, cerebral ischemia was produced by introducing agents known to cause platelet aggregation (arachidonic acid, adenosine diphosphate, and collagen) into the extracranial arterial circulation. Arachidonic acid caused seizures, adenosine diphosphate caused severe postural hypotension, and only collagen fibrils produced a picture resembling a transient ischemic attack. We propose a theory that intravascular activation of the prostaglandin cascade by chemical initiation may result in the pathophysiologic changes of transient cerebral ischemia.

Orthostatic Hypotension Occurring After Discontinuation of Long-Term Minoxidil Therapy

Minoxidil (Loniten), a potent predominant arteriolar vasodilator, provides prompt and effective reduction of blood pressure in many patients with severe hypertension. Minoxidil results, however, in profound reflex tachycardia and increased plasma volume almost always necessitating concomitant use of beta-adrenergic blocking agents and diuretics. Hypertrichosis and massive fluid retention are troublesome adverse reactions that may require discontinuation of minoxidil and initiation of an alternative antihypertensive agent. When minoxidil is discontinued, diuretic dosage requires re-evaluation and possible tapering to prevent volume depletion. Volume depletion is a risk factor in patients with persistent peripheral edema, sodium deprivation or dehydration; these states may interfere with physiologic mechanisms that maintain adequate cerebral perfusion upon standing, triggering orthostatic hypotension and potential syncope. Hypertension clinic visits should routinely include supine followed by sitting and standing blood pressure determinations to ensure detection of orthostatic hypotension. Described in the article is a case study in which a patient developed severe orthostatic hypotension one month after minoxidil was discontinued. Pathophysiologic mechanisms are discussed.

Treatment of neurogenic orthostatic hypotension with amezinium metilsulfate, a new indirect sympathomimetic drug.

Amezinium metilsulfate is a new, indirectly acting sympathomimetic drug which exclusively affects postganglionic sympathetic neurons and inhibits both intraneuronal monoamine oxidase and norepinephrine reuptake. We examined the short-term effects of amezinium in five patients with severe neurogenic orthostatic hypotension. Single-dose administration of amezinium (10 mg) raised both the supine and sitting mean blood pressures by 15 to 45 mm Hg for 8 hours, with a slight increase in the plasma norepinephrine level. Repeated administration of amezinium (10 to 40 mg/d) produced an increase in sitting blood pressure in three patients and improvement of the orthostatic symptoms in all patients without remarkable recumbent hypertension. The heart rate was increased in two patients. The results indicate that amezinium is of therapeutic value for the treatment of neurogenic orthostatic hypotension. The adrenergic effect of amezinium on the blood pressure and heart rate apparently was related to a slight increase in endogenous norepinephrine in the presence of alpha- and beta-adrenoreceptor supersensitivity.

Cisplatin and Hyponatremia

Letters and Corrections1 May 1988Cisplatin and HyponatremiaXAVIER MARIETTE, M.D., BERNARD PAULE, M.D., PASCAL BENNET, M.D., DIDIER CLERC, M.D., MICHEL BISSON, M.D., PIERRE MASSIAS, M.D.XAVIER MARIETTE, M.D.Search for more papers by this author, BERNARD PAULE, M.D.Search for more papers by this author, PASCAL BENNET, M.D.Search for more papers by this author, DIDIER CLERC, M.D.Search for more papers by this author, MICHEL BISSON, M.D.Search for more papers by this author, PIERRE MASSIAS, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-108-5-770_2 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Hutchinson and associates (1) reported renal salt wasting in 7 of 70 patients treated with cisplatin. These patients had severe persistent orthostatic hypotension requiring prolonged treatment with fludrocortisone and sodium chloride supplements. Six of these patients had hyponatremia (116 to 132 mmol/L). Plasma renin activity and aldosterone concentration were low. The stimulation of vasopressin activity by the resultant hypovolemia might account for the hyponatremia.Of 20 patients treated with cisplatin during the last 2 years for skeletal metastases, we observed six episodes of transient hyponatremia (less than 130 mmol/L) without symptomatic orthostatic hypotension in 3...

Severe orthostatic hypotension during treatment of falciparum malaria.

Severe orthostatic hypotension during treatment of falciparum malaria.

Quantitative study of lateral horn cells in 15 cases of multiple system atrophy.

Nerve cell counts of the lateral horns of the spinal cord were performed in 15 cases of multiple system atrophy (MSA) and three age- and sex-matched controls. The patients with MSA were comprised of eight with severe postural hypotension, three with orthostatic hypotension and little or no disability and four without any signs of autonomic failure. All cases of MSA had lost more than half their lateral horn cells but nerve cell loss could not be correlated with the degree of dysautonomia. These results confirm the involvement of the intermediolateral columns of the spinal cord in MSA. However, the lack of correlation between cell loss and severity of autonomic failure in our cases, suggests that lesions of other sites, such as sympathetic ganglia or the dorsal vagal nuclei, are also implicated in dysautonomia.

Renal salt wasting in patients treated with cisplatin.

Although cisplatin nephrotoxicity is well documented, renal sodium wasting has rarely been reported. Seven of seventy patients treated with cisplatin over 18 months developed salt-wasting nephropathy and orthostatic hypotension. All patients presented 2 to 4 months after starting cisplatin with severe orthostatic hypotension (mean orthostatic change in blood pressure, -37 +/- 8 mm Hg) without preceding extrarenal volume loss or diuretic use. Urinary sodium concentration was 85 to 145 mmol/L, fractional excretion of sodium was 1.0% to 8.0%, and urinary osmolar concentration was 340 to 619 mmol/kg, while orthostatic hypotension was present. Six patients were hyponatremic (116 to 137 mmol/L). Serum creatinine and urea levels were elevated in five patients but fell after rehydration. Vasopressin averaged 5.4 pg/mL (2.1 to 12.7 pg/mL) (n = 5) and was suppressed with hydration (mean, 2.5 pg/mL, 1.5 to 4.3 pg/mL). Plasma renin activity was undetectable in two patients and low in three patients, and aldosterone was low in six patients despite clinical volume depletion. Cisplatin may produce renal salt wasting causing symptomatic orthostatic hypotension and hyponatremia associated with abnormalities of the renin-aldosterone system.

EFFECT OF UNNATURAL NORADRENALINE PRECURSOR ON SYMPATHETIC CONTROL AND ORTHOSTATIC HYPOTENSION IN DOPAMINE-BETA-HYDROXYLASE DEFICIENCY

A patient with severe orthostatic hypotension due to dopamine-beta-hydroxylase deficiency was treated with the unnatural aminoacid D,L-threo-3, 4-dihydroxyphenylserine (DOPS) in the hope that it would serve as a substrate of aromatic-L-aminoacid decarboxylase to produce (-)-noradrenaline. With a dose of 500 mg twice daily by mouth, blood pressure rose gradually from 100/55 to 145/85 mm Hg, and orthostatic hypotension disappeared. After 4 months' treatment the patient is free of symptoms and able to live a normal life. DOPS switched on the production of noradrenaline and reduced the excessive production of dopamine. During treatment plasma noradrenaline rose normally after standing and after infusion of tyramine, a biogenic amine that liberates stored neurotransmitter from sympathetic nerve terminals. These data demonstrate that in congenital dopamine-beta-hydroxylase deficiency dopamine instead of noradrenaline is released as the sympathetic neurotransmitter but that the integrity of the sympathetic neuron is otherwise intact.

Cardiovascular Effects of Imipramine and Bupropion in Depressed Patients with Congestive Heart Failure

There has been a long-standing concern over the cardiovascular effects of tricyclic antidepressants, particularly in patients with preexisiting cardiac disease. Recent studies have demonstrated that imipramine causes no deleterious effect on ejection fraction as determined by radionuclide angiography in patients with impaired left ventricular function (LVF). However, the high rate of severe orthostatic hypotension induced by imipramine makes use of the drug problematic in these patients. Bupropion is a new antidepressant of the aminoketone class which is structurally unrelated to the tricyclics and which is relatively free of cardiac side effects in healthy depressed patients. We compared imipramine and bupropion in 10 depressed patients with impaired LVF in a random, double-blind crossover study. Neither imipramine nor bupropion adversely affected ejection fraction or other indices of LVF. However, as previously reported, severe orthostatic hypotension requiring discontinuation of drug developed in 50% of patients on imipramine. This difficulty did not occur with bupropion. From a cardiac perspective, bupropion may offer a safe alternative to imipramine in depressed patients with congestive heart failure.

Substantial effect of acute hydration on blood pressure in patients with autonomic failure.

The effect of acute hydration on arterial blood pressure levels was investigated in ten patients with severe postural hypotension due to autonomic failure. Blood pressure and heart rate were determined in the supine and 60-degree head-up tilted position. Plasma volume and left ventricular ejection fraction were measured in the supine position. Measurements were repeated after rapid infusion of 11 of isotonic saline. Acute hydration resulted in increased supine mean blood pressure levels (P less than 0.01) despite normal plasma volumes in all patients. The postural reductions in mean blood pressure were reduced from 40 mmHg before to 20 mmHg after saline (median values, P less than 0.01). The results indicate that normal plasma volumes do not ensure optimal circulatory status in patients with autonomic failure. Acute hydration with isotonic saline may be used for immediate corrections of blood pressure levels in patients with autonomic failure and the response to acute hydration may be used as an indicator of the circulatory status in these patients.

CONGENITAL DOPAMINE-BETA-HYDROXYLASE DEFICIENCY: A Novel Orthostatic Syndrome

A woman was referred with severe orthostatic hypotension at the age of 21. Ptosis, skeletal muscle hypotonia, and recurrent hypoglycaemia had been noticed in early childhood. There was noradrenergic denervation and adrenomedullary failure but baroreflex afferents, cholinergic innervation, and adrenocortical function were intact. Noradrenaline and adrenaline were undetectable in plasma, urine, and cerebrospinal fluid (CSF), but dopamine was 7-fold to 12-fold normal in plasma, 4-fold normal in urine, and 20-fold normal in CSF. Measurements of catecholamine metabolites showed further evidence for impairment of noradrenaline and adrenaline biosynthesis due to deficient dopamine-beta-hydroxylation. Dopamine-beta-hydroxylase was undetectable in plasma and CSF. Physiological and pharmacological stimuli of sympathetic neurotransmitter release caused increases in plasma dopamine rather than plasma noradrenaline.

Pharmacodynamics of midodrine, an antihypotensive agent

Midodrine is an orally active adrenergic agonist useful in the treatment of hypotension. We have investigated the pharmacodynamics of its active metabolite after oral midodrine therapy in nine patients with severe orthostatic hypotension. Peak plasma levels of the metabolite were reached in 60 to 90 minutes and ranged from 25 to 56 ng/ml. The mean values for distribution volume, plasma clearance, and t1/2 were 4.0 L/kg, 23 ml/min/kg, and 2.1 hours, respectively. Heart rate increased after 5 to 10 mg doses and the increases were statistically significant (P less than 0.05) at 120 minutes. An apparent increase in blood pressure was not statistically significant. The patients said that they felt better.

Subcutaneous Thoracentesis Utilizing an Ommaya Reservoir in Amyloid Cardiomyopathy

RECURRENT, clinically significant pleural effusions developing in benign and malignant disorders require either repeated thoracentesis or ablation of the pleural space. The former is associated with a risk of pneumothorax and infection, the latter with constitutional symptoms at the time of sclerosis. We recently treated a man whose clinical problems included infiltrative cardiomyopathy, lifethreatening severe pleural effusions, and supine and orthostatic hypotension secondary to primary amyloidosis. 1 Attempts to manage these problems with sodium restriction, diuretics, inotropic agents, and electrical pacing were inadequate and necessitated repeated thoracentesis. Pleural sclerosis was rejected because of two concerns. First, anecdotal reports of procedure failure in effusions secondary to congestive heart failure were known. Second, we believed that pleural ablation might lead to worsening of the contralateral pleural effusion or development of a pericardial effusion. Ommaya reservoirs as currently employed allow access to the cerebral ventricles, allowing for simple and safe sampling of cerebrospinal

Management of chronic orthostatic hypotension

Chronic orthostatic hypotension is characterized by recurrent symptoms of cerebral hypoperfusion due to low upright blood pressure levels. The initial approach should be to identify and correct reversible causes. Persistence of orthostatic hypotension suggests autonomic failure. The goal of management is to minimize symptoms and maximize functional capacity; therefore the magnitude of blood pressure fall is not as important as the advent of symptoms. Therapy is based upon the underlying pathophysiology and the risk/benefit ratio of interventions. Patient education and nondrug measures form the cornerstone of management. Drug therapy is often limited by unacceptable supine hypertension. Rational drug use can be governed by individualized trials of therapy. Patients with moderate or severe orthostatic hypotension are difficult to treat, but can be helped toward resumption of a normal life.

Effect of Oral L-threo-3, 4-Dihydroxyphenylserine on Patients with Severe Orthostatic Hypotension Secondary to Autonomoic Neuropathy

Effect of Oral L-threo-3, 4-Dihydroxyphenylserine on Patients with Severe Orthostatic Hypotension Secondary to Autonomoic Neuropathy

Hyponatremia Due to Cerebral Salt-Wasting Syndrome. Combined Cerebral and Distal Tubular Lesion

A 76-year-old white man was evaluated for a syndrome of hyponatremia, hypotension, and high urinary sodium excretion. There was evidence of inappropriate secretion of antidiuretic hormone and renal salt in the presence of a normal glomerular filtration rate. He had a distal tubular acidification defect and unresponsiveness to standard doses of mineralocorticoids. The renin aldosterone axis was normal, as were thyroid and adrenal function. The patient could not dilute the urine, nor excrete a standard water load. Renal concentrating ability was normal, but there was no additional response to exogenous vasopressin. With modest salt restitution, the patient continued to lose large quantities of sodium in the urine, resulting in severe postural hypotension. Renal biopsy showed normal glomeruli with distinct degeneration of the distal tubules. There was no evidence of an acute inflammatory interstitial nephritis. The patient did not respond to therapeutic doses of mineralocorticoid (fludrocortisone), but treatment with water restriction, increased salt intake, and large doses of mineralocorticoids resulted in a normal serum sodium level and blood pressure. This case falls in the category of cerebral salt wasting syndrome. The cause was a combination of idiopathic secretion of antidiuretic hormone and distal tubular degeneration resulting in pseudohypoaldosteronism.

Adverse Reactions to Monoamine Oxidase Inhibitors. Part II. Treatment Correlates and Clinical Management

From a review of the clinical charts of 198 depressed outpatients, information was extracted on common major treatment emergent side effects associated with phenelzine, tranylcypromine, and imipramine. These included hypertensive reactions, severe orthostatic hypotension, hypomania, significant weight gain, sexual dysfunction, and a residual category of multiple side effects which together culminated in drug discontinuation. In this report, frequency of their occurrence for each drug, level of severity, relation to dose and treatment duration, and physician response at the time the side effect was recorded are described. In addition, procedures found useful in the clinical management of these side effects are discussed.

Hyponatremia due to cerebral salt-wasting syndrome: Combined cerebral and distal tubular lesion

A 76-year-old white man was evaluated for a syndrome of hyponatremia, hypotension, and high urinary sodium excretion. There was evidence of inappropriate secretion of antidiuretic hormone and renal salt wasting in the presence of a normal glomerular filtration rate. He had a distal tubular acidification defect and unresponsiveness to standard doses of mineralocorticoids. The renin aldosterone axis was normal, as were thyroid and adrenal function. The patient could not dilute the urine, nor excrete a standard water load. Renal concentrating ability was normal, but there was no additional response to exogenous vasopressin. With modest salt restitution, the patient continued to lose large quantities of sodium in the urine, resulting in severe postural hypotension. Renal biopsy showed normal glomeruli with distinct degeneration of the distal tubules. There was no evidence of an acute inflammatory interstitial nephritis. The patient did not respond to therapeutic doses of mineralocorticoid (fludrocortisone), but treatment with water restriction, increased salt intake, and large doses of mineralocorticoids resulted In a normal serum sodium level and blood pressure. This case falls in the category of “cerebral salt wasting” syndrome. The cause was a combination of idiopathic secretion of antidiuretic hormone and distal tubular degeneration resulting in pseudohypoaldosteronism.

Primary dysfunction of the afferent limb of the arterial baroreceptor reflex system in a patient with severe supine hypertension and orthostatic hypotension

A 33 year old man with a history of recurrent episodes of orthostatic dizziness since adolescence was noted to have a supine blood pressure of 200/120 mm Hg and a standing blood pressure of 90/60 mm Hg. Results of extensive laboratory studies for secondary hypertension were negative. Studies of the autonomic nervous system function revealed normal plasma catecholamines, cold pressor test and response to 4 minute 30% of maximal static handgrip contraction and an appropriate increase in heart rate on intravenous injection of atropine. In contrast, the heart rate response to phenylephrine and sodium nitroprusside infusion, carotid massage and graded neck suction with an airtight chamber was very abnormal, indicating marked dysfunction of the afferent limb of the arterial baroreceptor reflex system. Methyldopa decreased the supine hypertension and increased the standing blood pressure.