Synergistic effect of norepinephrine transporter blockade and α-2 antagonism on blood pressure in autonomic failure.

Patients with autonomic failure have disabling orthostatic hypotension because of impaired sympathetic activity. Norepinephrine transporter blockade with atomoxetine raises blood pressure in autonomic failure by increasing synaptic norepinephrine concentrations in postganglionic sympathetic neurons. This effect requires tonic release of norepinephrine, which is decreased in patients with low sympathetic tone. We hypothesized that increasing residual sympathetic outflow with the α-2 antagonist yohimbine would potentiate the pressor effect of norepinephrine transporter blockade with atomoxetine and improve orthostatic tolerance in peripheral autonomic failure. Seventeen patients received a single oral dose of either placebo, yohimbine 5.4 mg or atomoxetine 18.0 mg, and the combination yohimbine and atomoxetine in a single blind, crossover study. Blood pressure was assessed while patients were seated and standing for ≤10 minutes before and 1 hour postdrug. Neither yohimbine nor atomoxetine significantly increased seated systolic blood pressure or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated systolic blood pressure and orthostatic tolerance (P<0.001 and P=0.016, respectively) in a synergistic manner. The maximal increase in seated systolic blood pressure seen with the combination was 31±33 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement in orthostatic symptoms. In conclusion, the combination of yohimbine and atomoxetine had a synergistic effect on blood pressure and orthostatic tolerance in peripheral autonomic failure, which may be explained by an increased release of norepinephrine in peripheral sympathetic neurons by α-2 antagonism combined with a reduced norepinephrine clearance by norepinephrine transporter blockade. Safety studies are required to address the clinical usefulness of this pharmacological approach.

The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale.

BACKGROUND: There is no widely accepted validated scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension (NOH). The Orthostatic Hypotension Questionnaire (OHQ) was developed, with two components: the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms. Validation analyses were then performed on the two scales and a composite score of the OHQ. METHODS: The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV, double blind, randomized, cross over, placebo-controlled trial of the alpha agonist midodrine. Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health questionnaire scores. Test-retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change. Responsiveness was examined by determining whether worsening or improvement in the patients' underlying disease status produced an appropriate change in OHQ scores. RESULTS: Baseline data were collected in 137 enrolled patients, follow-up data were collected in 104 patients randomized to treatment arm. Analyses were conducted using all available data. The floor and ceiling effects were minimal. OHQ scores were highly correlated with other patient reported outcome measures, indicating excellent convergent validity. Test-retest reliability was good. OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine, a pressor agent commonly used to treat NOH. CONCLUSION: These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment.

Neurogenic orthostatic hypotension of Parkinson's disease: what exploration for what treatment?

The aim of this short review is to illustrate, using orthostatic hypotension as an example, the clinical problems related to autonomic features in Parkinson's disease. Orthostatic hypotension is frequently encountered in Parkinson's disease and its diagnosis remains manometric (a fall of at least 20 and/or 10 mmHg in standing blood pressure). It is often associated with supine hypertension to be taken into account before prescribing. To distinguish between the role of disease and of drugs (not only antiparkinsonian drugs), a simple clinical test of autonomic nervous system activity (deep breathing test and standing test with measurement of 30/15 ratio) can be used. When diagnosis with multisystem atrophy is discussed, cardiac [¹²³I]-metaiodobenzylguanidine (MIBG) scintigraphy is of value showing in Parkinson's disease a decreased uptake of the radiopharmaceutical indicating postganglionic sympathetic denervation. Concerning treatment, nonpharmacological methods have to be systematically used since no drug has been specifically evaluated for the treatment of orthostatic hypotension of Parkinson's disease.

[General anesthesia in a patient with idiopathic orthostatic hypotension]. / Allgemeinanästhesie bei einem Patienten mit idiopathischer orthostatischer Hypotonie.

Idiopathic orthostatic hypotension (formerly known as Shy-Drager syndrome) is a multiple system atrophy, which is characterized by autonomic dysregulation. Providing perioperative hemodynamic stability during narcosis is therefore a particular challenge. The effects of general anesthesia on systemic vascular resistance and cardiac output in a patient with idiopathic orthostatic hypotension undergoing retropubic prostatectomy will be reported. In the case presented perioperative hemodynamic stability was achieved by aggressive volume therapy guided by global end-diastolic volume measurement and low-dose catecholamine therapy.

Pyridostigmine treatment trial in neurogenic orthostatic hypotension.

BACKGROUND: Midodrine hydrochloride is the only drug demonstrated in a placebo-controlled treatment trial to improve orthostatic hypotension (OH) but it significantly worsens supine hypertension. By enhancing ganglionic transmission, pyridostigmine bromide can potentially ameliorate OH without worsening supine hypertension. OBJECTIVE: To evaluate the efficacy of a single 60-mg dose of pyridostigmine bromide, alone or in combination with a subthreshold (2.5 mg) or suprathreshold (5 mg) dose of midodrine hydrochloride, compared with placebo. DESIGN: We report a double-blind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. A total of 58 patients with neurogenic OH were enrolled. After 1 day of baseline measurements, patients were given 4 treatments (3 active treatments [60 mg of pyridostigmine bromide; 60 mg of pyridostigmine bromide and 2.5 mg of midodrine hydrochloride; 60 mg of pyridostigmine bromide and 5 mg of midodrine hydrochloride] and a placebo) in random order on successive days. Blood pressure (BP) and heart rate were measured, both supine and standing, immediately before treatment and hourly for 6 hours after the treatment was given. RESULTS: No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85). In contrast, the primary end point of the fall in standing diastolic BP was significantly reduced (P = .02) with treatment. Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04) and pyridostigmine and 5 mg of midodrine hydrochloride (BP fall of 27.2 mm Hg vs 34.0 mm Hg with placebo; P = .002). Standing BP improvement significantly regressed with improvement in OH symptoms. CONCLUSIONS: Pyridostigmine significantly improves standing BP in patients with OH without worsening supine hypertension. The greatest effect is on diastolic BP, suggesting that the improvement is due to increased total peripheral resistance.

Fludrocortisone in patients with familial dysautonomia--assessing effect on clinical parameters and gene expression.

The common familial dysautonomia (FD) mutation causes a splicing defect that leads to production of both wild-type (WT) and mutant (MU) IKBKAP mRNA. Because drugs may alter splicing, seven drugs, fludrocortisone, midodrine, diazepam, albuterol, clonidine, caffeine, and dopamine were screened. Since only fludrocortisone negatively altered gene expression, we assessed fludrocortisone's efficacy in treating postural hypotension, and its effect on survival and secondary long-term FD problems. For 341 FD patients we obtained demographic data and clinical information from the last Center evaluation (most current or prior to death) including mean blood pressures (supine, 1 min erect and 5 min erect) and history regarding syncope and presyncope symptoms. For 175 fludrocortisone-treated patients, data from the evaluation prior to start of fludrocortisone and from the last Center evaluation were compared. The fludrocortisone-treated patient cohort was compared to the nontreated patient cohort with respect to overall survival and event-free survival for crisis frequency, worsening gait, frequent fractures, spine curvature, renal insufficiency, and pacemaker insertion. Overall survivals of patients on fludrocortisone alone, on fludrocortisone and midodrine, and on neither drug were compared. Cumulative survival was significantly higher in fludrocortisone-treated patients than in non-treated patients during the first decade. In subsequent decades, the addition of midodrine improved cumulative survival. Fludrocortisone significantly increased mean blood pressures and decreased dizziness and leg cramping, but not headaches or syncope. Fludrocortisone was associated with more long-term problems, which may reflect more symptomatic status associated with longer survival. Our data suggest that fludrocortisone has clinical efficacy despite negative in vitro observations on gene expression.

Drug treatment of orthostatic hypotension because of autonomic failure or neurocardiogenic syncope.

Orthostatic hypotension either because of autonomic failure or neurocardiogenic syncope can be very incapacitating and should be treated accordingly. Drug therapy is frequently needed to alleviate orthostatic symptoms. The physiopathological basis of neurocardiogenic syncope and of autonomic failure is completely different and their treatment should be distinct. In the past 5 years, many randomized, placebo-controlled trials have shed light on the efficacy of specific pressor drugs. In patients with orthostatic hypotension because of autonomic failure, alpha-adrenoceptor agonists, and midodrine in particular, have been shown to increase standing blood pressure and decrease orthostatic symptoms. Other drugs such as octreotide, indomethacin or ergotamine have also been shown to elevate standing blood pressure and/or orthostatic tolerance. Fludrocortisone is a well known and frequently used pressor drug but randomized controlled studies are needed to measure its efficacy. In patients with orthostatic hypotension associated with neurocardiogenic syncope, clinical trials have demonstrated that beta-blockers, especially beta(1)-selective agents without intrinsic sympathomimetic activity such as atenolol, midodrine and paroxetine can decrease recurrence of syncope. Treatment algorithms, such as those presented in this review, should always be interpreted in the light of individual patient characteristics. Many of the drugs used for orthostatic hypotension have multiple indications and contraindications that should influence therapeutic decisions. Little is known about the effectiveness and tolerability of specific combinations of pressor drugs. Consequently, sound clinical judgment and close follow-up of patients should always guide combination therapy.

[Blood pressure and heart rate regulation in diabetics]. / Régulation de la pression artérielle et de la fréquence cardiaque chez les diabétiques.

Cardiac autonomic neuropathy (CAN) is frequent in subclinical stages. Its prognostic value has been demonstrated. Cardiac autonomic neuropathy induces different functional cardiac changes, especially a reduction in left ventricular contractility and changes in ventricular repolarisation. It is also associated with changes in the daily variations in blood pressure. The association of CAN and silent myocardial ischaemia significantly worsens the prognosis. The investigation of CAN in the greatest number of diabetic patients is therefore justified. The study of heart rate variations during deep respiration, active orthostatism or Valsalva manoeuvre, is still the reference. This method is simple, reproducible and may be carried out in the clinical setting in 10 to 15 minutes. The results must be strictly interpreted with rigour with respect to age. Orthostatic hypotension is a late sign of sympathetic nervous system disease. Spectral analysis of blood pressure variations on orthostatism or the study of cutaneous blood flow during activating the sympathetic system tests of greater sensitivity, should be developed. The demonstration of subclinical CAN should lead to the careful use of drugs which may induce orthostatic hypotension and certain antiarrhythmics, to search for disorders of ventricular repolarisation and for silent myocardial ischaemia in diabetics with several risk factors.

[Shy-Drager syndrome: a rare cause of orthostatic hypotension]. / Das Shy-Drager-Syndrom. Seltene Ursache einer orthostatischen Hypotonie.

HISTORY AND ADMISSION FINDINGS: A 71-year-old man was admitted because of treatment-resistant orthostatic hypotension of unknown aetiology. When aged 64 years he developed some impotence and later urinary incontinence and urinary frequency. At 68 years he noted vertigo on physical activity, and a year later he had signs of reversible cerebral ischaemia. At this point the Schellong test demonstrated vasovagal circulatory dysfunction. After his 70th birthday the unsteadiness on walking and standing got worse and he had recurrent syncopes. He was in a wheel-chair when hospitalized and even the unsteady walk he could maintain for only a few seconds. INVESTIGATIONS: Plasma and urinary concentrations of catecholamines were at the lower limit of normal but failed to increase during orthostasis. Hormonal, cardiological and infectious causes of the orthostatic hypotension were excluded. Orthostatic tests after Schellong and with the tilting table showed orthostatic hypotension without increased sympathetic activity but hypertensive blood pressure levels during the recumbent period. Intravenous infusion of norepinephrine produced an excess rise in blood pressure (raised norepinephrine sensitivity). The recurrent urinary infection was shown to be due to a hypotonic bladder detrusor muscle. Neurological examination revealed cerebellar dysfunction, signs of pyramidal tract abnormality and sensory polyneuropathy. A Shy-Drager syndrome was diagnosed on the basis of the history, absent blood pressure rise and lack of catecholamine release during orthostasis with increased epinephrine sensitivity and characteristic neurological signs. TREATMENT AND COURSE: Physiotherapy and elastic stockings with administration of mineralocorticoids as well as of one direct (norfenefrine) and one indirect (amezinium) sympathomimetic drug failed to improve adequately the abnormal orthostatic response. But on additional administration of an alpha 2-receptor antagonist (yohimbine) the patient was able to stand and walk for a few minutes, but the urinary incontinence and the other neurological signs remained treatment-resistant. CONCLUSION: If orthostatic hypotension occurs together with neurological symptoms, a Shy-Drager syndrome should be taken into account.

[A case of impending neuroleptic malignant syndrome associated with Shy-Drager syndrome].

We report a 55-year-old man with impending neuroleptic malignant syndrome who showed a remarkable dysautonomia such as dysuria and was treated with L-dopa under the diagnosis of Shy-Drager syndrome. The patient demonstrated fever, leukocytosis and elevated serum creatine kinase by a decrease in L-dopa dose. Probably, he developed impending neuroleptic malignant syndrome, induced by urinary tract infection as well as decrease in L-dopa dose. Since Shy-Drager syndrome is often treated with antiparkinsonian drugs, neuroleptic malignant syndrome can possibly develop after the change in dosage of catecholaminergic drugs. The imbalance of neurotransmitters and receptors in the central autonomic nervous system may participate in the development of neuroleptic malignant syndrome. Accordingly, Shy-Drager syndrome can easily be associated with neuroleptic malignant syndrome because of its severe disturbance in the autonomic nervous system. However, autonomic nervous dysfunction, a major sign of neuroleptic malignant syndrome, might be masked by symptoms of Shy-Drager syndrome. Therefore, diagnosis of neuroleptic malignant syndrome is often delayed. Careful observations of patients with Shy-Drager syndrome related with an antiparkinsonian drug are necessary, especially when the dose of drugs is changed or the general condition deteriorates.

Ambulatory infusion of noradrenaline for long-term treatment of Shy-Drager syndrome.

A 70-year-old female patient with advanced Shy-Drager syndrome exhibited severe orthostatic hypotension, low serum catecholamine levels, and autonomic dysfunction. She was bedridden despite oral medication with fludrocortisone, etilefrin, dihydroergotamine, L-dopa, yohimbine, and amezinium methyl sulfate. Only intravenous application of noradrenaline (30 ng/kg/min) provided complete mobilization. After implantation of a port-a-cath system, intravenous noradrenaline treatment could be continued on an outpatient basis. Over the following 5 years, the patient was throughout sufficiently mobile and did not show any significant side effects of this treatment. However, during the 5th year she suffered from nonhemorrhagic brain stem infarction due to cerebral hypoperfusion after orthostatic stress in the absence of noradrenaline infusion. We conclude that ambulatory noradrenaline infusion is a new valuable tool for long-term treatment of advanced Shy-Drager syndrome.

Recent advances in the treatment of orthostatic hypotension.

Orthostatic hypotension is a fall in blood pressure on standing that causes symptoms of dizziness, visual changes, and discomfort in the head and neck. The goal of treatment is the improvement of the patient's functional capacity, rather than a target blood pressure. For treatment to be successful, it must be individualized. Non-pharmalogic interventions include carefully managed exercise, scheduled activities, and monitoring of the environmental temperature. Agents such as fludrocortisone, midodrine, and epoetin alfa offer successful pharmacologic interventions. Although these measures ease the symptoms of orthostatic hypotension, current approaches neither reverse nor stabilize the disease process in autonomic disorders.

[Orthostatic hypotension]. / Orthostatische Hypotonie.

We report about a 67-year-old woman presenting with progressive orthostatic vertigo, urinary incontinence and clinical signs of Parkinson's disease. The Schellong test revealed deficient sympathetic orthostatic pressure response without an increase of plasma norepinephrine; therefore, a Shy-Drager syndrome was diagnosed. Because of inefficiency of the general measures (compressive pantyhose), the sympathomimetic agonists, and the centrally active alpha-2-antagonists, norepinephrine was administered via a miniature dosing pump. By this therapeutic regimen a marked improvement of orthostatic hypotension was achieved.

[Shy-Drager syndrome].

An 81-year-old man with a history of chronic pulmonary disease due to heavy smoking and ischemic heart disease had been suffering for the past few years from chronic constipation and urinary incontinence and was receiving medication for cardiopulmonary symptoms and urinary incontinence. He was admitted for repeated falling for a few months prior to admission. When put in the supine position, his blood pressure fell. He had bilateral pulmonary rales, consistent with lung disease, eccentricity of the left pupil (after cataract surgery), constriction of the right pupil, and absence of the pupillary light reflex. There was generalized hyperreflexia and a bilateral Babinski sign. He had normocytic, normochromic anemia; B12, folic acid and ferritin were within normal ranges, ESR was rapid, there was hyperglobulinemia (IgA and IgG), urea nitrogen and creatinine were increased but returned to normal after rehydration. ECG and chest X-ray were consistent with his cardiopulmonary status. Bone-marrow biopsy showed hypocellularity. IVP and barium enema were normal. Echocardiography revealed a possible old posterior wall myocardial infarction. CT-scan showed moderate cerebral and cerebellar atrophy, calcifications in the carotid and vertebral arteries, and small infarcts in both hemispheres. At this point, after an extensive survey of the literature, the diagnosis of Shy-Drager syndrome was proposed and proved by monitoring ECG and serum levels of noradrenaline during postural changes. He was treated with Fluorinef and there were no more episodes of postural hypotension. Several weeks after discharge he reported that he was feeling well and had not fallen since discharge.

High beta-adrenoceptor density on peripheral blood mononuclear cells in progressive multiple sclerosis: a manifestation of autonomic dysfunction?

In multiple sclerosis (MS) up-regulation of beta-adrenoceptors on peripheral blood mononuclear cells (PBMCs) has been attributed to either autonomic dysfunction, inflammation or a combination of the two. We have compared secondary progressive MS patients with normal subjects (NS) and two models of autonomic dysfunction; pure autonomic failure (PAF) and multiple system atrophy (MSA, Shy-Drager syndrome). There was up-regulation of beta-adrenoceptors on PBMCs in MS and PAF patients but not in MSA patients. Only in PAF patients beta-adrenoceptor up-regulation was correlated with low plasma levels of noradrenaline (NA) and adrenaline (Ad). In addition to studies in the basal state, measurements also were made after the centrally acting sympatholytic agent clonidine. These were combined with haemodynamic and neurohormonal measurements. After clonidine, there was a fall in blood pressure in NS and MSA patients but not in MS and PAF patients; a rise in growth hormone (GH) in NS and PAF patients but not in MS and MSA patients; and an up-regulation in PBMCs beta-adrenoceptors in NS but not in MS, MSA and PAF patients. Up-regulation of beta-adrenoceptors on PBMCs in MS could be attributed to autonomic dysfunction but the disparity between MS and PAF patients when considering their plasma levels of NA and Ad argue against. Although the neurohormonal responses to clonidine and the physiological assessment of autonomic function in progressive MS patients, demonstrate central autonomic dysfunction resembling that of the MSA patients, the normal basal beta-adrenoceptor densities in the latter, suggests that the up-regulation of these receptors is independent of the central autonomic dysfunction in MS.