Insulin-induced hypotension and neurogenic orthostatic hypotension

Insulin-induced hypoglycemia induced a fall in blood pressure (BP) in patients with idiopathic orthostatic hypotension (IOH) and multiple system atrophy (MSA), but not in control subjects. Only in IOH was there a correlation between plasma norepinephrine (NE) levels and maintenance of BP during the test. The hypotension was not affected by pretreatment with propranolol. Hypotension during insulin-induced hypoglycemia is manifested in patients who lack an adequate NE response. The hypotension, however, may be due to a central action of insulin because not all MSA patients with impaired NE release become hypotensive.     

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.     

Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes

BACKGROUND: Neurogenic orthostatic hypotension (OH) characterizes pure autonomic failure (PAF), multiple system atrophy (MSA), and Parkinson disease (PD) with autonomic failure. We used neuropharmacologic probes that might distinguish these diseases based on loss of sympathetic noradrenergic nerves in PAF and PD + OH but not in MSA, and related the results to neurochemical and neuroimaging findings in the same patients. METHODS: Patients with neurogenic OH (PD + OH; N = 35), MSA (N = 41), and PAF (N = 12) received iv trimethaphan (TRI), which inhibits sympathetic nerve traffic, or yohimbine (YOH), which stimulates sympathetic traffic. Dependent measures included blood pressure, plasma norepinephrine (NE) levels, and interventricular septal myocardial radioactivity after iv injection of the sympathoneural imaging agent, 6-[F]fluorodopamine. RESULTS: The PD + OH and PAF groups had smaller pressor responses to YOH (12 +/- 8 and 13 +/- 1 mm Hg) and depressor responses to TRI (-14 +/- 8 and -17 +/- 7 mm Hg) than did the MSA group (43 +/- 8 mm Hg, -57 +/- 8 mm Hg; P = 0.01, P = 0.03). The PD + OH and MSA groups did not differ in NE responses to YOH and TRI. The depressor response to TRI, the pressor response to YOH, and the blood pressure difference between YOH and TRI all correlated positively with myocardial 6-[F]fluorodopamine-derived radioactivity. CONCLUSIONS: The PD + OH resembles PAF and differs from MSA in hemodynamic responses to drugs that alter NE release from sympathetic nerves. The results fit with sympathetic noradrenergic denervation in PD + OH and PAF but not in MSA.     

Mechanisms underlying unawareness of neurogenic orthostatic hypotension

Clinical Autonomic Research -     

Primary orthostatic hypotension syndromes without somatic neurologic signs--idiopathic orthostatic hypotension and primary sympathicotonic orthostatic hypotension

Idiopathic orthostatic hypotension (IOH) and primary sympathicotonic orthostatic hypotension (PSOH) are conspicuous orthostatic hypotension syndromes without overt somatic neurologic signs. IOH, also referred as pure autonomic failure, is a syndrome of chronic pandysautonomia, and its clinical features include supine hypertension, anhidrosis, impotence, neurogenic urinary and bowel disturbances. PSOH is different from IOH in which it is not accompanied with autonomic features outside of cardiovascular symptoms, and has been most commonly described in German-Scandinavian literatures. The controversy in the nosology of IOH and PSOH has prevented the both concepts from world-wide acceptance, and little has been known about IOH in Japanese population. In the present study, statistical analyses were made to elicit the cases of orthostatic hypotension syndrome without somatic neurologic signs from the pooled results of hemodynamic autonomic functional tests in our laboratory. The subjects were 287 Japanese cases comprising 253 normotensive volunteers and 34 hypertensive patients. Apart from hypertension, none of the subjects exhibited abnormal findings on physical, neurological and routine laboratory examinations. The test of 70 degrees passive head-up tilt and other hemodynamic tests were performed upon the subjects, and the results were pooled by ages. By means of the method of maximum normed residual, statistically screened out were 7 cases with extremely great orthostatic fall in systolic blood pressure (OH-I). Another OH group (OH-II) consisted of 24 cases who showed orthostatic decrease in systolic blood pressure of 30 mmHg or more, but did no fall into the extreme observation. Assuming that the orthostatic regulation mechanism of blood pressure was well maintained in the remaining 256 cases, they were used as the control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Norepinephrine reuptake blockade to treat neurogenic orthostatic hypotension

Clinical Autonomic Research -     

Management of neurogenic orthostatic hypotension: an update

Orthostatic hypotension (OH) is common in elderly people and in patients with disorders such as diabetes and Parkinson's disease. Grading of the severity of OH and its effect on the patient's quality of life are important. The symptoms vary with orthostatic stress, and subtle symptoms such as tiredness and cognitive impairment should be recognised. Standard drug treatment for OH is effective but worsens supine hypertension, whereas pyridostigmine can improve OH slightly but significantly without worsening of supine hypertension. Because orthostatic stress varies from moment to moment and drug treatment is suboptimal, drug treatment of OH needs to be combined with non-pharmacological approaches, such as compression of venous capacitance beds, use of physical counter-manoeuvres, and intermittent water-bolus treatment.     

Cerebellar impairment during an orthostatic challenge in patients with neurogenic orthostatic hypotension

ObjectiveCompare activation patterns within the cortical autonomic network in patients with neurogenic orthostatic hypotension (NOH) versus healthy age-matched controls during an orthostatic challenge.MethodsFifteen health controls and 15 NOH patients performed 3 Valsalva maneuvers, and 5-min of lower-body negative pressure (LBNP) during a functional brain MRI.ResultsCompared to controls, NOH patients had significantly less activation within the cerebellum during both LBNP and VM. Both groups had significant activation of the bilateral insula and left thalamus during LBNP. No significant differences were found during the recovery phase of LBNP.ConclusionsThe cerebellum, which plays an important role in vestibulo-sympathetic reflexes, important for blood pressure adjustments during postural changes, appear to be affected in patients with NOH. The cerebellum also appears to be affected during other baroreflex mediated stressors such as the VM.SignificanceOrthostatic reflexes mediated by the cerebellum may be impaired in patients with NOH. The results suggest an additional pathological pathway in patients with autonomic failure.     

Factors contributing to racial differences in neurogenic orthostatic hypotension

Clinical Autonomic Research -     

Standing worsens cognitive functions in patients with neurogenic orthostatic hypotension

In previous studies, addressing the association between orthostatic hypotension and cognitive decline, patients underwent neuropsychological evaluation in sitting position, and blood pressure values and cognition were not measured concurrently. Furthermore, no studies assessed the acute effects of orthostatic hypotension on cognitive performances. The aim of our study was to evaluate the effect of a documented fall in systolic blood pressure (SBP) of at least 20 mmHg on a battery of cognitive tests in patients with neurogenic orthostatic hypotension. Ten consecutive patients with neurogenic orthostatic hypotension, normal brain imaging, and a normal Mini Mental State Examination in supine position were enrolled in the study. Patients underwent a detailed neuropsychological assessment (Brief Mental Deterioration battery and computerized tests) over two test sessions: the first while tilted to an angle able to cause a fall of at least 20 mmHg in SBP; the second while supine, after 30 min of rest. Parallel forms of the tests were presented on each testing session. Patients scored significantly worse in the visual search test, analogies test, immediate visual memory, and the measure of global cognitive functioning of Brief Mental Deterioration battery during the orthostatic challenge compared to the supine position. Orthostatic hypotension was associated with a significant worsening of cognitive performances, affecting both global cognitive functioning and specific tasks, mainly exploring executive functions. The assessment of cognitive function in patients with neurogenic orthostatic hypotension should be performed considering the body’s position of the subject.     

Arrhythmic syncope in neurogenic orthostatic hypotension: two case reports

Patients with autonomic failure experience orthostatic hypotension (OH) often leading to syncope. Arrhythmias may cause severe syncope, characterized by an increased risk of mortality. We report two cases of patients with primary autonomic neuropathy suffering from both severe OH and arrhythmic syncope.     

Functional effects of cardiac sympathetic denervation in neurogenic orthostatic hypotension

BackgroundDiseases characterized by neurogenic orthostatic hypotension (NOH), such as Parkinson disease (PD) and pure autonomic failure (PAF), are associated with cardiac sympathetic denervation, as reflected by low myocardial concentrations of 6-[¹⁸F]fluorodopamine-derived radioactivity. We studied the impact of such denervation on cardiac chronotropic and inotropic function.MethodsCardiac inotropic function was assessed by the pre-ejection period index and the systolic time ratio index in response to the directly acting beta-adrenoceptor agonist, isoproterenol, and to the indirectly acting sympathomimetic amine, tyramine, in patients with PD + NOH or PAF (PD + NOH/PAF group, N = 13). We compared the results to those in patients with multiple system atrophy, which usually entails NOH with normal cardiac sympathetic innervation (MSA, N = 15), and in normal control subjects (N = 5).ResultsThe innervated and denervated groups did not differ in baseline mean pre-ejection period index or systolic time ratio index. Tyramine increased cardiac contractility in the MSA patients and controls but not in the PD + NOH/PAF group. For similar heart rate responses, the PD + NOH/PAF group required less isoproterenol (p < 0.01) and had lower plasma isoproterenol levels (p < 0.01) than did the MSA group.ConclusionsAmong patients with NOH those with cardiac sympathetic denervation have an impaired inotropic response to tyramine and exaggerated responses to isoproterenol. This pattern suggests that cardiac denervation is associated with decreased ability to release endogenous norepinephrine from sympathetic nerves and with supersensitivity of cardiac beta-adrenoreceptors.     

Patterns of plasma levels of catechols in neurogenic orthostatic hypotension

Patients with neurogenic orthostatic hypotension can have deficits in sympathetic neural function at any of several levels of the sympathetic neuraxis. We determined whether patterns of plasma levels of dopa, norepinephrine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid would distinguish patients with orthostatic hypotension associated with multiple system atrophy, pure autonomic failure, or deficiency of dopamine-beta-hydroxylase. Plasma levels of catechols were normal in most patients with multiple system atrophy, consistent with relatively intact peripheral sympathetic neurons; in contrast, most patients with pure autonomic failure had decreased levels of all four catechols, consistent with degenerative loss of sympathetic nerve endings. Patients with deficiency of dopamine-beta-hydroxylase had increased levels of dopa and dihydroxyphenylacetic acid and markedly decreased levels of norepinephrine and dihydroxyphenylglycol, suggesting compensatory increases in sympathetic nerve activity in the absence of norepinephrine biosynthesis. Subgroups of patients with pure autonomic failure or multiple system atrophy had low levels of norepinephrine with normal levels of dopa, dihydroxyphenylglycol, and dihydroxyphenylacetic acid, consistent with normal catecholamine biosynthesis and decreased postganglionic sympathetic nerve traffic or decreased exocytotic release from sympathetic nerve endings. The results demonstrate the value of examining patterns of plasma levels of catechols to elucidate mechanisms of neurogenic orthostatic hypotension.     

Clinical and neurohormonal characteristics in African Americans with neurogenic orthostatic hypotension

Clinical Autonomic Research - Neurogenic orthostatic hypotension (nOH) is the hallmark of neurodegenerative forms of autonomic failure, including pure autonomic failure, multiple system atrophy,...     

Initiating droxidopa for neurogenic orthostatic hypotension in a patient with Parkinson disease

Clinical Autonomic Research -