Tonette L. Opfer-Gehrking

A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension

Objective: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). Background: Midodrine is a peripherally acting α-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. Design/Methods: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patients overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. Results: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was ∼4 hours. Conclusion: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.

The Autonomic Symptom Profile A new instrument to assess autonomic symptoms

Objective: To develop a new specific instrument called the Autonomic Symptom Profile to measure autonomic symptoms and test its validity. Background: Measuring symptoms is important in the evaluation of quality of life outcomes. There is no validated, self-completed questionnaire on the symptoms of patients with autonomic disorders. Methods: The questionnaire is 169 items concerning different aspects of autonomic symptoms. The Composite Autonomic Symptom Scale (COMPASS) with item-weighting was established; higher scores indicate more or worse symptoms. Autonomic function tests were performed to generate the Composite Autonomic Scoring Scale (CASS) and to quantify autonomic deficits. We compared the results of the COMPASS with the CASS derived from the Autonomic Reflex Screen to evaluate validity. Results: The instrument was tested in 41 healthy controls (mean age 46.6 years), 33 patients with nonautonomic peripheral neuropathies (mean age 59.5 years), and 39 patients with autonomic failure (mean age 61.1 years). COMPASS scores correlated well with the CASS, demonstrating an acceptable level of content and criterion validity. The mean (±SD) overall COMPASS score was 9.8 (±9) in controls, 25.9 (±17.9) in the patients with nonautonomic peripheral neuropathies, and 52.3 (±24.2) in the autonomic failure group. Scores of symptoms of orthostatic intolerance and secretomotor dysfunction best predicted the CASS on multiple stepwise regression analysis. Conclusions: We describe a questionnaire that measures autonomic symptoms and present evidence for its validity. The instrument shows promise in assessing autonomic symptoms in clinical trials and epidemiologic studies.

Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects

Normative data are limited on autonomic function tests, especially beyond age 60 years. We therefore evaluated these tests in a total of 557 normal subjects evenly distributed by age and gender from 10 to 83 years. Heart rate (HR) response to deep breathing fell with increasing age. Valsalva ratio varied with both age and gender. QSART (quantitative sudomotor axon‐reflex test) volume was consistently greater in men (approximately double) and progressively declined with age for all three lower extremity sites but not the forearm site. Orthostatic blood pressure reduction was greater with increasing age. HR at rest was significantly higher in women, and the increment with head‐up tilt fell with increasing age. For no tests did we find a regression to zero, and some tests seem to level off with increasing age, indicating that diagnosis of autonomic failure was possible to over 80 years of age.

Acetylcholinesterase inhibition: a novel approach in the treatment of neurogenic orthostatic hypotension

Background: Pharmacological treatment of orthostatic hypotension is often limited because of troublesome supine hypertension. Objective: To investigate a novel approach to treatment using acetylcholinesterase inhibition, based on the theory that enhanced sympathetic ganglion transmission increases systemic resistance in proportion to orthostatic needs. Design: Prospective open label single dose trial. Material: 15 patients with neurogenic orthostatic hypotension caused by: multiple system atrophy (n = 7), Parkinson’s disease (n = 3), diabetic neuropathy (n = 1), amyloid neuropathy (n = 1), and idiopathic autonomic neuropathy (n = 3). Methods: Heart rate, blood pressure, peripheral resistance index (PRI), cardiac index, stroke index, and end diastolic index were monitored continuously during supine rest and head up tilt before and one hour after an oral dose of 60 mg pyridostigmine. Results: There was only a modest non-significant increase in supine blood pressure and PRI. In contrast, acetylcholinesterase inhibition significantly increased orthostatic blood pressure and PRI and reduced the fall in blood pressure during head up tilt. Orthostatic heart rate was reduced after the treatment. The improvement in orthostatic blood pressure was associated with a significant improvement in orthostatic symptoms. Conclusions: Acetylcholinesterase inhibition appears effective in the treatment of neurogenic orthostatic hypotension. Orthostatic symptoms and orthostatic blood pressure are improved, with only modest effects in the supine position. This novel approach may form an alternative or supplemental tool in the treatment of orthostatic hypotension, specially for patients with a high supine blood pressure.

Postural Tachycardia Syndrome: Clinical Features and Follow-up Study

OBJECTIVE To define the clinical features and outcome of postural tachycardia syndrome (POTS). MATERIALS AND METHODS In this cross-sectional study of the autonomic symptom profile, inclusion criteria were orthostatic heart rate increment of 30 beats/min or greater, orthostatic symptoms, completion of a standardized autonomic test battery, and follow-up of 18 months or longer. We used 2 instruments. The first part was a structured and validated autonomic symptom profile (108 patients). The second part was a structured questionnaire focused on autonomic status on prospective follow-up (40 patients) (mean +/- SD follow-up, 67+/-52 months). RESULTS Most patients had frequent, persistent, and at least moderately severe symptoms for less than 5 years. The following orthostatic symptoms occurred in more than 75% of subjects: light-headedness or dizziness, lower extremity or diffuse weakness, disequilibrium, tachycardia, and shakiness. Nonorthostatic symptoms included dry eyes or mouth, gastrointestinal complaints of bloating, early satiety, nausea, pain, and alternating diarrhea and constipation. Half of the patients reported an antecedent illness presumed to be of viral origin. On follow-up, 80 % of patients were improved, 60% were functionally normal, and 90% were able to return to work. Patients who had an antecedent event appeared to do better than those with spontaneous POTS. Salt supplementation and beta-blockers were the most efficacious therapies. CONCLUSION In the majority of patients, POTS is self-resolving, especially in those with a triggering event.

Prospective Evaluation of Clinical Characteristics of Orthostatic Hypotension

OBJECTIVE To undertake a prospective study of the clinical characteristics of orthostatic intolerant patients referred to the Mayo Autonomic Reflex Laboratory with suspected orthostatic hypotension (OH). DESIGN Autonomic function tests were performed to quantify the severity of sudomotor, adrenergic, and cardiovagal failure and generate a composite autonomic symptom score (CASS). CASS was related to a symptom score, which was derived from the frequency of orthostatic intolerance and syncope and the standing time until occurrence of symptoms. RESULTS Three groups were defined by their response to a tilt study: group I, 90 patients with symptomatic OH, mean age, 63.6 years; group II, 60 patients who had symptoms without OH, mean age, 48.9 years; and group III, 5 patients with asymptomatic OH, mean age, 68.0 years. Group I had a significantly higher CASS (P < 0.001) than did those without OH. Further analysis was done on the 90 patients in group I. The most common symptoms were lightheadedness, weakness, impaired cognition, visual blurring, tremulousness, and vertigo. The most common aggravating factors were prolonged standing, exercise, warming, and eating. Most patients (75%) could stand for less than 5 minutes before symptoms occurred. Symptoms regressed significantly with CASS but not with the tilt grade. CONCLUSION Patients with generalized autonomic failure have a recognizable pattern of symptoms and aggravating factors that relate, albeit imperfectly, to the severity of autonomic failure.

Postural Tachycardia in Children and Adolescents: What is Abnormal?

OBJECTIVES To evaluate whether the use of adult heart rate (HR) criteria is appropriate for diagnosing orthostatic intolerance (OI) and postural tachycardia syndrome (POTS) in children and adolescents, and to establish normative data and diagnostic criteria for pediatric OI and POTS. STUDY DESIGN A total of 106 normal controls aged 8-19 years (mean age, 14.5±3.3 years) underwent standardized autonomic testing, including 5 minutes of 70-degree head-up tilt. The orthostatic HR increment and absolute orthostatic HR were assessed and retrospectively compared with values in 654 pediatric patients of similar age (mean age, 15.5±2.3 years) who were referred to our Clinical Autonomic Laboratory with symptoms of OI. RESULTS The HR increment was mildly higher in patients referred for OI/POTS, but there was considerable overlap between the patient and control groups. Some 42% of the normal controls had an HR increment of ≥30 beats per minute. The 95th percentile for the orthostatic HR increment in the normal controls was 42.9 beats per minute. There was a greater and more consistent difference in absolute orthostatic HR between the 2 groups, although there was still considerable overlap. CONCLUSION The diagnostic criteria for OI and POTS in adults are unsuitable for children and adolescents. Based on our normative data, we propose new criteria for the diagnosis of OI and POTS in children and adolescents.

Efficacy of compression of different capacitance beds in the amelioration of orthostatic hypotension

Orthostatic hypotension (OH) is the most disabling and serious manifestation of adrenergic failure, occurring in the autonomic neuropathies, pure autonomic failure (PAF) and multiple system atrophy (MSA). No specific treatment is currently available for most etiologies of OH. A reduction in venous capacity, secondary to some physical counter maneuvers (e.g., squatting or leg crossing), or the use of compressive garments, can ameliorate OH. However, there is little information on the differential efficacy, or the mechanisms of improvement, engendered by compression of specific capacitance beds. We therefore evaluated the efficacy of compression of specific compartments (calves, thighs, low abdomen, calves and thighs, and all compartments combined), using a modified antigravity suit, on the end-points of orthostatic blood pressure, and symptoms of orthostatic intolerance. Fourteen patients (PAF,n=9; MSA,n=3; diabetic autonomic neuropathy,n=2; five males and nine females) with clinical OH were studied. The mean age was 62 years (range 31–78). The mean ±SEM orthostatic systolic blood pressure when all compartments were compressed was 115.9±7.4 mmHg, significantly improved (p<0.001) over the head-up tilt value without compression of 89.6±7.0 mmHg. The abdomen was the only single compartment whose compression significantly reduced OH (p<0.005). There was a significant increase of peripheral resistance index (PRI) with compression of abdomen (p<0.001) or all compartments (p<0.001); end-diastolic index and cardiac index did not change. We conclude that denervation increases vascular capacity, and that venous compression improves OH by reducing this capacity and increasing PRI. Compression of all compartments is the most efficacious, followed by abdominal compression, whereas leg compression alone was less effective, presumably reflecting the large capacity of the abdomen relative to the legs.

Use of lower abdominal compression to combat orthostatic hypotension in patients with autonomic dysfunction.

Abstract.The aim of this study was to investigate in patients with neurogenic orthostatic hypotension the mechanism and usefulness of abdominal compression to increase standing blood pressure. In three protocols, 23 patients underwent abdominal compression. Protocol 1 evaluated in a 40–60° head-up-tilt position, the effect of abdominal compression on caval vein and femoral diameter, arterial blood pressure and hemodynamics. Protocol 2 documented the relationship between the level of compression and the arterial pressure response. Protocol 3 investigated the ability to maintain standing blood pressure by an elastic binder. During head-up-tilt, compression (40 mm Hg) resulted in a reduction in diameter of the caval vein (mean –2.6mm, range –1.4 to 0.6), without a change in femoral vein diameter. Stroke volume increased by 14 % (range –1 to 23) and blood pressure (systolic/diastolic) by 30/14 mmHg (range 7/2 to 69/36), both p < 0.05; 40 mmHg compression was associated with a higher pressure response than 20 mmHg (mean 18/8 mmHg, range 6/2 to 43/20 vs. mean 9/4 mmHg, range –1/0 to 18/8, p < 0.05). Elastic abdominal binding increased standing blood pressure with 15/6mmHg (range –3/3 to 36/14, p < 0.05). We conclude that in patients with neurogenic orthostatic hypotension, abdominal compression increases standing blood pressure to a varying degree by increasing stroke volume.

Complex Regional Pain Syndrome I (CRPS I): Prospective study and laboratory evaluation

OBJECTIVE To relate clinical features to autonomic laboratory indices used in the diagnosis of Complex Regional Pain Syndrome type I (CRPS I) (reflex sympathetic dystrophy) to generate improved diagnostic criteria. DESCRIPTION CRPS I is a chronic pain syndrome, characterized by diffuse limb pain with allodynia and prominent vasomotor and sudomotor dysfunction. METHODS We conducted a prospective study on 102 patients referred for possible CRPS I. These patients completed a structured questionnaire and underwent neurologic examination, with special attention to the evaluation of clinical features of vasomotor, sudomotor, motor, and sensory, including pain, dysfunction. All patients were tested using a standard autonomic protocol that compared side-to-side skin temperature, resting sweat output, and quantitative sudomotor axon reflex test (QSART) measurements. Composite autonomic clinical (CRPS-Sx) and laboratory (CRPS-LAB) scores were defined. The clinical (subjective and objective) and the laboratory data were analyzed using Pearsons correlation analysis and Bonferronis probability value to assess concordance and their value in correctly diagnosing CRPS I. RESULTS All cases occurred after limb injury. One-third of cases did not fulfill our criteria of CRPS I. Highly significant correlations (p<.001) were found among certain clusters of symptoms and signs that shared unifying pathophysiologies. CRPS-Sx correlated with CRPS-LAB (p = .035). The indices that correlated most reliably with clinical data and with each other were RSO, QSART, and skin temperature reductions. CONCLUSION Clinical and autonomic laboratory probability scores correlate in an internally consistent manner. Both CRPS-Sx and CRPS-LAB are sensitive and reliable tools to formulate a correct diagnosis of CRPS I and can be combined to provide an improved set of diagnostic criteria for CRPS I.