Faculty Bibliography

Background: Normally, during sleep, when cortical influences are minimized, blood pressure (BP) and heart rate (HR) fall (i.e., nocturnal dipping). In patients with afferent baroreflex failure, in whom BP and HR are highly dependent on cortical influences, this nocturnal dipping is usually preserved. There are, however, a number of patients with afferent baroreflex failure in whom BP does not dip at night. The reasons for this are unknown.
Method(s): We examined the 24-hour ambulatory BP profiles in 50 patients with afferent baroreflex failure of acquired (n = 6) or genetic origin (familial dysautonomia n = 44). BP and HR were captured at 30-minute intervals over a 24-h period. Nighttime sleep periods were identified from the patient's diary. Dipping was defined as a 10 % or greater fall in systolic and diastolic blood pressure at night.
Result(s): Normal BP nocturnal dipping was present in only 50 % of the patients; 33 % of patients had reversal of the circadian rhythm with higher blood pressures at night. In the remaining 17 %, nocturnal BP was similar to daytime BP. Patients with preserved nocturnal dipping had a significantly higher glomerular filtration rate (8430 mL/ min) than those that did not dip at night (6130 mL/min, p = 0.043).
Conclusion(s): Lack of nocturnal BP dipping in patients with afferent baroreflex failure was associated with impaired renal function. These findings suggest that in patients with FD, a non-dipping profile may involve abnormalities in extracellular volume and/or impaired regulation of vascular resistance (i.e., abnormal endothelial function)

The prodrug droxidopa increases blood pressure (BP) in patients with neurogenic orthostatic hypotension. The BP profile of droxidopa in neurogenic orthostatic hypotension patients (n = 18) was investigated using ambulatory BP monitoring. Following dose optimization and a washout period, 24-hour "off-drug" data were collected. "On-drug" assessment was conducted after 4-5 weeks of droxidopa treatment (mean dose, 444 mg, three times daily). Ambulatory monitoring off drug revealed that 90% of patients already had abnormalities in the circadian BP profile and did not meet criteria for normal nocturnal BP dipping. On treatment, both overall mean 24-hour systolic and diastolic BPs were higher compared to off drug (137/81 mm Hg vs. 129/76 mm Hg; P = .017/.002). Mean daytime systolic BP was significantly higher with droxidopa (8.4 +/- 3.1 mm Hg; P = .014). Although nocturnal BP was not significantly higher on droxidopa versus off treatment (P = .122), increases in nocturnal (supine) BP >/=10 mm Hg were observed in four cases (22%). Severe supine systolic hypertensive readings at night (>200 mm Hg) were captured in one case and only while on treatment. These data demonstrate that ambulatory BP monitoring is useful to evaluate the circadian BP profile after initiating treatment with a pressor agent.

Background: Stress-induced adrenergic hypertensive crises are a cardinal feature of familial dysautonomia (FD). Classically, this is treated with clonidine and benzodiazepines, which cause excessive sedation and can lead to respiratory arrest. Dexmedetomidine is a recently introduced compound, 8 times more specific for central alpha-2 adrenergic receptors than clonidine, resulting in less sedation. Advantages over clonidine are also that dexmedetomidine can be administered intravenously (IV), and its half-life is shorter (12 vs. 2 h), which allows an easy titration.
Method(s): Retrospective chart review of IV dexmedetomidine use to treat refractory hypertensive crisis in patients with FD.
Result(s): IV dexmedetomidine was used 15 times in 9 patients (mean age: 26 years; 44 % men) with acute adrenergic crisis. Crisis triggers included respiratory infection (n = 8), emotional stress (n = 3), surgery (n = 1), bacteremia (n = 1), gastroenteritis (n = 1) and bleeding gastric ulcer (n = 1). Before treatment, all patients had signs of adrenergic activation including skin flushing, nausea/retching, vomiting, diaphoresis, and agitation. Blood pressure (BP) was 1616/1026 mmHg and heart rate (HR) was 1134 bpm. IV dexmedetomidine was administered at an average rate of 0.510.13 mcg/kg/h. One hour post-infusion, BP decreased to 1165/586 mmHg (p<0.0001) and HR to 975 bpm (p = 0.002). Drowsiness occurred in one patient, although he was easily arousable. There were no episodes of rebound hypertension or respiratory depression. In one case, rapid titration at a high dose resulted in paradoxical hypertension, which subsided immediately upon dexmedetomidine discontinuation.
Conclusion(s): IV dexmedetomidine is an effective, well-tolerated approach for managing adrenergic crises in patients with FD. In contrast to other commonly used medications, dexmedetomidine does not induce excessive sedation or respiratory depression. In a small percentage of patients, rapid IV dosing may result in paradoxical hypertension due to its direct action on peripheral postsynaptic alpha2-adrenergic receptors

The ability of the skin to conduct electricity depends on sweat secretion. This is referred to as electrodermal or electrochemical skin conductance. Recently, a technique has been developed to assess electrodermal activity using reverse iontophoresis dependent on sweat chloride levels. This method can reliably identify patients with cystic fibrosis, a disease with well-described increases in chloride concentration in sweat. Our goal was to determine the relationship between electrodermal response and serum chloride levels in other patient groups. We conducted a cross-sectional study involving 38 subjects with HSAN-III (familial dysautonomia, FD) and 20 healthy controls. Electrodermal activity of the soles was assessed using stainless steelbased plate electrodes applied under the soles of the feet for 3 min (Sudoscan). The influence of age, serum electrolyte levels, and medications were analyzed.
Result(s): Electrodermal activity was normal (>60 microS) in 24 patients (63 %) and reduced (<60 microS) in the remaining 14. There was a direct correlation between electrodermal activity and serum chloride levels (p = 0.007). Reduced electrodermal activity was explained by low serum chloride in 6 patients, and likely by medications in 8 (clonidine). All controls had normal electrodermal activity, but because their serum chloride levels were normal in every subject (>97 mEq/L), no correlation could be established.
Conclusion(s): Low serum chloride levels result in reduced electrodermal activity. In addition to medications, serum chloride levels should be checked to properly interpret electrodermal activity measurements

Hereditary sensory and autonomic neuropathy type III features disturbed proprioception and a marked ataxic gait. We recently showed that joint-angle matching error at the knee is positively correlated with the degree of ataxia. Using intraneural microelectrodes, we also documented that these patients lack functional muscle spindle afferents but have preserved large-diameter cutaneous afferents, suggesting that patients with better proprioception may be relying more on proprioceptive cues provided by tactile afferents. We tested the hypothesis that enhancing cutaneous sensory feedback by stretching the skin at the knee joint using unidirectional elasticity tape could improve proprioceptive accuracy in patients with a congenital absence of functional muscle spindles. Passive joint angle matching at the knee was used to assess proprioceptive accuracy in 25 patients with HSAN III and 9 age-matched control subjects, with and without taping. Angles of the reference and indicator knees were recorded with digital inclinometers, and the absolute error, gradient and correlation coefficient between the two sides calculated. Patients with HSAN III performed poorly on the joint angle-matching test (mean matching error +/- SE 8.0 +/- 0.8 degrees , controls 3.0 +/- 0.3 degrees ). Following application of tape bilaterally to the knee in an X-shaped pattern, proprioceptive performance improved significantly in the patients (mean error 5.4 +/- 0.7 degrees ) but not in the controls (3.0 +/- 0.2 degrees ). Across patients, but not controls, significant increases in gradient and correlation coefficient were also apparent following taping. We conclude that taping improves proprioception at the knee in HSAN III, presumably via enhanced sensory feedback from the skin.