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Hypertension. 2005;45:469-476
Published online before print February 28, 2005, doi: 10.1161/01.HYP.0000158835.94916.0c
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*Autonomic Nervous System Disorders
*High Blood Pressure
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Right arrow Autonomic, reflex, and neurohumoral control of circulation
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(Hypertension. 2005;45:469.)
© 2005 American Heart Association, Inc.

Hypertension Grand Rounds

Management of Hypertension in the Setting of Autonomic Failure

A Pathophysiological Approach

Cyndya Shibao; Alfredo Gamboa; André Diedrich; Italo Biaggioni

From Division of Clinical Pharmacology, Department of Medicine and Pharmacology, and the Autonomic Dysfunction Center, Vanderbilt University School of Medicine, Nashville, Tenn.

Correspondence to Italo Biaggioni, MD, 1500 21st Avenue South, suite 3500, Clinical Trials Center, Vanderbilt University, Nashville, TN 37212. E-mail Italo.biaggioni{at}vanderbilt.edu


*    Abstract
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 *Abstract
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We discuss 2 cases presenting clinically with disabling orthostatic hypotension and severe supine hypertension. This is a common presentation of autonomic failure, and one that challenges conventional treatment. Clinical findings of isolated autonomic failure were the most prominent manifestation in case 1, whereas a movement disorder was the key finding in case 2. The differential diagnosis and treatment of orthostatic hypotension is discussed from a pathophysiological approach. Understanding of the underlying mechanisms of disorders of the autonomic nervous system is fundamental for an effective management of these patients and provides insight into more common disorders such as essential hypertension.


Key Words: atrophy • autonomic nervous system • hypertension • hypotension

Case 1
An 83-year-old white man was referred to the Autonomic Dysfunction Center for evaluation of orthostatic hypotension and supine hypertension. He had been relatively healthy until 3 years before evaluation, when he started experiencing extreme fatigue with frequent dizziness, lightheadedness, and confusion on standing. His symptoms progressively limited his daily activities, forcing him to remain seated most of the day. He developed urinary symptoms, having to strain to void completely, and complained of a persistent nocturia. He reported feeling worse early in the morning and after meals. He also noticed that sweating was limited to the left side of his body. On questioning, he reported a 10-year history of erectile dysfunction. His medical history was notable for hypothyroidism treated with replacement therapy, benign prostatic hypertrophy, and glaucoma. He gave no history of gastrointestinal symptoms.

On admission, the patient’s blood pressure was 193/70 mm Hg while supine, and it decreased to 77/40 mm Hg on standing. He could remain in the upright posture for only 3 minutes before developing presyncopal symptoms. His heart rate was 44 bpm when supine and 60 bpm when standing, an inappropriate response considering the magnitude of his orthostatic hypotension. Cardiac examination showed regular rhythm with no murmurs. The remainder of the physical examination was negative.

Hemoglobin was 12.7g/dL, red blood count was 4.16 million/µL with normal red blood cell morphology; other hematological parameters were normal. Urinalysis and chemistry were normal. Blood samples for catecholamines, renin activity, and aldosterone were taken while supine and standing, after at least 3 days on a metabolic ward on sodium balance. Standardized autonomic functions showed severe autonomic failure (Table 1). ECG was positive for first-degree atrioventricular block and occasional atrial and ventricular premature contractions, QT was 454 msec, and QTc was 418 msec. A Holter monitor revealed normal sinus rhythm with no significant bradyarrythmias. Echocardiography showed normal left ventricular systolic function with ejection fraction >60% and wall thickness within normal limits.


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  		TABLE 1. Assessment of Neurohumoral and Endocrine Parameters During Orthostatic Stress

Case 2
A 66-year-old woman was referred to the Autonomic Dysfunction Center for several episodes of syncope often resulting in trauma and severe supine hypertension refractory to treatment. Her symptoms developed gradually over 5 to 6 years. She reported dizziness and lightheadedness in the upright posture and inappropriate diuresis when supine. Other symptoms were decreased sweating, constipation, and difficulty swallowing. She had urinary incontinence but had to strain to void completely. Two years before admission, she noticed progressive difficulty walking, in part caused by dizziness but also because of stiffness and bradykinesia. Her voice become hoarse and she noticed micrographia. She had mild snoring but no clear history of sleep apnea. Because of severe supine hypertension, she was treated with a calcium channel blocker (verapamil 90 mg orally every day), but did not receive any treatment for her orthostatic hypotension and was disabled by her extreme dizziness on standing.

Her medical history was significant for long-term essential hypertension, a previous episode of pulmonary embolism, congenital ventricular septal defect surgically repaired, and frequent urinary tract infection with at least 1 episode of urosepsis. She has a strong family history of hypertension, with both parents affected.

The patient’s supine blood pressure and heart rate were 223/104 mm Hg and 72 bpm, respectively, and 104/70 mm Hg and 94 bpm on standing. Her lungs were clear to auscultation. Cardiac examination showed a regular rhythm, normal S1 and S2, and a score of 2 of 6 systolic ejection murmur in crescendo, located in the apex, with a pattern radiating to both carotids. The abdominal examination was negative. The neurological examination was significant for decrease in facial expression, speech with slightly decreased volume and prosody, postural tremor, mild rigidity, a score of 4 of 5 muscle strength, coordination deficit with moderate loss of finger tapping, and bradykinesia with greater compromise of the left side. She required assistance to stand up, postural reflexes were impaired, and her gait was characterized by shard shuffling steps. She was treated with levodopa but this was discontinued because of visual hallucinations and poor response.

Complete blood count, urinalysis, and chemistry profile were normal; hemoglobin was 13.8 g/dL, red blood count was 4.71 million/µL. ECG showed a sinus rhythm with a frequency of 65 bpm, a QT of 354 msec, and a QTc of 401 msec. No voltage criterion for left ventricular hypertrophy was observed. Results of autonomic function tests are presented in Table 1.


*    Discussion
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 *Discussion
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Orthostatic hypotension is defined as a decline in systolic blood pressure >20 mm Hg associated with symptoms of cerebral hypoperfusion. Mild to moderate orthostatic hypotension is relatively common in the elderly and is an independent risk factor for cardiovascular mortality.1 The prevalence of orthostatic hypotension in community dwellers older than 65 years is 16.2%,2 and the incidence increases with age. Multiple disorders can cause this syndrome. It can be seen as a side effect of medications, and this possibility always needs to be considered. The most common culprits are tricyclic antidepressants, {alpha}-blockers used to treat prostatism in males, and diuretics. Any disease causing peripheral neuropathy can involve autonomic nerves and induce orthostatic hypotension; the most common is diabetes mellitus. If a patient presents with acute or subacute onset of autonomic neuropathy, the possibility of an autoimmune neuropathy3–5 or a paraneoplastic syndrome, most commonly associated with small cell lung cancer or light chain disease, must be considered.

The 2 cases presented here had no evidence of a systemic illness causing autonomic neuropathy. The magnitude of their orthostatic hypotension would be most unusual for a drug-induced disorder or other common causes of this syndrome in the elderly. The presence of severe orthostatic hypotension without an appropriate compensatory heart rate increase, the evidence of widespread autonomic impairment, and the lack of an underlying disease in case 1 is consistent with a diagnosis of pure autonomic failure (PAF). Impotence in males caused by erectile dysfunction is often the first symptom of autonomic failure, as exemplified by this case. Decreased sweating is very common, but this symptom may not be apparent in patients who are inactive because of disabling orthostatic hypotension. Symptoms of urinary retention are usually present and can dominate the clinical picture in some patients. Gastrointestinal symptoms (constipation sometimes alternated with diarrhea) are common, but they are not as severe in PAF as they are in patients with autoimmune autonomic neuropathy or in autonomic neuropathy secondary to diabetes.6 Case 2 presented with Parkinsonian symptoms in addition to widespread autonomic failure. The combination of autonomic failure and a movement disorder (Parkinsonism or cerebellar ataxia) is characteristic of patients with multiple system atrophy (MSA).

Common Pathophysiology and Clinical Differences in Primary Forms of Autonomic Failure
Understanding the underlying pathophysiological mechanisms of these disorders is important not only to explain the similarities and differences in their clinical presentations but also to develop tests that may help in their differential diagnosis. All of these disorders are associated with cellular lesions involving protein precipitates that are rich in {alpha}-synuclein. Hence, they are termed collectively {alpha}-synucleinopathies. It is not surprising, therefore, that there is clinical overlap between these conditions. The molecular mechanisms that cause these precipitates are not known, but the different clinical presentation that characterizes these disorders can be explained by the site of the lesion.

In MSA, protein precipitates are found in glial cells (glial cytoplasmic inclusions) and are present in basal ganglia with a clinical predominance of Parkinsonian features (MSAP), in cerebellar structures with a clinical predominance of truncal ataxia (MSAC), or in brain stem centers involved in cardiovascular control with a clinical predominance of autonomic involvement (Shy-Drager syndrome).7

In PAF, protein deposits occur in neurons and form a characteristic pattern termed Lewy bodies. Their distribution is widespread and includes presynaptic and postsynaptic neurons in the spinal cord and autonomic ganglia8,9 but does not involve basal ganglia or the cerebellum. Paradoxically, these Lewy bodies are indistinguishable from those seen in classical Parkinson disease, and yet PAF patients do not have a movement disorder. Another condition associated with autonomic failure is dementia of Lewy bodies with prominent features of mental confusion and hallucinations (Table 2).


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  		TABLE 2. Presence (+) or Absence (–) of Clinical and Pathological Characteristics in Primary Disorders of the Autonomic Nervous System

There is little evidence of migration between MSA and the Lewy body disorders, but this may occur within the latter, Kaufmann et al10, eg, reported a patient initially diagnosed with PAF only to develop Parkinson disease 20 years later, and another who developed dementia with Lewy bodies 3 years after an initial presentation of PAF. These cases support the notion that Lewy body disorders constitute a single disease with a spectrum of clinical presentations, and suggest that peripheral autonomic neurons may be affected before the central nervous system.

Differential Diagnosis
Because there is no curative treatment for these conditions, the importance of an early diagnosis is limited to its prognostic value, given the poor prognosis of MSA compared with PAF or Parkinson disease.11 This is, of course, of great importance for the patients and their caregivers. There are 3 common diagnostic challenges between these disorders. First, it is often very difficult to differentiate early on in the disease process between PAF and MSA, because patients with MSA can present initially with isolated autonomic failure. It may be impossible to rule out MSA and make a definitive diagnosis of PAF during the first 1 to 2 years of disease onset. Follow-up may be required before a definitive diagnosis can be made. MSA has a more rapid progression, with disability caused by worsening of the movement disorder commonly occurring 6 to 8 years after onset of symptoms. Another differential diagnosis challenge occurs between MSA and Parkinson disease. Patients with otherwise classical Parkinson disease can present with orthostatic hypotension and autonomic failure. These patients probably have an intermediate form of classic Parkinson disease involving autonomic centers, often referred to as Parkinson plus. Patients with MSA, as in case 2, rarely have the unilateral resting tremor onset typical of Parkinson disease and in general respond poorly if at all to levodopa. Third, recent studies suggest that autoimmune autonomic neuropathy can present clinically as PAF. Autoimmune autonomic neuropathy is classically thought to have an acute or subacute presentation, hence the term acute pandysautonomia.12,13 It is now recognized that this disorder can be mediated by autoantibodies against the nicotinic (NN) receptor responsible for neurotransmission at the level of the autonomic ganglia and can be detected in plasma.5 It is not yet known the percentage of patients with acute pandysautonomia that are afflicted by this autoantibody. This antibody is also present in patients that had an insidious onset of illness indistinguishable from PAF,3 and at least in 1 such patient autonomic function could be restored by elimination of this antibody with plasmapheresis,14 indicating that the antibody was contributing to the pathophysiology, and was not merely generated as a secondary reaction to degenerative destruction of autonomic ganglia.

Several tests have been developed to differentiate between PAF, MSA, and Parkinson disease with autonomic failure. They are all based on the differences in the level of the lesion in these disorders. Patient with MSA have central lesions that involve autonomic nuclei and impair the baroreflex, but they have residual sympathetic tone and intact efferent postganglionic sympathetic nerves, as determined by normal or only slightly decreased plasma norepinephrine15 (case 2, Table 1), normal or elevated low-frequency variability of blood pressure,16 and intact cardiac uptake of 6-[18F]fluorodopamine or [123I]metaiodobenzylguanide (MIBG) determined by positron emission tomography17 or single photon emission computed tomography (SPECT).18 This suggests that pacemaker neurons where sympathetic tone originates are spared in MSA. Functionally, this is evidenced by a dramatic decline in blood pressure in response to the ganglionic blocker trimethaphan, indicating that their residual sympathetic activity was tonically maintaining blood pressure in the supine position, as in case 2 (Figure 1). This residual sympathetic activity is unmodulated and cannot be engaged when patients stand, hence their orthostatic hypotension. In contrast, patients with PAF have very low plasma norepinephrine (case 1, Table 1) and absent uptake of MIBG by the heart, suggesting loss of peripheral noradrenergic fibers.17 This is in agreement with the underlying pathology and by the comparatively modest effect on blood pressure of the ganglionic blocker trimethaphan, as in case 1 (Figure 1).



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  		Figure 1. Effect of autonomic withdrawal with trimethaphan on blood pressure and heart rate. In case 1, blood pressure decreased modestly compared with case 2. Heart rate and blood pressure variability decreased in both cases.

Abnormalities in central pathways are evident in patients with MSA; vasopressin levels do not increase in response to hypotension,19 and growth hormone levels do not increase in response to clonidine20 (Table 3). These responses are intact in PAF. Of interest, these responses are also preserved in patients with Parkinson disease.21 Finally, magnetic resonance imaging can also differentiate between these disorders.22 Brainstem atrophy is seen in patients with MSAP and MSAC. Putaminal atrophy is seen only in MSAP. Putaminal abnormalities are always mild in patients with Parkinson disease. Cerebellar abnormalities are seen in all patients with MSAC and some patients with MSAP, but are always mild in patients with Parkinson disease.


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  		TABLE 3. Differential Diagnosis Between Autonomic Disorders

Even though these tests differentiate between patients with severe cases of PAF or MSA, they have not been validated in patients in initial stages of disease, when the diagnosis can be particularly challenging but the differentiation most useful. They remain, therefore, investigational. Outside specialized autonomic centers, a definitive diagnosis can often be made during follow-up. Most cases of MSA are evident within 1 or 2 years of initial presentation.

Management of Orthostatic Hypotension
Orthostatic hypotension is often the dominant symptom in patients with autonomic failure and the cause of substantial disability. Severely affected patients are unable to stand but for few seconds before symptoms of cerebral hypoperfusion forced them to assume the seated or supine positions. Orthostatic hypotension per se is rarely hazardous; the complications are related to the risks associated with falls. The treatment, therefore, is symptomatic, and a stepwise approach is recommended based on the severity of the symptoms (Table 4). The first step is to avoid situations or medications that cause orthostatic hypotension. The predominant mechanism of orthostatic hypotension is an inability to compensate for the normal gravitational pooling of blood that normally occurs in lower limbs and abdomen on standing. The second step, therefore, includes nonpharmacological approaches to decrease venous pooling, avoid volume depletion or increase plasma volume. These include a high-salt diet, the use of abdominal binders or waist-high elastic stockings to decrease venous pooling, and prevention of excessive diuresis secondary to supine hypertension by simply avoiding the supine posture during the day. Drinking water can be a surprisingly useful treatment for orthostatic hypotension (Figure 2) and has a rapid onset of action with a peak effect at {approx}30 minutes.23


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  		TABLE 4. Stepwise Approach to Treat Orthostatic Hypotension



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  		Figure 2. Hemodynamic effect of ingestion of 16 ounces of tap water in case 1. Systolic blood pressure increased {approx}40 mm Hg, with a peak effect after 25 minutes.

The third step is to increase central volume. Fludrocortisone is commonly used because it increases plasma volume, but this effect is only transient, and its long-term benefit may be related to potentiation of the pressor effects of norepinephrine and angiotensin II.24,25 Fludrocortisone can induce or worsen supine hypertension, raising concerns about its long-term safety. In such cases it may be worth verifying its effectiveness by stopping it to determine if symptoms of orthostatic hypotension worsen and deciding if the symptomatic relief it provides is worth the potential deleterious effects of supine hypertension.

Anemia is now considered part of the clinical picture of autonomic failure26 and is caused by inappropriately low erythropoietin production. Treatment with recombinant erythropoietin resolves the anemia, is the most effective way of increasing intravascular volume, and has been shown to improve orthostatic tolerance in patients with autonomic failure.26–30 In some patients, however, the degree of symptomatic improvement is not sufficient to justify the cost and inconvenience of this treatment.

Finally, short-acting pressor agents can be added to the previous regimen to increase blood pressure for 2 to 3 hours at a time. They should be given on a PRN-basis, only to allow periods during the day when patients can be active. We recommend that they be taken 30 to 45 minutes before activity. They should not be prescribed at fixed intervals with no consideration of the patient’s activity. The worst thing a patient can do is to take a pressor agent and remain seated or supine, because this with lead to excessive diuresis and volume depletion.

A list of pressor agents currently available and range of doses are included in Table 4. A comparison of the effectiveness of these medications in increasing blood pressure has been published previously.31 Direct acting {alpha}1 agonists, eg, midodrine, and {alpha}-2 antagonists, eg, yohimbine, are particularly effective. It should be noted, however, that the magnitude of responses varies significantly between patients. We recommend testing individual responses by measuring seated and standing blood pressure before and 2 hours after drug administration. All of these drugs will increase supine blood pressure, but the effect may be less pronounced with pyridostigmine, a cholinesterase inhibitor that facilitates cholinergic neurotransmission at the level of autonomic ganglia and, therefore, may increase blood pressure preferentially on standing, when residual sympathetic tone is increased.32

Current treatment with short-acting pressor agents is far from satisfactory. Most of these agents increase peripheral vascular resistance, and it is questionable that this is the most effective way of increasing upright blood pressure and cerebral perfusion. Arguably, drugs that induce venoconstriction and increase venous return may be more effective. There are only a few agents currently available with these characteristics. Ergotamine alone or in combination with caffeine is effective in increasing blood pressure and improving symptoms,33–35 but oral bioavailability is variable,36,37 and there is concern about its long-term use. Octreotide is also very effective, even when other agents fail, in part because of its ability to constrict the splanchnic circulation,38 where most of the orthostatic blood pooling occurs.39 Its use is limited by the need for parenteral administration, and by worsening of gastrointestinal symptoms in patients who have these symptoms at baseline. It is rarely tolerated in patients with diabetic autonomic neuropathy.

Management of Supine Hypertension
Supine hypertension is seen in approximately half of patients with either PAF or MSA. It may present as worsening of a pre-existing essential hypertension, as in case 2, or appear de novo, as in case 1. Managing supine hypertension in the setting of orthostatic hypotension may seem an insurmountable challenge, but a rational approach often leads to successful treatment. Supine hypertension is best treated during the daytime by simply avoiding the supine position. This seemingly obvious and simple measure is often overlooked. If patients need to rest, they should be instructed to sit in a reclining chair with the feet on the floor. During the night, tilting the bed with the head up at least 6 to 9 inches reduces blood pressure and nocturnal natriuresis, therefore improving orthostatic hypotension in the morning. The use of pressor agents and water boluses should be avoided close to bedtime. Other nonpharmacological measures are presented in Table 5.


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  		TABLE 5. Stepwise Approach to Treat Supine Hypertension

In many cases, as in those presented here, these approaches are not sufficient to control supine hypertension, and pharmacological interventions are necessary (Table 5). It is important to note that understanding the mechanisms underlying supine hypertension is very important to determine an adequate treatment. It is well-recognized that in patients with central autonomic dysfunction (ie, MSA), residual sympathetic tone contributes to supine hypertension.40 Case 2 illustrate this concept. This patient exhibited an extreme decrease in blood pressure (–98 mm Hg in systolic blood pressure) during the infusion of the ganglionic blocker trimethaphan (Figure 1). Therefore, we used clonidine 0.1 mg, an {alpha}-2 adrenergic agonist with predominant central sympatholytic actions, to mimic this effect (Figure 2).

In contrast, residual sympathetic tone contributes less to supine hypertension in patients with peripheral autonomic dysfunction (ie, PAF), and the use of direct vasodilators is recommended in such patients. In case 1, eg, systolic blood pressure decreased only {approx}30 mm Hg despite an infusion rate of trimethaphan known to completely eliminate sympathetic activity (Figure 1). Accordingly, clonidine had no effect in blood pressure, but nifedipine produced a dramatic decreased in blood pressure (Figure 3). Jordan et al41 demonstrated that transdermal nitroglycerin (0.1 to 0.2 mg/h) and short-acting nifedipine (30 mg) given at bedtime decrease supine blood pressure in both MSA and PAF patients. The ideal agent would also reduce nocturnal pressure natriuresis and, through this mechanism, may even improve orthostatic hypotension in the morning. Unfortunately, these medications do not reduce nocturnal pressure natriuresis; on the contrary, nifedipine increases it, probably because of direct renal vasodilatation. The reduction in supine blood pressure obtained with other vasodilators, such as minoxidil and hydralazine, is usually less pronounced compared with nitrates,42 but hydralazine may be useful in some patients. Whenever antihypertensive drugs are prescribed, patients should be warned about the potential risk of falls if they get up at night to urinate.



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  		Figure 3. Hemodynamic response to pharmacological treatments for supine hypertension during the night. Medications were given at 8 PM and blood pressure was taken every 2 hours during placebo, clonidine ({alpha} 2 agonist), or a vasodilator (nitroglycerin or nifedipine). In case 1 (PAF), blood pressure decreased with nifedipine but not clonidine. In contrast, in case 2 (MSA), blood pressure decreased effectively with clonidine.

Lessons Learned From Primary Autonomic Failure
Primary autonomic disorders are relatively rare, but they provide a unique learning opportunity. It is widely recognized that the sympathetic nervous system is pivotal for the short-term regulation of blood pressure, and the disabling nature of orthostatic hypotension in autonomic failure patients serves as witness to this role. In addition, the observation that autonomic withdrawal with trimethaphan resolves supine hypertension in MSA patients indicates that the sympathetic nervous system can contribute to sustained forms of hypertension.

Baroreflex function is completely lost in autonomic failure patients early in the course of their disease. The absence of the restraining function of the baroreflex unmasks pressor and depressor stimuli that would produce very little changes, if any, in normal subjects, eg, meals lower blood pressure on average 44±2 mm Hg in autonomic failure patients.43,44 This phenomenon has since been described in the elderly, and its presence increases the risks of falls.45,46 Similarly, the vasodilatory properties of insulin are readily apparent in patients with autonomic failure.47–50 This effect can contribute to the increase in sympathetic activity associated with the hyperinsulinemia of the metabolic syndrome51 and has practical implications in the management of diabetic patients with autonomic neuropathy.52,53

The absence of baroreflex function can also reveal pressor stimuli that are not normally apparent. Phenylpropanolamine, eg, was thought to have negligible effects on blood pressure and was formulated in numerous over-the-counter medications. Studies in autonomic failure patients revealed a potent pressor effect of this drug; an average increase in blood pressure of 30±6 mm Hg is seen in these patients at the lowest dose previously available in nasal decongestants.31,54 Phenylpropanolamine has since been removed from the market because its use was associated with hemorraghic strokes.55 Even water ingestion can produce a potent pressor reflex in autonomic failure, a phenomenon not previously recognized in humans.56 The presence of anemia and prolonged QT interval in autonomic failure patients exposed the role of the autonomic nervous system in the modulation of erythropoietin production26 and ventricular repolarization.57

In studying the pathophysiology, the differential diagnosis and the management of patients with autonomic failure, we have learned important lessons about autonomic cardiovascular control. We are grateful to our patients for their contribution to this knowledge. There is, however, much more to learn. We are able to improve the patients’ orthostatic symptoms, but treatment current relies on vasoconstrictor agents, and novel therapeutic approaches should be explored. The understanding of the role of the {alpha} synuclein in the pathogenesis of degenerative forms of autonomic failure opens new therapeutics options, including a curative treatment directed at inhibit or reversing protein aggregation.58 It will be important to elucidate the pathophysiology of the hypertension of PAF to improve the management of this condition, and our understanding of normal blood pressure regulation and essential hypertension.


*    Acknowledgments
 
This work was supported in part by grants PO1 HL56693 and HL67232, and the General Clinical Research Center Grant MO1 RR00095. Dr Shibao is recipient of the International Fellowship in Clinical Pharmacology supported by Merck Foundation.

Received December 20, 2004; first decision January 3, 2005; accepted January 27, 2005.


*    References
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