Autonomic Failure Management

05 November 2004

DIETARY MEASURES (Fealey and Robertson, 1997)

Salt and water intake: 175-250 meq of sodium and 2.0-2.5 liters of fluid daily. Foods rich in salt include canned soups, chili, ham, bacon, sausage, soy sauce, commercially processed canned products, fast food, salty snacks; salt can be added during preparation and at the table. Patients taking the potassium depleting mineralocorticoid florinef should eat high-potassium foods such as fruits, vegetables, No-salt, poultry, fish, beef and pork. Water can be given in amounts of 400 ml with meals and 200-300 ml in between major meals and with a bedtime snack. Juices and sports drinks containing some electrolytes and glucose can make up some of the fluid intake.

A high fiber diet with increased protein and reduced carbohydrate and smaller, more frequent meals is important to avoid constipation and postprandial exacerbation of OH. If supine hypertension is a problem a carbohydrate rich snack just before bedtime can reduced blood pressure for 1-2 hours. Vasodilators such as alcohol exacerbate OH and should be avoided.

Patients can be expected to gain from 2-4 kg (4-8 lb) above their ideal body weight when these dietary measures are coupled with volume expanding pharmacological treatment. Failure to gain weight may be due to enhanced nocturnal natriuresis and polyuria a problem that is discussed below in the section on ADVANCED DISEASE / TREATMENT COMPLICATIONS

PHYSICAL MEASURES (Wieling, 1996)

Head up tilt of bed can be accomplished with 4-6 inch blocks under the legs or a foam wedge can be used under the mattress; an electric hospital bed is justified and essential in severe cases to help reduce supine blood pressure elevation

Physical counter maneuvers are simple methods patients can learn to combat orthostatic dizziness. The beneficial effects leg-crossing, squatting, abdominal compression, forward bending and placing one foot up on a chair are demonstrated by observing the increased standing time and upright blood pressure that results. Such maneuvers can be applied instantly to prevent syncope or increase "standing time" (the amount of time after standing before orthostatic symptoms develop); the latter may increase by 1-2 minutes allowing many ADL's to be accomplished. Crossing legs at or above the knees and squeezing the thigh muscles together, bending forward as if to tie a shoe, raising a flexed leg up on a chair or squatting when able all act to increase thoracic blood volume and left ventricular filling pressure and cerebral perfusion. While sitting patients can cross and uncross their legs or sit knee-chest position to produce the same effects.

The role of compression stockings has been questioned recently because they can prevent peripheral edema or the natural "water jacket" that limits vascular volume available for orthostatic pooling. This effect may not be that important in some patients however compliance in wearing the garments can be a problem as they can be difficult to get on and are uncomfortable in hot climates.

An effective compromise is the wearing of a well fitting abdominal binder with or without thigh-high compression (30-40 mmHg) stockings. Many companies make these and they need to be fitted carefully, donned while still recumbent in the am. (see table)

VOLUME EXPANSION (Robertson, 1996) 

Fludrocortisone (Florinef) is a potent mineralocorticoid that remains a mainstay of treatment in autonomic failure. Florinef has a half-life of 3 hr. and is given twice a day. It's effect requires 1-2 weeks and the gain of a minimum of 3 lb. Multiple putative mechanisms of action include sensitizing blood vessels to endogenous norepinephrine, increasing vessel wall turgor and numbers of alpha-adrenoreceptors; renal cellular effects cause retained sodium and enhanced potassium excretion resulting in hypokalemia commonly and hypomagnesemia rarely. Starting dose is usually 0. l mg po bid Increments of 0.1 mg/dose/week are used until and effect on weight and blood pressure is realized. Doses above 0.4 mg/d are infrequently needed and higher doses produce undesirable side effects of glucocorticoid effect and congestive heart failure. Weekly potassium determinations for a month and then monthly should help determine the level of supplementation required.

SYMPATHOMIMETICS (Midodrine, phenylpropanolamine, yohimbine), (Fealey and Robertson, 1997; Freeman, 1996; Low, 1998)

Midodrine is an alpha- 1 adrenergic receptor agonist acting peripherally and constricting both arterioles and veins. It is the drug of choice currently. The drug is well absorbed from the GI tract and does not cause tachycardia or central stimulation side effects. Standing and supine blood pressure are raised. Half life is short with a pressor effect of 2-4 hr for a I0 mg dose. Starting doses are usually 2.5-5.0 mg bid to rid given about ~ hr. before meals. Piloerection, scalp itching, supine hypertension, urinary urgency and retention and nocturnal natriuresis are the main side effects. The drug is used with Florinef and dietary and physical measures for greatest benefit.

Phenylpropanolamine and similar drugs (ephedrine and pseudoephedrine) are indirect alpha- 1 agonists that theoretically require endogenous norepinephrine to be released to raise blood pressure. Phenylpropanolamine has recently been shown to be effective (Jordan et al., 1998) in both pure autonomic failure and multiple system atrophy patients and comparable with Midodrine in raising standing blood pressure. The starting dose is 12.5 mg tid and doses up to 50 mg tid have been used. Tachycardia and central nervous stimulation and supine hypertension occur with the higher doses.

Yohimbine is a alpha-2 adrenergic antagonist that acts at central and peripheral presynaptic receptors to increase sympathetic output. Theoretically some residual endogenous sympathetic output is required for its action. The dose is 5.4 mg tid; Jordan et al (Jordan et al., 1998) have recently shown a significant pressor with yohimbine in autonomic failure patients. Central nervous system stimulation, diarrhea and supine hypertension are side effects.

Advanced Disease Treatment & Complications 

POSTPRANDIAL EXACCERBATION OF OH

Ingestion of food can cause severe supine and upright hypotension in patients with neurogenic OH. Typically the blood pressure begins to drop 15 minutes into the meal and may stay low for up to 2 hr postprandially. Studies have suggested vasodilator peptides and insulin release and the lack of sufficient sympathetic response as the cause. Patients are often aware of this phenomenon and typically have trouble when eating out and having alcohol with their meal. Large, mixed component meals with a high carbohydrate content are generally the most likely to produce hypotension. Treatment includes smaller, more fi'equent low carbohydrate-high protein meals, avoidance of alcohol and the use of pharmacological agents caffeine, indomethacin, midodrine and in severe cases octreotide. (see specifics below)

SUPINE HYPERTENSION/UPRIGHT HYPOTENSION

Not infrequently severe dysautonomia with profound standing hypotension is complicated by worrisome supine hypertension that is both disease (loss of baroreceptor buffering effect) and treatment (sympathomimetics, volume expanders) related. Sustained blood pressures of over 200/120 develop at night with recumbancy. Indeed a characteristic of neurogenic OH is the loss of the normal reduction of blood pressure with sleep. Rarely a patient will suffer a hypertensive cerebral event; more commonly left ventricular strain and hypertrophy develop. The patient has increased renal perfusion and polyuria at night adding to sleep disruption. Fortunately there are several treatment strategies to manage this advanced disease complication. Helprial measures include head up tilt of the bed, a carbohydrate snack and exercise at bedtime, and the use of short acting antihypertensive drugs such as hydralazine.

NOCTURNAL DIURESIS AND NATRIURESIS

With advanced neurogenic OH there is supine hypertension and sympathetic dennervation of the kidney which produces a net loss of fluid and sodium during the recumbancy of night. This leads to volume depletion and suppression of the renin-angiotensin-aldosterone system with an exaccerbation of upright hypotension in the morning. Increasing the head up tilt of bed, the use of sodium retaining antihypertensive agents and vasopressin-like agents can largely prevent this complication. The details are described in the next section.

CHRONIC ANEMIA OF AUTONOMIC FAILURE (Ando et aL, 1996; Biaggioni et al., 1994; Hoeldtke and Streeten, 1993; Perera et al., 1995)

A relatively recent observation is a mild anemia that accompanies about 38% or more patients with severe autonomic failure and neurogenic OH. There is evidence for relatively decreased erythropoietin levels with lack of kidney sympathetic stimulation especially of the beta2 adrenoreceptors. This observation led to trials of recombinant erythropoietin (cpoerin alfa) to reverse the anemia of autonomic failure and to date most patients respond not only with an increase of red cell volume and hematocrit but the blood pressure is increased in both the supine and upright posture. Mechanisms involved in the pressor effect are postulated to involve increased sensitivity to angiotensin II, increased plasma endothelin levels and enhanced renal tubular sodium reabsorption. The drug is administered parenterally and not all patients respond .(Keselbrener et al., 1997)

Treatment Strategies for Difficult Situations

WHAT DIETARY CHANGES CAN REALLY MAKE A DIFFERENCE?

The composition of a meal matters. Postprandial aggravation of OH can be offset by eating smaller, more frequent meals with a reduced carbohydrate content .(Mathias and Bannister, 1992). Patients are frequently volume depleted, (even though blood volume measurements can be normal) (Mehlsen and Boesen, 1987; Wilcox et al., 1984) and I-2 liters of normal saline i.v. over 3-6 hr. followed by a maintenance of 2.0-2.5 I of fluid daily by mouth is helpful. More severe cases require feeding tube placement (percutaneous gastrojejunostomy) and high protein liquid meals with I000 kcal daily to prevent negative nitrogen balance in addition to i.v. fluids. A high salt diet is given. Foods with a high salt content include canned soups, chili, ham, bacon, sausage, additives like soy sauce, fast food. A dietician is often consulted to provide a 200-250 meq sodium diet. A high fiber diet is recommended to help avoid constipation and straining. Patients on florinef (which depletes K+) should eat potassium rich foods like fruits, vegetables, No-salt, poultry, fish, beef and pork. A salt tablet known as Thermotabs contain about 475 mg of sodium with 30 mg of potassium and can be used once to three times daily. Patients should avoid alcohol with meals (a vasodilator). With supine hypertension a snack at bedtime can lower BP for several hours.

WHAT CAN BE DONE TO TREAT POSTPRANDIAL HYPOTENSION (PPH) ?

One can limit meal size (Puvi-Rajasingham andMathias, 1996) and restrict the carbohydrate content. Caffiene taken as a 200 mg qam dose can be helpful. This may be due to blockade of adenosine receptors or to a direct vasoconstrictor effect. Its effect is rarely dramatic and some have not found it helpful. (Jordan et al., 1998) Indomethacin has been shown to prevent postprandial hypotension by several authors (Fealey and Robertson, 1997; Jordan et al., 1998). The dose is 50-75 mg po rid to qid about '/2 hr. before meals. Midodrine 5-I0 mg tid has also been advocated. It is given about 45 min. before meals. The norepinephrine precursor DL-DOPS has been helpful in eradicating PPH (Freeman, 1996) The somatostatin analog Octreotide has been more extensively investigated. This drug is given sub q usually as a 0.2 microgram/kg with meals to start. Larger doses up to 1.0 micrograms/kg are often required especially with breakfast. The mechanism of action may involve splanchnic vasoconstriction via inhibition of vasodilator polypeptides. Side effects include nausea, loose bowel movements, cramps, gall stones/cholecystitis and hyperglycemia. One day/week drug holiday has been recommended for long term use. The combination of 1.0 microgram sub q Octreotide with meals and l0 mg Midodrine po given 30 min. beforehand is more effective than either drug alone; the larger doses of these drugs are necessary if postprandial ambulation is desired.(Hasler et al., 1996; Hoeldtke et al., 1998). Very recently a microencapsulated long-acting formulation (LAR) of Octreotide has been compared with q8h sub q Octreotide. The LAR formulation of 20 mg given once monthly i.m. was equivalent to 0.3-0.9 mg/d sub q in the treatment of diarrhea in a patient group with Carcinoid syndrome.(Rubin et al., 1999) Whether this formulation works in dysautonomic PPH remains to be seen.

HOW DOES ONE TREAT DANGEROUS SUPINE HYPERTENSION WHEN THE PATIENT IS HAVING HYPOTENSIVE SYNCOPE WHILE SITTING OR STANDING? WHAT ABOUT NOCTURNAL NATRIURESIS AND DIURESIS? 

Supine hypertension in the range of 180/100 or higher if sustained during the night can lead to left ventricular hypertrophy, nocturnal natriuresis and diuresis and inhibit endogenous release of renin-angiotensin-aldosterone. Morning OH is aggravated. Rx. therefore is important and consists of head up tilt of the bed, avoiding pressor drugs after 8 pm, ingestion of a carbohydrate snack hs, exercising in bed and the use of a short acting antihypertensive drug. My choice has been hydralazine 25-100 mg po hs. This drug can deplete pyridoxine and effect DOPA to clopamine conversion and so pyridoxine 50 mg/day should be given. The pyridoxine may aid in reducing the natriuresis hs. Unfortunately this drug was not compared in Jordan's recent study on vasodilators for supine hypertension. The older literature would indicate however it does not share the undesirable effects of nifedipine and nitroglycerine on renal sodium excretion. (Jordan et al., 1999). The synthetic vasopressin analog desmopressin (DDAVP) has been studied by Mathias and associates specifically for the relief of nocturnal diuresis (Mathias et al., 1986). They found reversal of nocturnal weight loss and polyuria and increased supine BP by morning and better standing tolerance after intramuscular injection and intranasal admnistration. The doses used were 2-4 micrograms i.m. given at 8 pm and 5-40 micrograms via nasal inhalation hs. The drug acts mainly at V2 receptors on the renal tubules and reduces flee water excretion. Hyponatremia can rapidly develop as natriuresis often continues as before and vigorous sodium supplementation combined with florinef is usually needed to maintain normal osmolality. The drug is managed initially in the hospital setting. The V 1 receptor agonists (triglycyl-lysine vasopressin) can cause vasoconstriction and raise BP; supine hypertension limits its use in practice. (Mathias et al., 1986)

HOW AND WHEN DOES ONE USE ERYTHROPOEITIN?

As a general rule if the patient has a mild anemia after rehydration and there is no other obvious cause for it I assume its due to autonomic failure and recommend erythropoeitin. Erythropoeitin levels are normal to mildly reduced and are not critical in the decision making. The patient has to be able to give themselves an injection or a spouse has to be able. Training to give a sub q injection can be done by the nursing staff and the dose is 25-50 units/kg body weight given 3X a week. The treatment is expensive but justified in severe cases. The duration of Rx. should be 1-3 months at least. The Fe/TIBC or ferritin levels should be monitored as should the potassium levels and Hgb. The Hgb typically can be raised by 2-4 mg% in one month. Supine and upright BP is raised and there is a general sense of well-being. Side effects include supine hypertension, headache, edema, bone pain, diarrhea, weakness and nausea. 

NEUROGENIC DIARRHEA + ORTHOSTATIC HYPOTENSION:LOSS OF THE SYMPATHETIC INHIBITORY BRAKE, WHAT TO DO?

 This situation is not uncommon in diabetic autonomic failure and immune mediated autonomic neuropathies and is seen occasionally in Pure Autonomic Failure (PAF). The usual workup for other causes of diarrhea (infectious, maiabsorption etc.) should be done and a trial of a broad spectrum antibiotic (i.e. tetracycline or metronidazole or ciprofloxacin) is given. Trials of gluten free diet, bile acid binders, pancreatic exocrine enzymes may be needed in diabetics. The next step is a trial of loperamide (Imodium) (2-4 mg qid po) or the drug diphenoxylate combined with atropine (LoMotil) (2.5-5 mg qid). At times a bulk forming laxative is helpful (metamucil). Should these fail, two drugs are worthy of a try but require careful titration and patient selection. The first is Clonidine an alpha 2 adrenergic receptor agonist that reduces central sympathetic output. When disease has already caused marked sympathetic failure clonidine may paradoxically raise blood pressure while it produces inhibition of intestinal motility and reduces colonic water secretion by an alpha 2 stimulation effect on enterocyte adenylate cyclase. This is available as a 0.1 mg tablet and the starting dose is 0. I mg po bid. Increments of 0.1 mg/dose daily until diarrhea stops or side effects become limiting (sedation, hypotension). The drug is also available as a patch for transdermal delivery; the lowest patch strength (TTS-I) supplying 0.1 mg clonidine is tried first. If no effect for a few days the patch is removed and the next size (TTS-2), 0.2 mg patch is tried and so on. The limit is 0.6 mg daily for both methods; the patch may be less likely to cause hypotension. The second drug to try is Octreotide, a long-acting somatostatin analog. At low doses of 50-75 micrograms sub q twice daily the drug inhibits small intestinal motility and improves diarrhea. Higher dose may aggravate diarrhea and cause unwanted fluctuations in glucose tolerance with the need to reduce exogenous insulin doses by 25%. Injection site stinging can be minimized by warming the drug and injecting slowly. (Walker and Kaplan, 1993)