Introduction:
The treatment of chronic fatigue syndrome (CFS) with medications used for neurally mediated hypotension (NMH) is at a very preliminary stage. Evidence from randomized controlled trials is not yet available to guide treatment decisions or to confirm that the approach does more good than harm. We expect such trials to be completed in 2 years at the earliest. In the interim, we have developed this handout for physicians who would like to begin empiric trials of this approach while awaiting more definitive treatment guidelines. The handout should be regarded as a work in progress, and tailored for each patient.
Many cardiologists with subspecialty interest in electrophysiology, along with experts in disorders of the autonomic nervous system, have years of experience treating patients with recurrent syncope or presyncope due to neurally mediated hypotension or related autonomic disorders such as postural orthostatic tachycardia syndrome. These individuals will have familiarity with the medications we describe and they may be willing to provide local guidance in each city. The bibliography at the end of this sheet lists a number of excellent reviews and treatment studies from which you will gain a more complete picture of this common problem.
General approach: fluids and sodium
NMH is also known as the vasovagal reflex, neurocardiogenic syncope, and vasodepressor syncope. A less cumbersome term for patients is "the fainting reflex." With NMH. blood volume is often low, or it is mobilized ineffectively when individuals are Upright. To treat this, we usually start people on at least 2 liters per day of fluid (water is fine), along with an increased intake of sodium. We suggest that they add as much salt to their foods as they find palatable, supplementing this as needed with salt tablets. Because some of our patients report nausea with the 1 gram salt tablets, we recommend a buffered salt tablet which causes fewer upper gastrointestinal symptoms, starting at a dose of 900 mg TID (Thermotabs, which contain 450 mg sodium chloride and 30 mg potassium chloride; available from Menley and James, 1-800-321-1834). We recognize that 900 mg TID of salt tablets and an increase in dietary salt may be a relatively small amount of salt supplementation. Some authorities who treat patients with similar disorders in autonomic control recommend a total daily sodium intake of 10-20 grains, well above the usual 4 gram per day intake in North America. Not all of our patients can tolerate this sort of increase without discomfort. The ideal intake of sodium for this population is not known, and patients should be told to pick a degree of supplementation that is comfortable for them. The diet sheets in the General Information handout list foods with a relatively high sodium content.
It is important for patients to be well hydrated before starting medications, and it is usually reasonable to begin increasing salt intake slowly. Accordingly, we often recommend a one-two week period of focussing on fluids and salt alone. After this time, when blood volume is improved, medications seem to be better tolerated and there may be fewer adverse effects. When individuals are in extreme discomfort because of NMH symptoms, transient relief lasting 12-36 hours can usually be provided using intravenous normal saline in volumes of 1-3 liters (at rates of 1 liter per hour), but this is a relatively costly method of rehydration, and needs to be employed judiciously. We usually give 1-2 liters of saline at the completion of the upright tilt table test to help reverse the symptoms provoked during the test. An alternative method of administering fluids is to use a new oral rehydration solution which contains 2.2 grams of sodium per liter (CeraLyte 70, available at many pharmacies, or by calling toll-free 1-888-237-2598 (1-888-CERALYTE).
Stopping potentially harmful medications:
Some drugs have the potential to make symptoms of neurally mediated hypotension worse. The following should be avoided where possible: drugs that reduce blood volume, interfere with vasoconstriction, or provide some beta-adrenergic stimulus. For example, acetazolamide (Diamox) is sometimes used for symptomatic control of headache, but has the potential to increase sodium loss in the urine. Narcotic analgesics and phenothiazine antiemetics may lead to excessive venous pooling, and many medications (including niacin) can cause vasodilation.
Albuterol and other beta-agonists can trigger shakiness and fatigue in those with NMH. If patients are using albuterol for asthma. we usually try to decrease their reliance on this drug, usually by switching them to an inhaled steroid.
Tricyclic antidepressants have to be used with caution because they have the potential to lower blood pressure and cause further orthostatic intolerance. Some of our patients have had good responses to these medications, and some of our psychiatrist colleagues feel that at appropriate doses these medications can reverse the autonomic dysfunction seen during depressive illnesses, so the picture is not entirely clear for these medications. It would be ideal to have better prospective studies to guide therapy in this regard.
Medications for NMH:
If an increased intake of salt and fluid leads to an improvement in symptoms, there may be no need to move to medications. Our experience thus far, perhaps based on a sicker group of Chronic Fatigue Syndrome patients with NMH, has been that increased salt intake alone is rarely adequate.
Our choice of medications has evolved somewhat since the publication of the first paper from our group (Lancet, March 11, 1995). We now start most individuals on fludrocortisone (Florinef) 0.1 mg per tablet, starting at low doses of 1/4 tablet per day for a week, going up in increments of 1/4 tablet at intervals of 3-7 days until a dose of 1/2 tablet twice daily is reached. Some patients who have elevated blood pressures at baseline experience a reduction in blood pressure as Florinef is started, so mild hypertension is not an absolute contraindication to its use. Nonetheless, those with hypertension must be monitored carefully.
Each patient's tolerance of the drug, and response to it is somewhat different, so we recommend regular visits while the doses are being adjusted. If patients continue to experience some benefit from week to week at a particular dose, it makes sense to continue on that dose. If there are no adverse effects on a dose of 0.1 mg per day, but no impressive therapeutic benefits have occurred after about a month, we will try increases to a maximum of 0.15 or 0.2 mg (1 1/2 - 2 tablets) per day. Whether further increases would be beneficial is unclear.
We have found that a sustained release potassium supplement (such as K-Dur 10 mEq, or Slow-K 8 mEq once daily) helps patients tolerate the Florinef better, and helps avoid problems with mineralocorticoid-induced hypokalemia. We now start potassium 8-10 mEq/day at the beginning of Florinef therapy. In addition, a diet containing food high in potassium is important (see diet instructions in the General Information brochure). A potassium intake of 20 mEq or more may be needed as the Florinef dose gets to 0.15 mg or higher.
Adverse effects of Florinef include the obvious effects of mineralocorticoids (hypokalemia, hypematremia, hypertension). We recommend periodic examinations to exclude these possibilities. The optimal frequency for checking electrolytes and blood pressure has not been determined, but every 2-4 weeks until the patient is on a stable dose of drug may be a useful guideline. Patients who do not tolerate Florinef may develop worse CFS symptoms (more lightheadedness or fatigue), GI discomfort of a new type or severity, new chest discomfort, or tearfulness and depression. The latter occurs in fewer than I in 20 patients, but patients need to be aware of this when they start on the drug, and to know to stop Florinef promptly if such depressed mood occurs. Some have found that minor side effects will disappear after a couple of weeks, and it is worth persevering with the medication provided that they are, in fact, minor adverse effects. However, no patient should continue on the medication if he or she reports a substantial worsening of any symptoms. Some develop worse acne on Florinef.
Florinef leads to some improvement in about 30-50% of individuals with NMH. In those who have a modest, but incomplete improvement, we usually recommend remaining on Florinef and the increased salt and fluid intake, as some have experienced a continued, slow improvement over time, but we usually find it necessary to add another medication. If we are adding another medication, we usually add a beta-blocker, most commonly atenolol (Tenormin), starting slowly at 12.5-25 mg per day, and increasing gradually to a dose of about 1mg of atenolol per kg of body weight. For a 62 kg woman, for example, the ideal dose would be 50-75 mg.
Adverse effects of atenolol can include worse fatigue and lightheadedness, headache, bronchoconstriction, and the other common adverse effects of this class of medication. For those with mild asthma, our impression has been that an inhaled steroid (e.g., Azmacort or Flovent) can allow patients to tolerate the beta-blocker without increased airway reactivity. Other investigators use other beta-blockers (metoprolol, propranolol, newer ones). Until better evidence from comparative studies is available, it may simply be a matter of developing familiarity with one of the drugs.
If Florinef makes people feel worse, we will switch to monotherapy with beta blockers, and if beta-blockers and Florinef are both associated with adverse effects, the next drug we try is either disopyramide (Norpace) or a selective serotonin reuptake inhibitor. If we elect to use Norpace, we start at a dose of 100 mg of the CR [sustained release] capsule, and work gradually up to 200 mg twice daily. A typical dosage schedule is 100 mg per day for a week, then 100 mg BID for a week, then 200 mg in the AM and 100 mg in the PM, then 200 mg BID. Improvements are expected at doses of 300-400 mg per day, but some patients have benefited from lower doses.
Common adverse effects of disopyramide can include nausea, abdominal pain. dry mouth, constipation, blurred vision, impaired urination. and worse orthostatic tolerance. The drug, can activate glaucoma. The drug should not be taken with erythromycin, clarithromycin, azithromycin, phenothiazines, trimethoprim-sulfamethoxazole, cisapride, or other Class 1a anti-arrhythmic agents because of concerns about widening of the QRS complex. Q-T prolongation, and dysrhythmias. For similar reasons, it should be used with great caution in those on tricyclic antidepressants. Due to the negative inotropic effect of disopyramide and its potential for triggering dysrhythmias, its use should be considered very carefully in those with heart disease, or in those already taking beta-blockers or calcium channel blockers.
If Florinef, atenolol, and disopyramide are ineffective or associated with adverse effects, we usually try serotonin reuptake inhibitors (sertraline, Zoloft 50 mg each morning). Grubb and colleagues have found these medications effective in a subset of non-depressed patients with NMH refractory to other therapies. Our experience has been similar, especially among those with an increased degree of worry or perfectionism. Whether other SSRIs or other antidepressant medications would provide similar improvements, even in non-depressed patients, awaits study.
We will occasionally begin sertraline instead of disopyramide as the third agent. Again, until better evidence from comparative studies becomes available, this choice is based on limited information from experience with patients here and in other centers.
Other medications that have been found useful in published case series for patients with neurally mediated syncope are:
Theophylline at low doses (e.g., Slo-Bid 200 mg BID).
Ephedrine or pseudoephedrine
Midodrine (recently introduced), an alpha-agonist. The main side effects of this drug in those with orthostatic hypotension are: supine hypertension 15-20%, pruritis 10-15%, paraesthesias 5-10%, urinary urgency/full bladder 5%. Patients should be warned to expect piloerection and scalp tingling. The main caution has to do with blood pressure monitoring during the early part of the treatment period. Individuals with NMH should not be at risk for the same degree of supine hypertension as those with orthostatic hypotension, but one needs to watch for this. We recommend a starting dose of 2.5 mg each morning for a couple of days to ensure that the dose is tolerated, increasing to three times daily. A reasonable dose progression follows:
2.5mg three times a day for 3 days
5.0mg three times a day for 3 days
7.5mg three times a day for 3 days
10.0 mg three times a day as the highest dose
The drug effect lasts only about 3-4 hours, so the medication may need to be spaced differently once it is clear that it is having a beneficial effect.
Dextroamphetamine and methylphenidate
(See bibliography for specific papers)
Several drugs used in the treatment of orthostatic hypotension have not been evaluated for those with NMH, but may eventually be shown to have a role. These include erythropoetin, clonidine, yohimbine, and cimetidine.
Response to treatments:
The time until an improvement is seen is variable. Usually with the beta-blockers people notice a difference in as short as two weeks on the correct dose for their body weight. With Florinef, everything depends on the appropriate dose, but improvements have been noted in as little as a few days, to over one month. If drugs aren't causing side effects, we try to persevere until the therapeutic effect reaches a plateau. Many have noticed that they gradually feel better by paying attention to the triggers of their symptoms, and we cannot emphasize enough the importance of good fluid intake.
We hope this is helpful, but would obviously urge that the usual review of side effects and drug interactions take place before starting any individual on specific treatments. We have been very gratified by the responses reported by many of the patients, but don't pretend to have effective treatments for all of them, and are hoping that our work will stimulate others to try different approaches when the ones outlined above aren't working. The best data will undoubtedly come from randomized trials. Good luck.
Peter C. Rowe, MD
Department of Pediatrics
Hugh Calkins, MD
Department of Medicine
Jean Kan, MD
Department of Pediatrics
John Flynn, MD
Department of Medicine
Sally Snader, RN
Karen DeBusk, RN
Johns Hopkins Hospital, January 1997
Reference list is available from the CFS/ME Society office.