# Orthostatic Intolerance Orthostatic stress refers to being in an upright standing or sitting position where the cardiovascular system must work against gravity to deliver blood to the brain Orthostatic intolerance is the development of symptoms during upright posture that are relieved by laying down. Chronic orthostatic intolerance may present subtly as brain fog, nausea, heat sensitivity, fatigue or headaches. The Institute of Medicine Diagnostic Criteria lists orthostatic intolerance as a core feature of ME/CFS. # NASA Lean Test The NASA Lean Test (NLT) is an alternative measure of orthostatic intolerance that is both more sensitive than testing only for orthostatic hypotension and more accessible than a tilt table test or continuous heart rate monitoring. In a 2020 study by Lee et al. the NLT was performed on 150 patients with CFS and 75 healthy age-matched controls. The CFS patients were divided up into 2 equal groups, one with patients who had been sick less than 4 years and one with patients who had been sick more than 10 years. The study showed that there were statistically significant differences in results of the NLT in CFS patients vs healthy controls, though the disparity was less prominent when the patients had been sick longer, suggesting that the body had developed compensatory mechanisms over many years. The NLT results in CFS patients vs healthy controls were characterized by 4 areas of statistical significance: - a higher resting heart rate: CFS patients averaged 71 bpm (59-83) vs 62 bpm in controls (51-73) - a greater increase in diastolic blood pressure with standing: CFS patients experienced an 11 point increase on average compared to a 9 point increase in the control group. - an abnormally narrow pulse pressure: a pulse pressure proportion is calculated as the pulse pressure (systolic BP - diastolic BP) divided by systolic BP. An abnormally narrow pulse pressure is defined as a pulse pressure proportion less than 25%. This abnormality was seen more commonly in the CFS group sick less than 4 years. The CFS group sick greater than 10 years did not fall below this threshold on average but did present with a lower pulse pressure proportion compared to controls. - a higher frequency of spontaneously reported symptoms: 55% of CFS participants reported orthostatic intolerance symptoms compared to 21% of controls. Jihyun Lee, Suzanne D. Vernon, Patricia Jeys, Weam Ali, Andrea Campos, Derya Unutmaz, Brayden Yellman, Lucinda Bateman. Hemodynamics during the 10-Minute NASA Lean Test: Evidence of circulatory decompensation in a subset of ME/CFS patients. *Journal of Translational Medicine*. 2020;VOL(ISSUE);314.10.1186/s12967-020-02481-y ## Physician Instructions **To perform a NASA Lean Test:** 1. Prepare as if for a tilt table test by holding medications that affect heart rate and blood pressure if needed to make a diagnosis 2. Have the patient lay down for 15 minutes 3. Get a baseline heart rate (HR) and blood pressure (BP). If heart rate is elevated, it may be helpful to have the patient relax and then test again as it can mask a POTS diagnosis. 4. Prepare the patient by letting them know that they should report any symptoms they experience and let you know if they feel they are at risk of passing out. 5. Have the patient stand and lean against a wall 1. Heels 6 inches from the wall 2. Tops of shoulder blades only touching the wall 6. Record a BP and HR every minute for 10 minutes. Also record symptoms. **To interpret a NASA Lean Test** POTS is diagnosed with an increase in HR of 30 BPM or greater than 120. Orthostatic hypotension is diagnosed with a decrease in systolic BP of at least 20 mmHg or diastolic of 10 mmHg within 3 minutes of standing. Narrow pulse pressure proportion is less than 25%. Also look for signs of blood pooling (red/purple feet, tingling in the extremities) to suggest dysautonomia. ## Patient Instructions As part of your physical exam, we will be doing a "poor man's tilt table" test to look for POTS and orthostatic hypotension. It can also help me identify more subtle signs of orthostatic intolerance that can help support disability applications with objective findings. I will lead you through the test which will take about 15 minutes. Please have someone else around to help hold the phone and blood pressure cuff and make sure you are safe during and after the test. As always, reach out anytime with questions or concerns. [Download the Patient's Guide to the NASA Lean Test](https://assets.zyrosite.com/Yan71Q2lBqFv0Xp8/nasa-lean-patient-preparation-instructions-1-YleM2e6Xv5cgyxbr.pdf) ### Should I Stop My Medications for the Test? In short, no. The provided guide instructs you on the most effective way to assess the severity of your current orthostatic illness. This involves holding current treatments for the sake of the accuracy of the test. **I don't recommend this** except in one special circumstance: If you do not yet have an official POTS / orthostatic hypotension diagnosis AND it is important that you receive that diagnosis (for a disability application, for example) then I would recommend holding current interventions so that the test captures the full severity of your illness. Otherwise, I recommend continuing current medications and lifestyle interventions. This will help me assess how well the interventions are working and see if you would benefit from more medication or a new lifestyle change. ### Instructions - Schedule a time to do the test when you will have someone with you to help out and make sure you are safe if you were to get too dizzy or be tired afterwards. - You will need a blood pressure cuff that monitors heart rate (or a blood pressure cuff and pulse ox) - You will also need a space where you can lean against the wall that is as close to your couch or bed as possible - 15 minutes before the test starts, put on the blood pressure cuff and lay down on the couch or your bed. - Have your helper join the Google Meet call with me at the appointed time - I will walk you through the test and record the results. - It will start with measuring your pulse and blood pressure after laying down for 15 minutes. - I will then have you go lean against a wall. Your feet should be about 6 inches from the wall and only the tops of your shoulder blades should be touching the wall as you lean against it. - We will measure and record your blood pressure and pulse every minute for 10 minutes in this position. - If at any point you feel like you may pass out, just sit down. - Be prepared for this test to take a lot out of you if you do have orthostatic intolerance. Do it on a day when you don't have much else going on. # Orthostatic Hypotension Defined as a reduction in SBP of at least 20 mmHg or DBP of 10 mmHg within 3 minutes of standing. # Postural Orthostatic Tachycardia Syndrome Postural Orthostatic Tachycardia Syndrome (POTS) is defined as chronic symptoms of orthostatic intolerance (> 6 months) accompanied by an increase in heart rate of at least 30 beats per minute or a heart rate that exceeds 120 beats per minute within 10 minutes of standing in the absence of orthostatic hypotension. ## Mechanism There are 3 subtypes of POTS: Hypovolemic Neuropathic Hyperadrenergic Most ME/CFS patients have a mixture of all three subtypes. **Hypovolemic POTS** is due to reduced blood volume. People with ME/CFS have been found to have lower blood volume than the average population so this likely plays a role in most ME/CFS patients. **Neuropathic POTS** is when dysautonomia inhibits normal regulation of blood vessel tone. This often results in pooling of blood in the dependent areas of the body and, sometimes, hypohydrosis of the lower extremities. **Hyperadrenergic POTS** is caused by higher than normal levels of norepinephrine with standing. This norepinephrine surge can cause transient hypertension (blood pressure fluctuations), palpitations, anxiety, tremor, sweating and urinary urgency when upright. Hyperadrenergic POTS can result from the other two types of POTS. These patients should avoid norepinephrine uptake inhibitors which can worsen symptoms. The administration of midodrine and pyridostigmine, either in combination or alone, can cause worsening of the hyperadrenergic state in patients with hyperadrenergic POTS ## First line Treatment First line treatment for POTS are as follows: 1. Fluids and electrolytes 2. Compression garments 3. Leg muscle pump technique ## Second line Treatment Second line treatment options for POTS are as follows: 1. Saline infusions 2. Beta blockers 3. Vasopressor therapy 4. Fludrocortisone 5. Pyridostigmine ## Third line Treatment 1. Droxidopa 2. Ivabradine 3. Methylphenidate ## Electrolyte Goals for POTS Supplementing with salt and other electrolytes is essential to treat hypovolemia in POTS. I recommend starting with an additional 1,000 mg of sodium per day, taken in food or water. It is best taken early in the day. Other sources of electrolytes can include sports beverages, electrolyte packets, oral rehydration salts, canned soup, olives, and pickles. 1,000 mg of sodium is equivalent to: - 1 LMNT electrolyte packet - 4 Normalyte capsules - 4 Klaralyte capsules - 4 Vitassium capsules - 3 servings (6 short squeezes) of Buoy drops - 1/2 tsp table salt - 1 bouillon cube The later recommendations are not balanced with potassium so I recommend adding potassium chloride in a 1:1 ratio. See "homemade electrolyte solution" below for an example. Increase sodium intake slowly, up to 4,000 mg daily. My favorite sodium source is Normalyte because the capsules are easy to take (no taste), they have a clean ingredient list, they contain potassium to balance out the sodium, and they are the cheapest of the pill options. I don't recommend IV Hydration because it contains B6, and at the high doses needed for POTS, it is possible to cause B6 toxicity. ### Homemade electrolyte solution - 1/4 tsp table salt - 1/4 tsp potassium chloride (salt substitute) - 1/4 tsp buffered vitamin C (which contains magnesium carbonate, [[Calcium]] carbonate, potassium carbonate) - 2 cups water Drink 4-6 cups early in the day. ## Fluid Goals for POTS POTS patients should be drinking at least 96 oz of water per day (around 3 L). They should not be drinking more than 4 L daily or there is risk of hyponatremia. If your patient is drinking more than 4L, especially if their salt intake is on the lower side, polydipsia driven by hyponatremia should be considered and a 3L fluid restriction implemented with increased sodium intake while electrolytes are monitored (given that the hyponatremia is mild). ## Compression Garments Waist-high stockings at 30-40 mmHg are helpful but not always well tolerated. Abdominal binders at 10 mmHg, may be more effective, more easily removed and applied, and less uncomfortable than compression stockings. For those that do not tolerate compression stockings, I have some patients who report [this brand of leggings](https://www.amazon.com/dp/B0D49CGWDC?ref=ppx_pop_mob_ap_share) is comfortable and better tolerated. They do not provide medical grade compression but some compression is better than none. ## Engaging the “muscle pump” Engaging the “muscle pump” of the legs (eg. tensing muscles, crossing legs, weight shifting) can provide immediate symptom relief. Exercise is very beneficial for the treatment of POTS but is not well tolerated by those with ME/CFS. As the ME/CFS symptoms subside, the patient should be encouraged to engage in exercise as tolerated. Exercise done in a semirecumbent position, such as rowing or swimming, may be better tolerated. Lower extremity resistance training is also helpful. If the patient experiences PEM then the activity was too intense and should be reduced in time or intensity until it is tolerated. ## Beta Blockers Blunt heart rate elevations. Propranolol and metoprolol are the best studied but have not been compared. Fatigue is a limiting side effect. I recommend Propranolol at 20 mg daily. ## Fludrocortisone ### Dosing Starting dose: 0.1 mg fludrocortisone daily in the morning. Maintenance dose: 0.2 mg fludrocortisone daily in the morning. ### Side Effects Like midodrine, fludrocortisone comes with a risk of [[Supine Position Explained]] hypertension. However, lying supine is an important part of treatment for patients with ME/CFS so I recommend monitoring supine blood pressure and lowering the dose (to a minimum of 0.05 mg daily) if it becomes a problem instead of forbidding the patient from lying down. Hypokalemia is a common side effect. Hypomagnesemia is also possible. This can exacerbate underlying arrhythmias. Electrolyte monitoring is encouraged 1 week after changing dose and every 3-4 months during therapy. Acute onset of heart failure with reduced ejection fraction is a rare but serious side effect that can occur, more commonly in older adults. ### Monitoring I recommend resting potassium and magnesium levels 1 week after starting or increasing the dose of fludrocortisone. If there is a concern for hypertension, you can have the patient monitor their supine blood pressure at home. ## IV Saline Therapy for POTS Some patients receive saline bolus therapy (500-1,000 cc) 1-2 times per week for symptomatic treatment. This is best reserved as short term treatment though some patients choose to get a port and have infusions done long term. This is not recommended due to risk of infection and other complications. ## Midodrine Vasopressor Therapy **Midodrine** is most widely used at a dose of 2.25 mg to 10 mg three times daily (morning, midday, late afternoon). This can cause supine hypertension so supine blood pressure should be monitored or the patient should be instructed not to lay down within 4 hours of taking midodrine but this can be burdensome to the average patient with ME/CFS. ## Guanfacine Patients starting guanfacine should be regularly monitored for blood pressure, heart rate, and any side effects. Given the potential for sedation, it's important to adjust dosing schedules to suit individual tolerance levels. ## Ivabradine An off-label treatment for POTS with the benefit of not lowering blood pressure while reducing heart rate. Mechanism is selective inhibition of the sinoatrial node funny current which reduces heart rate without reducing blood pressure. It is effective and well tolerated but expensive. Must be taken with food or there is a steep decrease in absorption rate. Normal dose is 5 - 7.5 mg twice daily. Do not drink grapefruit juice while on ivabradine. Effective contraception is recommended in patients who could become pregnant. Ivabradine can be obtained legally via a Canadian pharmacy for cents per pill rather than $20/pill. They source it from the UK or India - still made by Abbot! If you have a patient who needs the more specific MOA/receptor action but even with insurance can’t get it covered, it’s something to consider. Otherwise, a 30 day supply (60 tablets) costs $100 with a Singlecare coupon used at CVS. ### Side Effects The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 1% to 10%: Cardiovascular: Bradycardia (4% to 10%), hypertension (9%), atrial fibrillation (8%) Central nervous system: Phosphene (3%) Frequency not defined: Cardiovascular: Heart block, sinoatrial arrest <1%, postmarketing, and/or case reports: Angioedema, diplopia, erythema, hypotension, pruritus, skin rash, syncope, torsades de pointes, urticaria, ventricular fibrillation, ventricular tachycardia, vertigo, visual impairment Use increases the risk of atrial fibrillation; monitor cardiac rhythm. Discontinue if atrial fibrillation develops. Bradycardia, sinus arrest, and heart block may occur; monitor heart rate prior to initiation and with any dosage adjustment. Bradycardia may increase the risk of QT prolongation, which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs. Ivabradine may cause teratogenicity (not safe for use in pregnancy).