, Rohit Arora3, 4, Nicholas L. DePace5 and Aaron I. Vinik6
(1)
Autonomic Laboratory Department of Cardiology, Drexel University College of Medicine, Philadelphia, PA, USA
(2)
ANSAR Medical Technologies, Inc., Philadelphia, PA, USA
(3)
Department of Medicine, Captain James A. Lovell Federal Health Care Center, North Chicago, IL, USA
(4)
Department of Cardiology, The Chicago Medical School, North Chicago, IL, USA
(5)
Department of Cardiology, Hahnemann Hospital Drexel University College of Medicine, Philadelphia, PA, USA
(6)
Department of Medicine, Eastern Virginia Medical School Strelitz Diabetes Research Center, Norfolk, VA, USA
Background
A very common question is: “All the software seems to recommend1 is alpha-lipoic acid,2 Coreg,3 nortriptyline,4 and midodrine.5 I do not use these drugs. So how is this useful?” First and foremost, please remember that the software does not “know” the patient’s history. Second, it would not be appropriate to practice medicine through software. Third, there are four autonomic imbalances (see Fig. 30.1) and eight classes of medications (see Table 30.1) that may restore imbalance. The recommendations of ALA, carvedilol, nortriptyline, or midodrine are simply examples of how an autonomic condition may be addressed. The application of the representative class must always be considered in light of the patient’s history and experience of the physician. For example, while carvedilol may be optimal to address an autonomic condition such as PE with CAN, it would be contraindicated for a severe asthmatic. For the severe asthmatic, a combination of selective beta-blocker and anticholinergic may be considered in its place. Note that carvedilol is suggested primarily for compliance issues. Prescribing the patient with a single agent that may pull double duty is often preferable to two agents for the same outcome. As another example, midodrine is but one of a range of therapies useful in treating various levels of orthostatic dysfunction. As indicated in the peer-reviewed article [1], the selection criteria for low-dose midodrine therapy excluded any patient with a resting BP greater than or equal to 160/90 and any patient whatsoever with supine hypertension. In these cases, alternatives must be considered, such as mineralocorticoids or other volume builders and compression stocking, at least until the patient’s BP is reduced to qualify for the exclusion criterion.
Fig. 30.1
The four P&S imbalances. These are the only four abnormal autonomic states (Fig. 6.1 repeated here for convenience)
Agent classification | Associated nervous system | Primary site of action | Primary effect |
|---|---|---|---|
Beta-1 adrenergic antagonists (“beta-blockers”) | Sympathetics ↓ | Heart | ↓ Heart rate |
Angiotensin–renin antagonists (e.g., ACE-Is, ARBs) | Sympathetics ↓ | Kidneys | ↓ Blood pressure |
Calcium channel blockers | Sympathetics ↓ | Heart | ↓ Blood pressure |
Alpha-adrenergic antagonists (“alpha-blockers”) | Sympathetics ↓ | Peripheral vasculature | ↓ Blood pressure |
Cholinergic antagonists (“anticholinergics,” e.g., tricyclics, SNRIs) | Parasympathetics ↓ | Entire body | ↓ Parasympathetic activity |
Acetylcholinesterase inhibitors (e.g., Mestinon [10]) | Parasympathetics ↑ | Entire body | ↑ Parasympathetic activity |
Beta-2 adrenergic agonists (e.g., bronchodilators) | Sympathetics ↑ | Lungs | ↑ Airflow |
Alpha-adrenergic agonists (vasopressors) | Sympathetics ↑ | Vasculature | Constrict vasculature |
A note regarding alpha-lipoic acid (ALA). This is a particular antioxidant that is selective for nerves. It can be related to patients as “orange juice for the nerves.” When they are feeling poorly, they take more vitamin C. This is just another antioxidant. It does not help balance, because it affects both ANS branches (and the rest of the nervous system) equally. ALA is always recommended when there is any autonomic dysfunction, short of CAN, for its intent is to slow the onset of CAN.
The main utility in P&S testing is not necessarily to cure disease (although it does happen). The main utility in P&S testing is to provide more information to help physicians improve differential diagnoses, patient outcomes, and, possibly, reduce medication load and hospitalization. Often, P&S results simply help to reduce morbidity and mortality so that the physician may be more aggressive towards the primary disease. See the first case study below as an example.
Case Study #1: A Depressed Hypertensive
A 46 y/o female, 5′0″, 172# (BMI = 33.59 #/in2), is diagnosed with hypertension, complaining of fatigue, sleep disturbance, exercise intolerance, and persistent weight gain. At rest, she demonstrates normal HR (80 bpm), high BP (138/81), normal P&S activity (S = 7.67 bpm2, P = 1.64 bpm2), and high SB (4.68; see baseline response graph, Fig. 30.2). Her DB response is low, indicating (early) autonomic dysfunction. In response to Valsalva, her sympathetics are normal and parasympathetics are high (indicating PE; see parasympathetic response graph, Fig. 30.2). Her autonomic and hemodynamic responses to standing are normal. Her rhythm strip is unremarkable, and the reported 3 ectopic beats were isolated and corrected according to FDA-approved procedures. Her history includes 50 mg Lopressor bid.
Fig. 30.2
A depressed hypertensive
She demonstrates both SE and PE (see Fig. 30.2, third graphic from top). Which is the primary autonomic dysfunction? High (resting) SB indicates a resting sympathetic excess (SE). Resting SE is associated with high resting BP. Consider titrating higher a sympatholytic (antihypertensive or beta-blocker) to establish and maintain normal SB (0.4< SB <3.0) and normalize BP. PE (whether Valsalva or standing) is associated with difficult to control BP, blood glucose, or hormone level; difficult to describe pain syndromes; unexplained arrhythmia (palpitations) or seizure; and symptoms of depression, fatigue, exercise intolerance, sleep or GI disturbance, dizziness, or frequent headache or migraine.
From an autonomic perspective, she demonstrates PE associated with (preclinical) depression and SE associated with hypertension. Both ends of her “seesaw” are high. The seesaw is broken. Worse, from a clinical perspective, depression would be treated with anticholinergics and hypertension would be treated with antihypertensives. As you know, an effect of anticholinergics is raised BP and an effect of antihypertensives is raised parasympathetic activity, possibly exacerbating depression. So which is the primary?
According to the P&S test, her (resting) SB is high, indicating that the SE is the primary diagnosis. This is an example of a primary static, or resting, imbalance. This choice is based on the observation that by the time an autonomic dysfunction presents as a resting autonomic dysfunction, it has been present for some time. Challenge response dysfunctions are known to be earlier in the progression of autonomic dysfunction. For high SB with PE, the recommendation would be to consider switching to carvedilol (see Carvedilol Therapy), history dependent, against establishing and maintaining normal SB.
After 4 months of 6.25 mg carvedilol bid, her follow-up test demonstrated normal SB (2.54), lower resting BP (134/78), normal parasympathetic response to Valsalva, and reduced fatigue with improved sleep habits. She reports a willingness to try starting an exercise regimen to reduce her weight.
Unexplained Dizziness
Case 2: Sympathetic Withdrawal and Orthostasis
An otherwise healthy 35 y/o female, 5′5″, 115# (BMI = 19.60 #/in2), complains of dizziness. At rest, she demonstrates normal HR (67 bpm), BP (108/66), normal autonomic activity (S = 3.36 bpm2, P = 3.77 bpm2), and low-normal SB (0.89). Her breathing challenge responses are within normal limits. Upon standing, she demonstrates sympathetic withdrawal (SW; see stand response graph, Fig. 30.3) with a normal BP response and a 59 bpm increase in HR. Her rhythm strip is unremarkable. She reports a history of Cymbalta 30 mg.
Fig. 30.3
Orthostatic dysfunction
The cardiorespiratory coupling plot from the first minute of the stand challenge is displayed in Fig. 30.3 (red graphing HR and gray graphing respiratory activity). The HR response is abnormal in that it does not return to baseline after the initial response, and then continues to increase over the course of the challenge. This is an example of a dynamic autonomic imbalance. SW is considered the autonomic definition of orthostatic dysfunction (see Orthostatic Dysfunction, Chap. 23).
Her SB is normal, and she is in balance at rest (the bottom graphic in Fig. 30.3) which is why she seems otherwise healthy. However, low-normal SB is recommended for geriatric patients, and may be too low, given her age. Low SB indicates a resting parasympathetic excess (PE). Given that her history with Cymbalta has been more than 3 months, the resting PE indicates that it is either not enough or she is not responding as expected. SW can involve marginal brain perfusion, resulting in preclinical depression-like symptoms.
For SW, recommend proper daily hydration (i.e., six to eight glasses of water throughout the day with fewer caffeinated, sugary, and alcoholic drinks), and also consider titrating lower any diuretic. SW with an abnormal HR response to standing is associated with possible postural orthostatic tachycardia syndrome (POTS). The recommendation would be low-dose midodrine (ProAmatine, 2.5 mg QD, dinner), assuming no supine hypertension. The patient is negative for supine hypertension. There was no change to the Cymbalta.
After 6 months, her follow-up test shows a slightly higher SB (1.04) and a reversal of SW. Her resting HR is 69 bpm and her resting BP is 113/72. Her HR response to standing is more normal (see Fig. 30.4, stand response plot), with a 31 bpm increase upon standing. She no longer reports dizziness and has started to self-wean from Cymbalta. After 12 months, she was weaned from the midodrine and was medication-free with no recurrence of SW or dizziness. As shown in Fig. 30.4 (circles), the sympathetic response to standing (section ‘F’), which is very low at baseline testing, is significant after 12 months, suggesting that the sympathetics have been retrained to respond properly to PC.
Fig. 30.4
Follow-up results from an orthostatic dysfunction patient. See text for details
Notes:
We have noticed that about 40 % of our SW patients are simply dehydrated. In other words, with proper daily hydration, about 40 % of SW is reversed and the majority of the patients also report a reduction or relief of symptoms, including afternoon headache or fatigue, evening edema, and dizziness or lightheadedness.
We have also seen where volume depletion increases cardiac workload as measured by higher resting BP, and reversing SW may reduce resting BP. We hypothesize that in these patients, the higher resting BP is compensatory for the drop in BP upon standing. By increasing the resting BP, when the drop occurs, the resulting PC BP is still great enough to perfuse the brain and prevent associated symptoms, including dizziness. This may be why some patients do not seem to tolerate their antihypertensive, because the antihypertensive unmasks the (preclinical) orthostatic dysfunction.
Remember that some artificial sugars are alcohol based and dehydrate just as readily. So they should be reduced or avoided as well.
It may be argued that the most important glass of water each day is the first glass in the early morning. Many people object to it, however, stating that they either do not like the taste or that it makes them nauseous. As for the former, if the water is pure and therefore tasteless, then perhaps if patients brush their teeth before drinking the water, it will not taste as bad. As for the latter, if the water is cold, remind the patient that the stomach temperature is near 98.6 °F. Cold water on a warm stomach will cause the stomach to contract, causing the sensation of nausea. If they drink hot water (remember, tea and coffee are just flavored hot water), they should not get the sensation of nausea.
Especially for women, remind patients that proper daily hydration will make their hair and skin more manageable, soft, and supple.
Case 3: Sympathetic Excess and Syncope
An otherwise healthy 29 y/o male, 5′6″, 175# (BMI = 28.24 #/in2), complains of lightheadedness and anxiety. At rest, he demonstrates normal HR (63 bpm) and BP (111/69), normal autonomic activity (S = 2.24 bpm2, P = 6.30 bpm2), and low SB (0.35; see Fig. 30.5, baseline response plot). His breathing challenge responses are within normal limits. Upon standing, he demonstrates both instantaneous (see Fig. 30.5, trend plot) and average (see Fig. 30.5, stand response plot) SE with a normal BP and HR response. His rhythm strip is unremarkable. He reports being tilt-negative and a history of Zoloft 50 mg for several years. Low SB indicates a resting parasympathetic excess (PE, “vagal dominance”). Given that his history with Zoloft has been more than 3 months, the resting PE indicates that it is either not enough or he is not responding as expected.
Fig. 30.5
Syncope
The stand cardiorespiratory coupling plot is from the first minute of the stand challenge (Fig. 30.5, red curves delineating instantaneous HR and gray curves delineating respiratory activity). From the stand cardiorespiratory coupling graph, the PC HR response is abnormal in that it does not return to baseline after the initial response, and then continues to increase over the course of the challenge. This is an example of a dynamic autonomic imbalance.
SE with standing is associated with tilt-positive patients and is considered the autonomic definition of possible (preclinical) syncope (see section “Syncope” in Chap. 23).
Stand SE may also indicate low brain perfusion and may be associated with his reports of anxiety. Stand SE with PE (whether resting, Valsalva, or standing) is associated with possible (preclinical) vasovagal syncope. The vagal excess has been found to be the primary dysfunction. The recommendation would be to switch the Zoloft to either low-dose Cymbalta or very low-dose nortriptyline.
After 4 months of 12.5 mg nortriptyline bid, his follow-up test demonstrated normal SB (1.08), higher resting BP (120/78), normal stand responses, and reduced anxiety and lightheadedness. Note that after 15 months, he began to self-wean the nortriptyline, and he was medication-free after 18 months with no recurrence.
Cardiovascular Autonomic Neuropathy (CAN)
This introduction is a review. CAN is a fact of life. Everyone who lives a “normal” life span will experience CAN. The only question is how soon it will be experienced. Therefore, CAN may be normal, especially for geriatric and many chronic disease patients: heart disease, diabetes, Parkinson’s, chronic pain, COPD, renal failure, hypertension, etc. While CAN indicates a greater mortality risk, it may simply mean that, “all else being equal,” the average “85-year-old” has a greater mortality risk than the average “45-year-old.” As a result, before any alarms are raised, CAN risk must be stratified. Even then, CAN risk is treatable [2, 3]. CAN risk is stratified with SB and CAN risk is treated by establishing normal SB [2, 4–7]:
CAN with normal SB (0.4< SB <3.0). Recommend cardiac work-up if first demonstration of CAN and not recent. No therapy change indicated by autonomic testing (the nerves controlling the heart are in balance, regardless of absolute level, which is the best that may be available). Therapy change may be indicated by cardiologic testing (the heart muscle itself, mechanically or electrically, may be abnormal). If therapy change is considered, titrate to establish and maintain low-normal SB (0.4< SB <1.0). Low-normal SB indicates more resting parasympathetic activity, as recommended in the cardiology literature as cardioprotective [8]. CAN risk is minimized with low-normal SB [6, 7]. Check for Valsalva or stand PE, and if demonstrated, consider switching the existing beta-blocker to carvedilol, history dependent, to treat both CAN and PE. Retest periodically to ensure all PE is relieved and proper SB is maintained.
CAN with low-normal SB (0.4< SB <1.0). Recommend cardiac work-up if first demonstration of CAN and not recent. CAN risk is minimal [6, 7]. Low-normal SB indicates more resting parasympathetic activity, as recommended in the cardiology literature as cardioprotective [8]. No therapy change indicated by autonomic testing (the nerves controlling the heart are in balance, regardless of absolute level, which is the best that may be available). Therapy change may be indicated by cardiologic testing (the heart muscle itself, mechanically or electrically, may be abnormal). If therapy change is considered, titrate to maintain low-normal SB. Check for Valsalva or stand PE, and if demonstrated, consider switching the existing beta-blocker to carvedilol, history dependent, to treat both CAN and PE. Retest periodically to ensure all PE is relieved and proper SB is maintained.
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