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AUTONOMIC FUNCTION TESTINGClinical Applications and Examples

Alejandro Ortiz-Burgos, MDUniversity of Miami, Internal Medicine

27 June 2006

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The Autonomic Nervous System

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ANS Overview

• ANS controls or coordinates every system in the human body

• ANS balance is required for health• Many “normal” people live with sub-clinical

issues or have lifestyles that adversely effect ANS balance

• Actual normals are few“Are you healthy or merely symptom free?”

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ANS Overview

• Physicians have been manipulating their patients’ ANS for decades– Cholinergic and Adrenergic Agonists and

Antagonists, Tricyclics, and SSRIs to name a few

• Now the effects on both ANS branches can be visualized quantitatively

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Recent Findings

• Medullary Feedback Pathway importance– Centrally acting agents can affect proper

balance when peripheral agents cannot• Many ANS dysfunctions tend to destabilize

a patient’s response to therapy and disease rather than present with overt symptoms– Dynamic Parasympathetic imbalances

underlie many difficult to manage cases

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ANS Review

• Sympathetics Mediate – In general, stress, “fight or flight”, and

increases metabolic activity– Specifically, peripheral vasoconstriction,

increases HR & contractility, drives BP, dilates pupils and bronchi, releases glucose stores and epinephrine and norepinephrine, decreases salivation & GI motility, relaxes bladder

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ANS Review

• Parasympathetics Mediate – In general, rest, relaxation, recovery, and

decreases metabolic activity– Specifically, peripheral vasodilatation,

decreases HR & contractility, constricts pupils, stores glucose, stimulates salivation & GI motility, contracts bladder, and mediates ventillation

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NON-INVASIVE TESTS OF THE AUTONOMICS

Sympathetics• Hand grip• Short Valsalva

Maneuver• Postural Change• Cold Water• Sweat Response

Parasympathetics• Deep Breathing• Postural Change• Long Valsalva

Maneuvers

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OTHER SOURCES OF ANS INFO

• Q-SART (Peripheral Autonomic Neuropathy)• Holter monitors, EKG monitors• Hand grip, Thermoregulatory, Tilt-table, Pupil

reaction– Qualitative, Clinical trends difficult– Only one branch or mixed measures– Assumptions about other branch only valid in

relatively healthy individuals

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OTHER SOURCES OF ANS INFO

• Teaching hospitals– Definitive work

• Requires up to two days• Intended for most severe cases

• Current technology enables a 15.5 minute study in the office– Designed to test those who would otherwise not

be considered for ANS function testing – like most diabetics

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HRV & RA = ANS

*RFa = Parasympathetic Measure

**LFa = Sympathetic Measure

LFa/RFa = Sympathovagal Balance

FRF

Normal, Healthy, Resting Cardiogram

SlowermHR

Faster RSA

**

*

Time (sec)

Time (sec)

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RESPIRATION IS THE KEY

• Respiratory analysis together with HRV analysis– Two measures for a two component system

• Characterized systemically• Quantified mathematically

– Respiratory analysis determines Vagal outflow

• “Measures” Respiratory Sinus Arrhythmia to determine systemic Parasympathetic activity

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Heart Rate Variability & Respirations

• Heart Rate Variability (HRV) with Respiratory Activity (RA) = ANS testing– Consider healthy resting cardiogram:

• Faster respiratory sinus arrhythmia (RSA) = Vagus (PSNS)

• Slower mean heart rate (mHR) changes = SNS– Analyze separately (“peel apart”) =

independent measures of both ANS branches• Spectral analysis is the only method

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Heart Rate Variability & Respirations

Akselrodat

MIT

1981198519871988

} HRV WITH RESPIRATIONS

Classical HRV[Malek, Circulation]

1996 } RESPIRATIONS OMITTED

Malek, 1996Low, 1997Uijtdehaage and Thayer, 2002Williams and Lopes, 2002Cammann and Michel, 2002Vinik and Freeman, 2003

} FOR ANS MONITORINGHRV MUST INCLUDERESPIRATIONS

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Who To Test?

• In-office:– Medicare pays for all chronic progressive

diseases, including Pain• Out patient clinic:

– Medicare pays for all chronic progressive diseases, including Pain

• In-hospital:– Patients with acute cerebro-vascular

diseases (Stroke) and other brain injuries

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Who To Test?

• Leadership recommends* ANS monitoring

*AHA1,2, ADA1,2,3,4, AAN5, AAFP6, JDIF1, NIH1

1. Joint Editorial Statement by the American Diabetes Association; the National Heart, Lung, and Blood Institute; the Juvenile Diabetes Foundation International; the National Institute of Diabetes and Digestive and Kidney Diseases; and the American Heart Association. Diabetes Mellitus: A major risk factor for cardiovascular disease. Circulation. 1999; 100: 1132-33.

2. Grundy SM, Benjamin IJ, Burke GL, Chait A. AHA Scientific Statement: Diabetes and Cardiovascular Disease, a statement for healthcare professionals from the American Heart Association. Circulation. 1999; 100: 1134-46.

3. Boulton AJM, Vinik AI, Arrezzo JC, Bril V, Feldman EI, Freeman R, Malik RA, Maser RE, Sosenko JM, Ziegler D. (2005) Diabetic Neuropathies: A statement by the American Diabetes Association. Diabetes Care. 28(4): 956-62.

4. Vinik AI, Freeman R, ErbasT. (2003) Diabetic autonomic neuropathy. Semin Neurol. 23(4): 365-72.

5. Low P and the Therapeutics and Technology Assessment Subcommittee (1996) Assessment: Clinical autonomic testing report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology, 46: 873-80.

6. Aring AM, Jones DE, Falko JM. (2005) Evaluation and Prevention of Diabetic Neuropathy. Am Fam Physicians. 71: 2123-30.

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Who To Test?

• ANS testing detects ANS imbalances in asymptomatic patients BEFOREneuropathy presents– Imbalances, whether the primary disorder

or caused by a primary disorder, can cause secondary disorders which can cause further disorders and so on….

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Who To Test?(A Partial List of ICD-9 Codes)

Neurology314.01 ADD/ADHD 332.0 Parkinsonism337.0 Idiopathic peripheral autonomic neuropathy337.2 Chronic Regional Pain Syndrome 337.9 Unspecified disorder of ANS340 Multiple sclerosis 346.0 - .9 Migraine352.3 Disorders of Pneumogastric (10th) N. 356.4 Idiopathic progressive neuropathy357 Polyneuropathy358.1 Myasthenic syndromes (Eaton-Lambert) 458.0 Orthostatic hypotension 596.54 Neurogenic bladder 780.2 Syncope and collapse 780.71 Chronic fatigue syndrome 784.0 Headache785.0 Tachycardia (postural)

Internal MedicineAll of the rest, plus:278.01 Morbid Obesity 279.3 AIDS 296 Depression or Bipolar Disease 300 Anxiety 307.4 Sleep Disorders 530.11 GERD536.3 Gastroparesis564.1 Irritable Bowel Syndrome 729.1 Fibromyalgia 780.50 Post-traumatic Stress Synd.782.3 Edema

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Who To Test?(A Partial List of ICD-9 Codes)

Cardiology401.0 - 405.99 Hypertension412 Post-MI 413 Angina414 Atherosclerosis424 Mitral Valve Prolapse

Syndrome425.4 Cardiomyopathy427 Cardiac Dysrhythmias428 Congestive Heart Failure

Endocrinology244 Acquired Hypothyroidism246 Thyroid Disorders 250.0 - 250.8 Diabetes256.3 Premature Menopausal

Symptoms627 Menopausal Syndromes

Pulmonology780.51, 780.53, 780.57 Sleep Apnea 493.90 - 493.93 Asthma 493.2 COPD

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Why Monitor The ANS?

• Autonomic Neuropathy signs and symptoms are late in the progression– Chronic Progressive Disease is the

indicator

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Why Monitor The ANS?

• Chronic disease leads to neuropathy– Neuropathy does not present “overnight”– ANS dysfunction precedes neuropathy

1. Autonomic dysfunction2. Peripheral autonomic neuropathy (PAN)3. {Diabetic autonomic neuropathy (DAN)}

• Loss of quality of life (eating, sleep, voiding, sex)

4. Cardiovascular autonomic neuropathy (CAN)• Loss of longevity

5. High risk of sudden cardiac death

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Why Monitor The ANS?

• Early detection and correction of ANS imbalance (dysfunction) helps to:– Protect ANS and related organs– Keep patient stable– Preserve quality of life– Preserve longevity

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ANS Testing

• Fully automated, any Technician can be trained and certified by Ansar in an hour

• The test itself is 15.5 minutes in duration

• Requires a plain straight-back chair, the test equipment, and a quiet room

• Technicians and nurses love it, one-on-one time with the patient and no interruptions

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ANS Testing

• Six challenges include:A) resting (initial) baseline,B) the parasympathetic challenge of deep

breathing,C) return to baseline,D) the sympathetic challenge of a series of short

Valsalva maneuvers,E) return to baseline, andF) Quick postural change (seated to standing)

followed by quiet standing

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ANS Test Results

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ANS Balance

• Resting balance– The overall effect of: Lifestyle, Disease,

History, Genetics, & Therapy– Lifestyle and Therapy can be modified to

restore balance• Dynamic balance

– Early indicator of disorders• Syncope, Orthostasis, GI upset, Sex dysfunction,

Sleep disorders– Pain indicator

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Correcting Resting Imbalance

• Establish and Maintain normal balance

Sympathetics Parasympathetics

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Correcting Resting ImbalanceSympathetic excess

Sympathetics

Parasympathetics

• Correct by reducing sympathetic levels– Adrenergic Blockade:

• Beta-blockers,• Angiotensin blockers,• Calcium Channel Blockers

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Correcting Resting ImbalanceParasympathetic excess

SympatheticsParasympathetics

• Correct by reducing parasympathetic levels– Initiate Cholinergic Blockade, e.g., tri-cyclics– Reduce Adrenergic Blockade

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ANS Test Results

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Correcting Resting ImbalanceCheck Titration

• Medication state indicates a net Adrenergic antagonist level

1. Normal balance = appropriate titration for pt2. Net excess sympathetic level, increase dosage3. Net excess parasympathetic level, decrease

dosage

Example:

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ANS Test Results

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Dynamic ANS ImbalanceSympathetic Withdrawal

• SW = a physiologic definition of Orthostasis

• Upon assuming an upright posture:– Parasympathetics withdrawal– HR increases– Exercise Reflex helps to maintain

vascular tone and blood flow to brain– Exercise Reflex ends and Sympathetic surge to maintain

vascular tone and blood flow to brain

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Dynamic ANS ImbalanceSympathetic Withdrawal

• SW can cause dizziness and precedes abnormal changes in:– BP, in Orthostatic Hypotension

• 20 and 10 mmHg drop in systolic and diastolic BP, respectively

– HR, in Postural Orthostatic Tachycardia Syndrome (POTS)

• 30 bpm increase in HR or HR in excess of 120 bpm

• Why wait for clinical symptoms?– Earlier intervention can be lower dose and short

term

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Dynamic ANS ImbalanceSympathetic Withdrawal

• Therapy– Mechanical intervention, e.g., stockings– Volume building (check resting BP)– Pyridostigmine (reintroduced by Mayo Clinic)– Vasopressors, e.g., Midodrine

• Start low dose, consider weaning when reversed and stabilized (in a little as six months if detected early)

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ANS Test Results

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Dynamic ANS ImbalanceSympathetic Excess at Stand

Normal Abnormal Abnormal

• Peak sympathetic response at the beginning of stand should be less than peak sympathetic response to Valsalva

• Physiologically it makes no sense if more sympathetic activity is required to stand than to perform a series of Valsalva maneuvers

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Dynamic ANS ImbalanceSympathetic Excess at Stand

• Sympathetic excess at stand is associated with tilt positive patients and Syncope

• Check HR– If HR increases (nerves are working) Syncope is

Cardiogenic– If HR does not increase, Syncope is Neurogenic

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Dynamic ANS ImbalanceVagal Dominance Throughout Test

• Elderly with little responsiveness– Vagal dominance throughout test is

associated with Vasovagal Syncope• Therapy

– Standard for different forms– Consider anti-cholinergics if Vagal dominance

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ANS Test Results

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Dynamic ANS ImbalanceSympathetic Excess at Stand (Part 2)

• Double headed arrow marks the beginning of the stand period

• Vertical line marks two minutes into standing

• Two minutes into standing is about when the exercise

• Ectopy occurs during quiet standing, but not during Valsalva or the gravitational response to stand?

reflex concludes

Two minutes into standing

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Dynamic ANS ImbalanceSympathetic Excess at Stand (Part 2)

• Arrhythmia 2 to 3 minutes into standing suggests POTS

• Therapy– Treat for Orthostasis

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Dynamic ANS ImbalanceParasympathetic Excess During Sympathetic Challenge

• Sympathetics are reactionary• Parasympathetics set metabolic threshold• If P abnormally respond to S challenges, S

forced into greater responses

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Dynamic ANS ImbalanceParadoxic Parasympathetic Syndrome

• PPS is the term created to label Parasympathetic Excess During Sympathetic Challenge

• PPS in general destabilizes the patient’s response to disease and therapy (i.e., BP, HR, Diabetes, Thyroid)

• Common to our Database (> 50%)

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Dynamic ANS ImbalanceParadoxic Parasympathetic Syndrome

• A finding unique to measuring both ANS branches simultaneously

• PPS is defined by several diffuse symptoms including: Sleep difficulties, GI upset, Frequent migraines or morning headaches, evening edema or restless leg syndrome

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Dynamic ANS ImbalanceParadoxic Parasympathetic Syndrome

• PPS can help to differentiate CRPS (plexus damage) from other forms of pain

• PPS associated with migraine, CFS, ADD/ADHD, Fibromyalgia, Sleep difficulties, Unexplained seizures, Depression/Anxiety/Bipolar Disorders

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Dynamic ANS ImbalanceParadoxic Parasympathetic Syndrome

• Requires centrally acting agents to correct– Peripherally acting agents further destabilizes

the patient• Not all adrenergic channels are block, so pt’s

systems finds a way to defeat the therapy to ensure proper brain perfusion

– Central agents help to settle the whole ANS by stabilizing both branches at the central communication point

• Effects the feedback point in the upper Medullary brain stem nuclei where the Limbic and systemic sympathetics input on to the nuclei that give rise to the Vagus N.

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Dynamic ANS ImbalanceParadoxic Parasympathetic Syndrome

• Therapy typically corrects PPS in 12-15 months, and can be weaned over 3 months (assuming no end-organ effects)– Reset and hold ANS “set point” (nervous

system plasticity)– Patient (ANS) drug free until some other

clinical event

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Dynamic ANS ImbalanceParadoxic Parasympathetic Syndrome

Nucleus & Tractus

Solitarius

Systemic Sympathetic

Input

Cingulate Gyrus(Limbic System)

Pons

Medulla

Block with Tricyclics(use for depression, anxiety, emotional triggers, & sleep

difficulties)

Systemic Parasympathetic

Outflow

Block with centrally acting adrenergic-antagonists

(eg, Coreg if Diabetic or has heart disease)

Limbic Input

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PAIN MANAGEMENT

• Quantify patient’s relative pain levels (relative to patient’s own baseline)

• Differentiate between Psychosomatic pain, Somatic or Sympathetic pain and CRPS

• Assist in titration of pain medication• Document progress in Physical Therapy

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PAIN MANAGEMENT• ANS monitoring can quantify patient’s

relative pain levels– Pain is a stressor– Sympathetics respond to stress– More or less Sympathetic activity indicates

more or less pain

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PAIN MANAGEMENT• ANS monitoring can differentiate pain classifications

– Psychosomatic pain• Normal to low responses• Consider addiction

– Somatic or Sympathetic pain• Elevated sympathetic levels either at rest (especially if medicated)

or in response to Valsalva• Parasympathetics are normal

– Reflex Sympathetic Dystrophy as it involves a plexus crush or restricted blood flow to a portion of the body

• Elevated sympathetic and parasympathetic levels– Sympathetics elevated due to pain– Parasympathetics elevated due to reduced tissue perfusion

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PAIN MANAGEMENT• Assist in titration of pain medication

– Properly titrated medications is indicated by normal resting (baseline) balance

• Document progress in Physical Therapy– Normalize ANS responses to challenges

• Continuous Monitoring also possible in hospital

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0

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2 4 7 9 11 13 16 18 20 22 25 27 29 31 154

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354

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Time (minutes)

LFa

& R

Fa (b

pm^2

)

LFaRFaIHR

57 y/o, M Patient in ERBlunt Trauma Pt #5568001

(Face, Chest)

Patient moving

Morphine injection (20% dose)

Patient coming light

Morphine injection (20% dose)

Maintenance dosing

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General TherapyAgent Associated

Nervous System

PrimarySite ofAction

Primary Effect

Beta-1 Adrenergic Antagonists

Sympathetics Heart ↓ Heart Rate

Beta-2 Adrenergic Agonists

Sympathetics Lungs ↑ Air Flow

Alpha Adrenergic Agonists

Sympathetics Vasculature Constrict Vasculature

Cholinergic Antagonists Parasympathetics Entire Body ↓ Parasympathetic activity

Angiotensin Blockers Sympathetics Kidneys ↓ Blood Pressure

Calcium-Channel Blockers

Sympathetics Heart ↓ Blood Pressure

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General Therapy

• Arrhythmia 2 to 3 minutes into standing suggests POTS

• Therapy– Treat for Orthostasis

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TESTS OF THE AUTONOMICS

• Most tests of the ANS really only test one ANS branch at a time

• The activity of the other branch is assumed based on the classical “push-pull”relationship between the two

• This relationship is only valid in healthy individuals

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Chronic Monitoring

• Provides info regarding patient stability– Under stress– After meals– Before retiring

• Detects trends early

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Chronic Monitoring

• NCVS• Tilt-studies• Sleep Studies• Sex Function Tests

• Q-SART• Sudomotor Testing• Vestibular Tests• Stress-tests• Holter-monitoring

• A 15 minute test to augment:

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Acute Monitoring

• Continuous “baseline” monitoring– Sleep studies (Apnea or Circadian Upset)– ER, OR, ICU

• Measures instantaneous physiologic changes

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Normal Children

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Normals Teenagers

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Normals: The Transition Years

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Normal Adults

34 y/o

44 y/o

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Normal Adults

60 y/o