Understanding baroreflex regulation of blood pressure from a patient with autonomic failure

Elapulli Sankaranarayanan Prakash, MBBS, MD

Mercer University School of Medicine

Division of Basic Medical Sciences

1550 College Street, Macon, GA 31207, USA

E-mail: ;

Phone: +1(478)-301-5507

Content / Page
List of Abbreviations / 3
Instructor’s Guide / 4
The Case / 9
Mini-Cases (Problem Solving Exercises) / 12
Guide for Students ǂ / 13
Materials for Instructors only:
Brief Analysis of the Case / 19
Case Discussion (Questions and Answers) / 20
Answers to Mini-Cases (Problem Solving Exercises) / 33
References / 34

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ǂ Problem-based learning curricula typically require the learner to identify learning issues and objectives from a preliminary analysis of the case. Intended learning objectives and the required reading mapping to the case presented here are included in the Instructor’s Guide as well as Guide for Students so that this submission to MedEdPortal is self-contained, and may be adapted by users for other learning formats such as self-study.

List of Abbreviations

BP / Blood pressure
bpm / Beats per minute
CBF / Cerebral blood flow
CSF / Cerebrospinal fluid
DA / Dopamine
DBH / Dopamine beta-hydroxylase
DOPA / Dihydroxyphenylalanine
E / Epinephrine
ECF / Extracellular fluid
ECG / Electrocardiogram
HR / Heart rate
HVA / Homovanilic acid
JVP / Jugular venous pressure
L-DOPS / L-dihydroxyphenylserine
MAP / Mean (systemic) arterial pressure
NE / Norepinephrine
NTS / Nucleus of tractus solitarius
OH / Orthostatic hypotension
OI / Orthostatic intolerance
Qs / Cardiac output (systemic blood flow)
SV / Stroke volume
SVR / Systemic vascular resistance
TPR / Total peripheral resistance (synonymous with SVR)
VMA
NMS / Vanillyl mandelic acid
Neurally mediated syncope
WNL / Within normal limits

Instructor’s Guide

Brief Description of Resource, Conceptual Background: This is a case study of a patient with autonomic failure written to facilitate an understanding of baroreflex regulation of blood pressure (BP) and a number of related concepts. The main patient encounter (hereinafter called the Case) in this resource was written to be one in a series of a dozen other case scenarios in the cardiovascular block of an integrated, organ system and case-based curriculum for second year medical students. These students had already been through 7 phases of case-based learning in basic medical sciences over a year and 6 weeks. They had been through curricular blocks (called Phases in MUSM’s Biomedical Problems program) including metabolism, genetics, hematology, host defense, the central nervous system, musculoskeletal system, and principles of behavioral science. This Case has been implemented once for a class of second year medical students, and the materials included here including the Case have been reviewed and updated based on the experience of its implementation.

The accompanying Mini-Cases (Problem Solving Exercises) may be used following the discussion of the Case to assess if students’ understanding of concepts in the Case transfers to similar contexts. The Guide for Students consists of intended learning objectives (noted below), recommended reading (noted below), and offers some guidance on how the Case may be analyzed. Additionally, there are materials that are intended for instructors only including a brief analysis of the Case, discussion of the Case formatted as questions and answers, answers to the problem solving exercises, and a list of references consulted in the preparation of this resource. While the Case was written for use in tutor facilitated small group tutorials consisting of 6-8 students, the materials available with this resource are intended to allow users to adapt it for other teaching-learning formats such as self-study or even in the context of an interactive lecture for a larger class of students.

Learning Objectives:

  • Review the structural and functional organization of the autonomic nervous system particularly in terms of the site of origin of preganglionic and postganglionic neurons, neurotransmitters released by pre- and postganglionic neurons, receptors on postganglionic neurons and effector organs.
  • Describe the steps involved in the biosynthesis of catecholamines.
  • Describe the role of alpha and beta adrenergic receptors in the regulation of heart rate and vascular resistance. Describe the function of presynaptic alpha-adrenoceptors in the regulation of sympathetic outflow.
  • Discuss the physiologic effects of orthostatic stress and responses that enable maintenance of upright posture.
  • Describe the components of the baroreflex arc (afferents, central controller or integrator, and efferent pathways), and the role of the arterial baroreflex in the regulation of blood pressure.
  • Discuss the clinical consequences of a persistent defect in baroreflex regulation of blood pressure.
  • Describe how cerebral blood flow is autoregulated.
  • Define orthostatic (postural) hypotension (OH). Propose causes of OH in terms of changes in the following: blood volume; ECF volume; functional integrity of baroreceptors and afferents from baroreceptors, central integrators in the brain stem, efferent neural pathways; target organ responses.
  • Define syncope. Classify syncope based on hemodynamic causes – in terms of cardiac output, systemic vascular resistance, and cerebral vascular resistance.
  • Discuss the physiologic principles underlying evaluation of a patient with chronic orthostatic intolerance (OI). When a defect in the baroreflex is thought as a cause of abnormal blood pressure regulation, explain how one can localize the defect to one or more of the following: afferent limb; central controller; sympathetic efferent pathway; parasympathetic efferent pathway; effector organs.
  • Describe the mechanism and clinical significance of respiratory sinus arrhythmia.
  • Describe the hemodynamic changes and reflex responses to Valsalva maneuver, and explain how changes in mean arterial pressure and heart rate during the maneuver can be used as a test of cardiovascular autonomic function.
  • Describe the blood pressure response to each of the following and the neural pathway involved:
  • Sustained isometric handgrip
  • Immersion of hand in ice cold water
  • Describe the short-term effects of atropine and other drugs* (listed below) affecting sympathetic neurotransmission on HR, vascular resistance, MAP with and without reflex responses, and describe the site and mechanism of action of these drugs.

*Epinephrine; Norepinephrine; Phenylephrine; Midodrine; Isoproterenol; Ephedrine; Tyramine; Clonidine; Phentolamine; Prazosin; Propranolol; Atenolol; Labetalol.

  • Discuss the physiologic basis of pharmacological and nonpharmacological strategies for management of OH and OI.
  • What is neurally mediated syncope (also known as vasovagal syncope)? Summarize the pathogenesis of this entity. How would you distinguish syncope due to OH from neurally mediated syncope?
  • Recognize that symptoms of autonomic dysfunction may be part of a wider disease process involving other parts of the central nervous system.

Recommended Reading:

  1. Barrett KE, Barman SM, Boitano S and Brooks HL. Chapter 32: Cardiovascular Regulatory Mechanisms. In: Ganong’s Review of Medical Physiology. 2012, McGraw Hill-Lange.
  1. Katzung B et al. Autonomic Drugs. In: Basic and Clinical Pharmacology. McGraw Hill-Lange, 2012. Review biosynthesis of catecholamines. Consider norepinephrine and drugs listed from each of the following classes in relation to the tests done to this patient.
  • Norepinephrine
  • Parasympatholytic agent - atropine
  • Alpha-1 selective adrenergic receptor agonist - phenylephrine, midodrine
  • Alpha-2 selective adrenergic receptor agonist - clonidine
  • Nonselective alpha-adrenergic receptor antagonist - phentolamine
  • Beta-2 adrenergic receptor agonist - isoproterenol
  • Beta-1 and beta-2 adrenergic receptor antagonist - propranolol
  • Indirect-acting sympathomimetics - tyramine
  • Direct and indirect acting (mixed) - ephedrine
  • Centrally acting sympatholytics – clonidine, methyldopa

For each drug, focus on mechanism of action, cardiovascular effects and applications related to cardiovascular conditions. It is important to consider drug effects in light of baroreflex responses, as well as in the absence of reflex responses.

  1. Low PA and Engstrom JW. Chapter 375: Disorders of the autonomic nervous system. In: Harrison’s Principles of Internal Medicine, 18th ed. New York: McGraw Hill, 2012. (In this chapter, it is sufficient to focus on the following subtopics: symptoms of OI; approach to a patient with OH; autonomic testing (exclude quantitative sudomotor testing); note the essential elements of pure autonomic failure, postural orthostatic tachycardia, and treatment of autonomic failure (focus on principles, note drugs and the pathophysiologic basis for use, omit drug dosages).

Additional Reading Suggested: Another suggested resource is the video by Dr Novak, an open access article available at The citation is: Novak P. Quantitative autonomic testing. J Vis Exp. 2011; (53): 2502. The first 8.5 min of this video may be helpful.

Why was dopamine-beta hydroxylase (DBH) deficiency chosen as the etiology of this presentation?

The primary focus of the curricular block for which this Case was written is to enable learning basic sciences relating to the cardiovascular system in the context of clinical cases. Syncope may be recurrent and orthostatic intolerance (OI) may be chronic and range in severity from mild to debilitating. The prevalence of syncope is estimated at 19% in the general population aged more than 45 years (Chen et al, 2006). Our patient has both. However, it may be uncommon for someone with chronic OI or recurrent syncope to be systematically evaluated to the point of identifying a specific underlying etiology such as DBH deficiency. The Case also illustrates the general principle that when a specific etiology is identified and therapy addresses the etiology directly, patient outcomes are better.

Several other clinical entities including vasovagal syncope, postural orthostatic tachycardia syndrome, Riley-Day syndrome, multiple system atrophy, and OI in a patient with long-standing diabetes were considered as candidates for a scenario. Though vasovagal syncope is commoner, often, it is a diagnosis of exclusion not requiring detailed evaluation of autonomic function. It would be a good mini-case in the context of this curricular block and does feature as a problem solving exercise (Question # 5, p. 9). Riley-Day syndrome is characterized by defects not only in visceral afferents but also somatosensory afferents. The phenotype is complex and includes defects in pain and temperature sensibility, impaired ventilatory responses to hypoxia and hypercapnia and other abnormalities well outside the scope of the Cardiovascular Block. Multiple system atrophy with autonomic failure was not chosen because students had had the neurology block before. Chronic OI in a diabetic was not chosen because physiology of pancreatic hormones, pathogenesis of chronic complications of diabetes and principles of management of diabetes are better exemplified in a later phase of learning (Endocrinology) in this curriculum.

Lessons learned:

The rarity of the specific diagnosis reached may concern some students and teachers. The actual specific diagnosis (DBH deficiency) reached is not the focal point of this Case. DBH deficiency is not an entity second year medical students need to know about. The core learning objective is to apply (and assimilate) knowledge of neural regulation of cardiovascular function, steps in catecholamine biosynthesis, and actions of norepinephrine, and consequences of its absence toward understanding how a patient presenting with syncope or OI may be evaluated and managed in practice. It is important for the tutor to exemplify during Case discussion concepts that 'transfer' to related clinical scenarios. Mini-Cases included in this resource provide some examples of more common clinical situations to which concepts related to this Case apply.

Some tutors and students felt the version of the Case implemented last year was too long. It was originally formatted as a more traditional patient note, and the history of present illness included more negative findings. Notes on physical examination were more elaborate including more negative findings. The Case has now been revised to include only pertinent history and physical exam findings. As for routine initial lab workup, values that are within normal limits are listed as WNL instead of including the observed value and a reference range for each. These changes have allowed the case to be condensed by about three quarters of a page.

Can this Case be further simplified?

Tests # 10 and 11 may be deleted and the diagnosis can still be established. The point of Test 10 is it provides evidence of a reflex increase in sympathetic nerve activity in response to a fall in BP but the transmitter released, in this patient, by sympathetic postganglionic neurons is dopamine rather than norepinephrine. If understanding the response to low dose clonidine in this patient is not an intended learning objective, Test 11 can be deleted.

Is the Guide for Students needed?

In my view, it is preferable to provide students one for this Case, though it depends on curricular objectives. This Case is somewhat unique in requiring a battery of autonomic function tests to reach a specific diagnosis. Even if this Guide is provided, there is still a lot of reading, analysis, and application for the learner to attempt before all findings in the Case can be explained. Providing guidance in advance may allow for tutor-facilitated discussion to focus more on analysis and application of knowledge, and potentially extend the discussion to related clinical entities in addition to recalling relevant factual information in the required reading. A student guide was requested at least by some students and tutors last year.

What topics in a typical basic science curriculum are prerequisite for optimal learning from this Case?

To optimize learning from this Case and to allow focus on the kinds of questions that are included in the Case Discussion (Questions and Answers) section of this module, it is recommended that students have had enough background in the following areas:

  • Interpret blood hemoglobin, RBC count, WBC count, and WBC differential and explain for example how anemia could moderate this presentation.
  • Significance of various aspects of clinical examination of the nervous system
  • Introduction to general physical examination so that terms such as pallor, icterus, pedal or presacral edema are not new to them.
  • Basic principles of mendelian genetics
  • Body fluid compartments and their composition

This Case should not be amongst the first few cases in a cardiovascular block, and the learner should have a basic understanding of the cardiac cycle, the physiologic interpretation of BP, heart rate, relationship between pressure, flow and resistance, determinants of tissue blood flow. Otherwise, this can very well be used as the first major case to introduce the learner to the functions of the arterial baroreflex and the two efferent limbs that regulate cardiovascular autonomic function. There is no need to have knowledge of the inner workings of the kidneys to understand this Case; the only concept needed is that chronic reduction in renal blood flow can decrease renal elimination of urea and creatinine. As far as cortisol and aldosterone, it is sufficient to note that aldosterone, a hormone secreted by the adrenal cortex, is the most potent endogenous mineralocorticoid hormone. Its major action is facilitating conservation of salt and water by the kidneys. The basis for using fludrocortisone is the notion that salt and water conservation and blood volume repletion might mitigate OH. Fludrocortisone has been found helpful when adrenocortical insufficiency is the cause of symptomatology. Our students have not had the Renal or the Endocrine Phase by the time they are doing this Case in the Cardiovascular Block.

The Case

Mr. Austen Miller is a 30 yr old man with a 10 yr history of disabling orthostatic intolerance and near-fainting spells. Near fainting spells were characterized by lightheadedness, blurring of vision, and weakness. An impending fainting spell could sometimes be aborted by tensing limb muscles and immediately lying down. These typically occurred within a few minutes of standing up or exerting following a period of recumbency. Symptoms were worse after heavy meals, in hot environments, sometimes resulting in transient loss of consciousness. He sweated profusely after severe spells of lightheadedness.

Mr. Miller had had fainting spells followed by convulsions during childhood; these were often provoked by exercise. This had been diagnosed and managed as epilepsy with phenytoin; however, this did not result in improvement.

Two years ago, he had been diagnosed with orthostatic hypotension and prescribed ‘low dose’ midodrine (taken in the morning) but this provided limited symptom relief. Six months later, he was prescribed fludrocortisone tablets. This also did not provide significant relief from symptoms. There was no history of diabetes, hypertension, or renal failure.

Mr. Miller was single and consumed alcohol in moderation on occasions. There was no family history of similar illness.

On physical examination, Mr. Miller appeared thin and worn out.

Height: 1.6 m; weight: 50 kg; body mass index: 19.5 kg/m2.

BP (supine): 104/60 mm Hg; pulse: 70 bpm, regular; respiration: 18 per minute; JVP: normal; temperature: 37°C. Within a minute of standing, the patient’s systolic pressure dropped to 70 mm Hg, pulse rate was 72 bpm, and this was accompanied by presyncopal symptoms.

There was no evidence of pallor, cyanosis, icterus, pedal or presacral edema. Examination of the heart, chest and abdomen were unremarkable. Ptosis was present bilaterally. Pupils were bilaterally constricted in dim light but reactive to light and accommodation. Otherwise, sensory system and cranial nerves were grossly intact, limb muscle tone, and deep tendon reflexes were normal. Plantar response was flexor.

Initial Lab studies: Blood hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell differential were within normal limits (WNL). Serum glucose, sodium, potassium, pH, cortisol, and aldosterone were also WNL. Serum urea nitrogen was 28 mg/dL (reference range 7-18 mg/dL) and serum creatinine was 1.5 mg/dL (reference range 0.6-1.2 mg/dL).

Resting 12-lead ECG was normal. The patient was referred for cardiovascular autonomic function evaluation after being on a 150 mmol/day sodium diet and off fludrocortisone for 5 days.

Results of cardiovascular autonomic function tests and related biochemical tests: They are summarized below in the order in which they were obtained. For each of these tests, baseline supine BP was 96-106/54-60 mm Hg and baseline HR was 65-70 bpm. Enough time was allowed for responses to a test to wane to baseline before the next test was done.

  1. HR variation during deep breathing at 6 breaths per minute was WNL.
  1. There was little change in diastolic pressure following immersion of the right hand in ice cold water at 4°C for 2 min. (Normal response: diastolic pressure increases by at least 10 mm Hg.)
  1. In response to isometric handgrip sustained at 1/3rd of maximal voluntary contraction for 1 min, diastolic pressure increased by 7 mm Hg. (Normal response: diastolic pressure increases by at least 15 mm Hg.).
  1. Resting HR did not change in response to a ‘standard’ intravenous bolus of propranolol; normally, it falls by 10-15 bpm.
  1. During the Valsalva maneuver (forced expiration into a manometer maintaining an expiratory pressure of 40 mm Hg for 15 seconds), HR increased from 70 to 100 bpm. MAP fell to 50 mm Hg during the strain phase of the Valsalva maneuver and it reproduced intense presyncope. The overshoot in MAP expected within the first few seconds of ceasing the Valsalva maneuver was absent. Atropine IV abolished the rise in HR noted during the maneuver. Propranolol IV did not affect the increase in HR during the maneuver.
  1. There was no change in HR, BP or plasma norepinephrine following a standard IV bolus of tyramine.
  1. The pressor response to an extremely low dose of IV phenylephrine, measured as the rise in diastolic pressure, was 15 mm Hg (exaggerated).
  1. The depressor response to an extremely low dose of IV isoproterenol, measured as the drop in diastolic pressure, was exaggerated as well.
  1. The following tests were then obtained:

Plasma (pg/ml) / Value / Reference range (pg/ml)
Norepinephrine / Not detected / 186-266
Epinephrine / Not detected / 14-46
Dopamine / 320 / 4-48
Dihydroxy phenylalanine / 3800 / 1490-2090

Urinary norepinephrine and vanillyl mandelic acid were undetectable, while homovanilic acid was abnormally increased. An assay for dopamine beta-hydroxylase did not detect any enzyme activity in plasma or CSF.