Circulatory Control Idiopathic Orthostatic...

Circulatory Control in Idiopathic OrthostaticHypotension (Shy-Drager Syndrome)

By JAMES T. BOTrICELL, M.D., MICHAEL H. KEELAN, JR., M.D.,FRANCiS F. ROSENBAUM, M.D., AND RAMON L. LANGE, M.D.

SUMMARYOf three patients with Shy-Drager syndrome, two presented with syncope related to

exercise and, in all three, exercise stress clearly defined the element of orthostatichypotension. Autonomic cardiovascular regulatory function was absent in two, butsome residual autonomic function was present in the form of heart rate response inone patient who had milder postural hypotension. Hemodynamic studies were carriedout with subjects supine and tilted 450 before and after exercise, following plasmavolume expansion, and during the effects of isoproterenol and atropine. Despite dis-ordered venoconstrictor responses demonstrated during exercise, hyperventilation, andafter the Valsalva maneuver, decrease in central blood volume and right atrial pressurewere not excessive with tilt, and total systemic vascular resistance remained essentiallyunchanged as did heart rate. Cardiac index may have decreased excessively (-24%),suggesting a cardiac component in production of hypotension. Absence of sympatheticcardiac effects, both chronotropic and inotropic, may play a significant role in ortho-static hypotension by limiting heart rate and preventing shift of the Frank-Starlingcurve to the left. Amelioration of postural effects by plasma volume expansion wasnoted along with increased cardiac output, stroke volume, and pulse pressure indicatingthat myocardial heterometric regulation was operative. Atropine had little effect,eliminating the possibility that parasympathetic depressor effects were responsible forpostural hypotension. Exercise, by decreasing systemic vascular resistance even thoughvenous return was adequate, produced hypotension even in recumbency and aggravatedpostural effects. Similarly, isoproterenol caused marked hypotension in supine subjects.Exercise, by reducing systemic vascular resistance, has a deleterious effect despiteincreased venous return and may precipitate postural symptoms. Exercise stress is ofvalue in the evaluation of patients with syncope or cerebral ischemia secondary toautonomic dysfunction where orthostatic hypotension is of doubtful significance at rest.

Additional Indexing Words:Venous return Vascular resistance

O RTHOSTATIC HYPOTENSION in theShy-Drager syndrome of multiple degen-

erative lesions of the central nervous systemis a consequence of impaired autonomic vaso-regulatory function." 2 The cases describedby Bradbury and Eggleston3 may representearlier examples of this syndrome. Hypovole-mia is not found, and the amount of blood

From the Department of Medicine, MarquetteSchool of Medicine, Milwaukee, Wisconsin.

Investigation was supported, in part, by GrantsHE-07434 and HE-07388 and Clinical ResearchCenter Grant, U. S. Public Health Service 5 MOIFR00058-07.

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Syncope Blood volume Venous tone

pooled in the lower extremity with standing isnot excessive, suggesting that arteriolar vas-oconstriction is inadequate when the patientassumes an upright posture.4 5 A cardiac con-tribution to the syndrome has not beenidentified.The three cases of Shy-Drager syndrome

reported herein exhibited unusual forms oforthostatic hypotension. Supine exercise in-duced arterial hypotension, and orthostatichypotension was aggravated during and fol-lowing exercise even though the venous re-turn was adequate. These features led to theexamination of vascular resistance and central

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IDIOPATHIC ORTHOSTATIC HYPOTENSION

blood volume as well as inotropic and chron-otropic cardiac responses to tilt, exercise,plasma volume expansion, and isoproterenol.

In the course of this investigation of thepathogenesis of postural hypotension, theeffect of exercise emerged as a means ofevaluating patients who complain of syncopeeven though mild hypotension occurs dur-ing quiet standing. In addition, the contri-bution of abnormal cardiac regulatory func-tion became evident in two of three cases.

Report of CasesCase I (K.E.), a man aged 74 years, was

seen initially by us on June 24, 1963 for part ofhis periodic examination. He had had a myo-cardial infarct in August 1952, from which he hadmade a good recovery. He worked regularly at hisreal estate business and had no symptoms duringmoderate physical activity. He appeared in goodhealth at examination. There was slight bilateralptosis, somewhat more pronounced on the leftside. The heart was not enlarged. There were noabnormal cardiac sounds. The heart rate was74/min. The blood pressure was 150/94 mm Hg.Fluoroscopic examination of the thorax revealedconsiderable tortuosity and broadening of thethoracic aorta. The electrocardiogram showedevidence of the old transmural anteroseptal myo-cardial infarction.When seen again on November 22, 1963, the

patient had noted dizziness from riding on anelevator; it had occurred when the elevatorstopped after descent. Two months later, he hada momentary attack of syncope just after walkingacross a street. Physical examination during thisperiod showed no change from the initial obser-vation. There were no bruits over the carotidvessels, symptoms were not produced by carotidsinus stimulation, and the blood pressure did notchange significantly with changes in position. Onone occasion at this period, the blood pressurewas 114/74 mm Hg in the recumbent position,114/74 mm Hg in the sitting position, 104/74mm Hg immediately after standing upright, and104/70 mm Hg after standing motionless for 5minutes. A small pulsating mass was found inthe midepigastrium. Radiographic study of thismass confirmed the clinical impression of ananeurysm of the abdominal aorta. An electro-encephalogram was within normal limits. He con-tinued to have occasional episodes of fallingdown when walking or when voiding in thestanding position. On frequent occasions, whenin these same situations, the patient had pre-monitory sensations of syncope without actuallyfalling.Circulation, Volume XXXVIII, November 1968

In July 1964, a fall in systemic blood pressurefrom 120/80 mm Hg in the sitting position to80/55 mm Hg in the standing position wasobserved. The patient was treated with meth-ylphenidate (Ritalin), 9-alpba-fluorobydrocorti-sone (0.2 mg/day) and, later, potassium saltsby mouth. He was fitted with garments designedto compress the venous system of the abdomenand lower extremities. There was some improve-ment until late in 1965, when the falling beganto be more frequent. It seemed to occur al-most exclusively when the patient was actuallywalking, especially when he was going up anincline, and hot weather seemed to render himmore susceptible. He would become weak, wouldlean up against a building for support, and thenwould slide down to the ground only to regainconsciousness almost immediately upon strikingthe ground. In a few moments, he was able to getup and move off again. There was no dyspnea orchest pain at the time of the attacks. Postmicturi-tion syncope continued to occur even whileseated. In addition, the patient noted that symp-toms occurred while he was seated after ingestionof large meals. Examination at this time discloseda systemic blood pressure of 174/100 mm Hgwhen recumbent and 108/60 mm Hg after stand-ing erect a few minutes. There was slightperipheral edema which was attributed to the9-alpha-fluorohydrocortisone (0.2 mg/day).The response to exercise in the erect posture

was also observed. The blood pressure, whenrecumbent, was 168/98 mm Hg. Immediatelyafter standing erect, it was 114/78 mm Hg. Thepatient then made 15 trips on and off a 9-inchstep. The serial observations of blood pressurethereafter were as follows: immediate 82/54;after 30 sec, 84/60; after 1 min, 100/72; after2 min, 114/78; and after 3 min, 108/78. Theexercise induced no appreciable change in theheart rate nor did the patient complain ofdizziness. Neurological evaluation revealed noevidence of peripheral sensory deficit althoughbilateral ptosis, muscular wasting, and fascicula-tions were observed. Although the patient hadan expressionless facies, associative movementsand the gait were normal. There was no evidenceof neurogenic or obstructive dysfunction of theurinary bladder. Sweating was absent over theentire body as demonstrated by the starch-iodinemethod.

Case II (N.S.), an 83-year-old white man, wasadmitted to the hospital in January 1964, com-plaining of increasingly frequent fainting spellsand diarrhea for the last 3 weeks. The patienthad been under treatment for "low blood pres-sure" for 1 year. Occasional syncopal episodesand frequent lightheadedness or "dizzy" spellsoccurred while he was standing or upon dressing.

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They could be aborted by sitting or lying downwhen dizziness first occurred. The patient deniedvertigo, aura, seizures, or postictal symptoms.He stated that, frequently during the past year,syncope and lightheadedness were precipitatedby rapid walking or standing after walking, andthat bending forward tended to relieve thesesymptoms. Others had noted that the patientwould begin to stagger after walking normally.The patient generally had a good appetite buthad lost 15 lbs during the previous 6 to 12months. He denied all symptoms of congestiveheart failure other than occasional dependentedema. Past history revealed only that the patienthad been treated for a renal calculus in 1957.The patient was a well-developed, thin, white

man in no acute distress. The heart rate was 75beats/min while lying down, and the blood pres-sure was 105/60 mm Hg. The funduscopic ex-amination revealed moderate tortuosity of theretinal arterioles. The cervical veins were notdistended. Examination of the lungs disclosed no

abnormalities. The heart was enlarged, extending2 cm to the left of the mid-clavicular line in thefifth intercostal space. An ejection murmurwhich extended toward the neck was heard at thecardiac base. The aortic closing sound was nor-mal.No abdominal masses were noted and the

peripheral pulses were palpable. There wasevidence of mild muscular wasting of the armsand shoulders, and fasciculation of muscles wasidentified. The patient had an expressionlessfacies and had lost associative movements. Theremainder of the neurological examination, in-cluding tests of sensory function, disclosed noabnormalities. Rectal and proctoscopic examina-tion revealed only external hemorrhoids.

Sweating, as demonstrated using the starch-iodine method, was patchy over the trunk butabsent on the extremities. The electrocardiogramshowed first degree atrioventricular block butwas otherwise normal. Radiographic studiesshowed aortic ectasia and mild cardiomegalywith aneurysmal dilatation of the thoracic de-scending aorta. The patient also had diverticulaof the duodenum and sigmoid colon.When the diarrhea was controlled and ade-

quate food intake was maintained, posturalhypotension became less severe, but it could beaggravated by exercise while standing. The pa-

tient became asymptomatic with administrationof g of NaCl three times daily and 9-alpha-fluorohydrocortisone, 0.2 mg daily. This was as-

sociated with a gain in weight of 5 kg andmoderate edema of the ankles. Although quietstanding produced a reduction in arterial pressure

from 180/80 mm Hg supine to 160/70 mm Hg,no syncope or symptoms of hypotension were

observed or reported unless associated with walk-ing. Symptoms returned, however, when treat-ment was discontinued by the patient.

Case III (W.K.), a 60-year-old white man,was admitted complaining of syncope of 2 to 3weeks' duration, during which time nausea andvomiting were frequent. The patient stated thatthe first episode of syncope had occurred 3 to 4months earlier but with only two such episodesuntil onset of the present illness. These episodesoccurred only upon arising. Episodes were de-scribed as sudden "blackouts" without aura. Lossof consciousness could, at times, be averted if hesat down with the earliest indication of faintness.Consciousness was regained almost immediatelyupon falling. The patient stated that he had al-most no sweating over the trunk and upperextremities but denied other neurological symp-toms.

History revealed alcoholism for about 10 yearsprior to admission with jaundice on one oc-casion. In addition, he had chronic bronchitiswith mild pulmonary emphysema.

At the time of hospitalization, the patient wasa well-developed man with recumbent bloodpressure of 136/86 mm Hg and pulse of 88/min.Upon standing, blood pressure fell to 80/60mm Hg and pulse increased to 100/min. Fol-lowing recumbent exercise, the blood pressurefell to lower levels during standing, but thepulse rate increased to 110/min. The patienthad a mildly increased anteroposterior chestdiameter. The heart sounds were normal. Ex-amination of the abdomen and extremities werewithin normal limits. Following treatment forpeptic ulcer, demonstrated by x-rays, the nauseaand vomiting disappeared, and the postural hy-potension was reduced in severity. Concomitantwith this improvement, a 7-lb gain in weightwas noted to the day of hemodynamic study.

Neurological examination revealed no cranialnerve dysfunction. The deep tendon and sensoryreflexes were intact as were all sensory mecha-nisms. Muscular strength was normal despitefasciculations. Sweating was absent over thetrunk and arms (starch-iodine method). Signsof the type associated with Parkinsonism wereabsent.

Results of laboratory studies, including de-termination of blood volume, ACTH stimulationtests, electroencephalography, glucose tolerancetests, and electrocardiography, were within nor-mal limits. Chest x-rays revealed only mildemphysematous changes.

MethodsPatients were studied while under observation

in the Clinical Research Center. Blood volumeswere determined using 131I-tagged human serum


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albumin and 5'Cr-tagged red blood corpuscles.Hemodynamic studies were carried out at 8 a.m.

with the subjects in a fasting state. Right atrial,femoral arterial, and for exercise, brachial arterialpressures were determined with P 23 Db strain-gauge pressure transducers. Cardiac output(flow) was estimated using the indocyanine-green indicator dilution method with a WatersX-300 densitometer. Heart rate was monitoredby electrocardiogram. Variables were recordedon a Visicorder (model 1108) and an 8-channelFM tape recorder. Central blood volume index(volume) was calculated using the method ofHamilton and associates.6 Systemic vascular re-

sistance index (resistance) was calculated byformula:Mean arterial pressure-right atrial pressure

(mm Hg) . cardiac index (L/min/M2) = resis-tance units.Central venous injection with sampling from thefemoral artery, including correction for samplingvolume delay, was employed except during exer-

cise, when the brachial artery was the samplingsite.Hemodynamic responses to upright tilt before

and after exercise were determined in each sub-ject as well as the response to an intravenousinfusion of isoproterenol (3,ug/min) and atropineadministered intravenously (0.5 to 1.5 mg). Toevaluate the effect of plasma volume expansion,the response to upright tilt was studied afterrapid intravenous administration of 500 ml of10% low molecular weight dextran in saline solu-tion. In all procedures, a steady state for at least45 sec, as indicated by blood pressure and heartrate, was achieved before determination of cardi-ac output.

Subsequently, the effect of the Valsalvamaneuver (40-mm Hg airway pressure for 20sec) and micturition during recumbency uponthe electrocardiogram and arterial pressure fol-lowing intravenous administration of atropine was

observed in case I. This study was made becausepostmicturition syncope occurred frequently, de-spite urination while seated.

Studies of venous tone were carried out bythe circulatory arrest method.7' 8 Following in-sertion of a short 20-gauge needle into a veinof either the foot or forearm, circulation to andfrom the extremity was occluded by rapid in-flation of an automatic tourniquet to 250 to 300mm Hg. Following equilibration of the venous

pressure (usually 30 sec), the response of venous

tone to the Valsalva maneuver, voluntary hyper-ventilation, and exercise of nonoccluded extremi-ties was inferred by changes in venous pressureof the isolated vascular segment. Studies withuse of both foot and forearm veins were carriedout in each subject. The arm was not occludedCirculation, Volume XXXVIII. November 1968

VOLUMERESTING EXERCISE ISUPREL IV EXPANSION

Supine Till Supine Till Supine Supine Tilt

A

110.

MEAN 90.ARTERIAL

PRESSURE 70460

Rm Hg 5

CARDIAC N( 3 A *

INOEX 2 Xf/mJM2 O. X

RESISTANCE 401

INDEX N4 80 4

Unils 2

X

1Fgr

Figure

A

'4

x.

A A

x

*AC5SI K.E.xCASET N.S.ACASEL W.K.

X Xl

1

Response of mean arterial pressure, cardiac index, andsystemic vascular resistance index to upright tilt atrest, following exercise, isoproterenol (Isuprel) infu-sion, and volume expansion are shown.

for more than 3 min and circulation was re-

established for at least 15 min between proce-

dures. The hydraulic system utilized (20-gaugeneedle and rigid tubing) has a frequency re-

sponse of 185 cycles/sec. The recording gal-vonometer is critically damped at 40 cycles/sec.

ResultsHemodynamic data are graphically de-

picted in figures 1 and 2. The alteration ofvariables in response to the experimentalmaneuvers are expressed as the mean per-

centage change related to supine resting

1.5.

CBVI 1.0.

I/ml 0.5.0.

RESTSupine

XVC

R. A. 10PRESSURE 5 i

mmHg

120.

110.

HEART 100.

RATE 90. A

BEATS/m 80

70.

60. x

TINGISUPREL VOLUME

EXERCISE IV EXPANSIONSupine Till

2s'A6

Ix

A

*CASEI K.E.xCASE I NS.ACASEX WE

A

x18

Tilt Supine Tilt Supine

41; s1e~~

44x

A

1X* 0

X

A

A

18X18

Figure 2

The responses of central blood volume, right atrialpressure, and heart rate to various maneuvers are

shown. Only patient III had a chronotropic responseto tilt, exercise, and Isuprel infusion.

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values (control) in the text. Anemia was notpresent, and blood volume was within nor-mal limits in all subjects at the time ofhemodynamic studies.

Effect of Passive TiltWith subjects supine and resting, control

flow values were normal in cases I and IIIand at the lower limits of normal in caseII. Values for mean arterial pressure weremildly elevated in all three cases, and con-sequently resistance was well above normalin case II. Although central blood volumewas greater than expected, right atrial pres-sure and heart rate were within normallimits. Upright tilt to 450 was followed bynearly proportional reduction in arterial pres-sure (27%) and flow (24%). Resistance wasunchanged. Right atrial pressure decreased50% and volume decreased 12%. Rate was un-affected by tilt in cases I and II; patient IIIexhibited an increase in rate and showed aless striking fall in pressure.

Tilt After ExerciseWith supine exercise (alternate straight-leg-

raising for 5 min), arterial pressure decreased16%, and flow rose 24% as resistance decreased38%. The heart rate increased significantly incase III only. Although right atrial pressurerose, central blood volume was unchanged.Immediately following exercise, patients werepassively tilted upright (450). Heart rateincreased further in case III, but remainedstable in the others. The response of rightatrial pressure and volume on tilt was similarto that at rest. Resistance was not alteredduring tilt, but flow decreased to the samelevels observed during resting tilt in cases Iand II, so that a marked decrease in arterialpressure was noted. Case III differed againin that the decrease in arterial pressure wasnot so severe.

Effects of Pharmacological AgentsIntravenous administration of isoproterenol

to supine patients resulted in marked hypo-tension; precluding upright tilt. Althoughvenous pressure was increased, little changein volume was nQted. Resistance decreased

proportionally more than the flow rose. Theheart rate increased modestly in cases I andII, but reached 120 beats/min in case III.Atropine (0.5 to 1.5 mg) by vein had littleeffect on the variables studied: rate, +12%;flow, -12%; volume, +2%; resistance, -6%; andarterial pressure, -15%, respectively. Venouspressure increased from 3.5 to 5 mm Hg(+50%). Atropine increased the rate in caseIII, but changes in arterial pressure, resis-tance, flow, right atrial pressure, and volumewere minimal. The effects of upright tiltclosely resembled the response to tilt beforeatropine.

Effects of Plasma Volume ExpansionFrom the change in hematocrit, infusion

of low molecular weight dextran producedan increase of plasma volume of approxi-mately 1 L. Venous pressure increased 350%,and volume, 21%. Flow increased and resistancedecreased with little change in arterial pres-sure in cases I and II and a slight increasein case III. Heart rate was unaltered. A 450upright tilt following dextran infusion pro-duced minimal alteration in rate and arterialpressure. Flow and resistance remained nearthe supine values as volume and venous pres-sure (during tilt) were substantially higherthan while the patients were supine priorto volume expansion.

Venous Tone ResponsesVenous tone in arm and leg, as tested by

the circulatory arrest method, did not changewith the Valsalva maneuver or during vol-untary hyperventilation. With exercise of thecontralateral leg, pressure in the isolatedvenous system rose from 35 to 55 mm Hg(average values) and remained elevated de-spite cessation of exercise in all subjects(fig. 3). However, when the isolated venoussystem of the arm was used, no responseto exercise of the leg was recorded.

Effect of Valsalva Maneuver and MicturitionWith subjects I and II recumbent, the Val-

salva maneuver produced the typical changesdescribed in subjects without autonomic


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N. S.I~-'~ CONTRALATERAL LEG EXERCISE10 sec.

mmHgPressure INSP

75.

ii IF in Pr S.

50. Tournique25. AppPressureA0.

HYPERVENTILATION

N.S.

1Osec ECG

mm HgPressure

50- ,1h oot Vein PressureToyrniquef M0%um"W

25 l Pressure

Figure 3

Effect of contralateral leg exercise on the venous pres-sure of foot with arrested circulation. Persistent eleva-tion of pressure is shown after cessation of exercise(indicated by altered respiratory rate). Right atrialpressure rose only during period of active exercise.Hyperventilation had no apparent effect on venoustone.

function.9 In subject I, the effects of the Val-salva and micturition were compared after in-travenous atropine (1.5 mg). With Valsalva,arterial pressure (200/108), rose during theinitial period of increased intrathoracic pres-sures (215/144) and after release of in-trathoracic pressure, it decreased to 150/96.With micturition, arterial pressure decreasedslowly over a 30-sec period from 200/108 toas low as 113/72 and then gradually returnedto control (20 sec). Mean arterial and pulsepressures seemed to be much more affectedby micturition than by the Valsalva maneuver,and no change in heart rate or rhythm occur-red in either case. The patient admitted to"bearing down" mildly at onset of micturi-tion, but otherwise respiratory movements didnot seem excessive.

Discussion

In the pathophysiology of orthostatic hypo-tension, three interrelated factors should beCirculation, Volume XXXVIII, November 1968

considered: (1) arteriolar resistance; (2)venous return; and (3) cardiac function,which includes heart rate and contractility.In addition to postural factors, the complexeffects of exercise play an important role, andhypotension with exercise has been noted byothers.3' 10

Normal Response

Normal subjects have several adaptivemechanisms which defend arterial pressure asthe upright position is assumed. Flow dimin-ishes since venous blood shifts to the lowerextremities, decreasing central blood vol-ume by approximately 25%.11 The consequentreduction in arterial pressure results in baro-receptor stimulation and reflex increase inrate, contractility, and arteriolar constric-tion.'2' 13 The response of a normal individualto respiratory maneuvers such as Valsalvaand micturition reflect these adaptive mech-anisms as well as changes in venous tone.

ResistanceThe primary disorder of regulation of re-

sistance in this syndrome was demonstratedby the observation that orthostatic hypoten-sion was much more severe when the vascularresistance was decreased by exercise. Presum-ably, failure of vasoconstriction in vascularbeds of visceral and other nonexercisingparts allowed reduction in mean resistance,13thereby requiring greater flow to maintainarterial pressure. The observation that syn-cope frequently followed exertion in cases Iand II is explainable. In case I, syncopecould have been precipitated by food inges-tion which may decrease splanchnic bed re-sistance'4 or, at other times, by high, effectiveenvironmental temperatures, causing vaso-dilatation of the skin vessels,15 again unop-posed by vasoconstriction in other vascularbeds.The reduction of arterial pressure, which

occurred in all three subjects with supineexercise, also occurred after beta-adrenergicstimulation by isoproterenol infusions. Al-though cardiac output increased, in part re-lated to decreased after-load, the reductionin vascular resistance was disproportionally

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greater. These responses resembled thoseseen in normal subjects with depletion ofcatecholamine stores.'6The possibility that parasympathetic vaso-

depressor effects were responsible for thepostural hypotension seems excluded sincevascular resistance did not change with up-

right tilt and atropine had little effect. Incase III, hemodynamic data and responses totilt differed little after atropine from restingtilt studies despite an increased heart rate.

Venous ReturnAlthough the various maneuvers did not

produce patterns of venous return whichdiffered from normal, hypotension did notevoke appropriate adaptive responses in ve-

nous tone. It seems clear that reduction ofarterial pressure in these subjects may occur

as vascular resistance decreases, even thoughvenous volume is maintained and venous re-

turn is sufficient for a rise in flow appropriateto the level of exercise. Many factors enhanc-ing venous return were operative with su-

pine exercise. These are: (1) reduction inarteriolar resistance; (2) rhythmic muscu-

lar contractions; and (3) the abdominothoracicrespiratory pump. During isoproterenol ad-ministration, rhythmic muscular contractions,important in muscular exercise, were absent.However, the venoconstrictor effect of isopro-terenol appeared to operate since an increasein central blood volume was noted, as withsupine exercise, in all three subjects. The de-crease in RA pressure in cases II and III,despite an increase in central blood volume,has been observed by others.'7With exercise in the upright position, ex-

cessive reduction of venous return would not

be expected since the mechanical effects ofmuscular contraction and respiration wouldstill enhance venous return. Although lab-oratory studies were not carried out duringexercise when upright, the hypotension whichoccurred in this circumstance could be dem-onstrated clinically in cases I and II, but not

in case III. Postural venous pooling was not

excessive. The mean decrease in flow (24%)was greater than reported by Lee and as-

sociates'8 for normal subjects of comparableage (10%), but was not excessive comparedto other studies of normal subjects.19As stated above, the effect of the upright

position on venous pooling has been studiedin normal subjects and in patients with pos-tural hypotension.4 5 It appears that the vol-ume of blood pooled in the lower extremitiesdoes not exceed normal. The reduction incentral blood volume in these subjects wasnot greater than one might expect in anormal subject despite the fact that the re-sponses of venous tone were subnormal orabsent. Samueloff and associates5 showedthat venoconstriction is not an essentialfeature of the adaptation to the upright posi-tion in normal subjects. The absence of veno-constriction when hypotension exists, however,is distinctly abnormal.20

Cardiac FactorsTwo of these subjects exhibited subnor-

mal chronotropic cardiac response. With pos-tural reduction in arterial pressure in normalsubjects, increased heart rate and contractilityrepresent important adaptive mechanisms.Warner and Toronto2' studied the effect ofexercise in dogs with controlled heart ratesand reported that cardiac output increasesproportionally with increased metabolic de-mands by increasing stroke volume, therebymaintaining blood pressure. They inferredthat some type of feedback control of cardiacoutput is mediated through autonomic mech-anisms. Whatever the normal control mech-anism, the blood pressure was not maintainedin these patients during a relatively briefperiod of exercise. Recumbent exercise re-sulted in decreased arterial pressure becausethe decrease in vascular resistance exceededthe increase in cardiac output. Inadequate ino-tropic sympathetic effect is implicated inthese subjects as the Frank-Starling curvewas not shifted to the left.22 In patient III,who exhibited a chronotropic and possiblyan inotropic cardiac response, the depressionof arterial pressure was less severe with tilt.Bruce and associates23 reported mild exer-

tional hypotension in patients with heartCirculation, Volu-me XXXVIII, November 1968

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disease due to inadequate cardiac output inrelation to the decreased vascular resistance.This occurred despite increased heart rateand was considered indicative of impairedcardiac reserve. Although the patients withShy-Drager syndrome also had limitation ofcardiac output, this seems more related toabsence of autonomic effects than to cardiacdisease. The increased stroke volume, cardiacoutput, and pulse pressure which occurredwith plasma volume expansion are consistentwith normal heterometric responses in theabsence of autonomic influences.24

Methodology of Measurements ofCentral Blood Volume

Exercise studies were designed to resemblethe activity which induced syncope and re-quired exercise of both legs. Brachial arterialsampling was employed where femoral arte-rial sampling might be hazardous. It hasbeen reported previously that sampling frombrachial artery could induce time delay andskewing of indicator-dilution curves whichmight preclude accurate estimation of centralblood volume.25 The delayed arterial transitof indicator encountered in some normal sub-jects was thought to be related to brachialarterial constriction. The rather fixed arterialresistance in our cases suggested, however,that skewing of curves would be minimal.Furthermore, calculated central blood volumefrom femoral arterial and brachial arterialindicator-dilution curves in the control statesupported this conclusion and permitted theuse of brachial arterial sampling duringstraight-leg-raising when femoral arterial sam-pling was not feasible.

Response to Respiratory Maneuversand MicturitionThe supine postmicturition hypotension ob-

served in case I would account for syncopewhen urination was performed while seatedand differs from the explanations publishedby others, which include cardio-inhibitory andvasodepressor effects leading to arrhythmiaand hypotension. These are related to theValsalva maneuver or depressor reflexes em-anating from the distended bladder.2>28 TheCirculation, Volume XXXVIII, November 1968

study carried out in case I indicated that,with micturition, a true Valsalva maneuverwas not performed because there was noinitial arterial pressure rise. The mild "bearingdown" to which the patient admitted wasapparently an increase in intra-abdominalpressure. Although the following explanationis conjectural, it seems reasonable to point outthat, when intra-abdominal pressure greatlyexceeds intrathoracic pressure, local collapseof the vena cava, compromising venous re-turn, may be expected. The resultant de-crease in cardiac output and stroke volumewas reflected in diminished mean arterial andpulse pressures.29 30 Since the hypotensionwas not accompanied by any alteration inheart rate or rhythm and the patient hadreceived 1.5 mg of atropine, it is unlikelythat vasodepressor effects of parasympatheticorigin were responsible.The blood pressure response to a vigorous

Valsalva maneuver (airway pressure of 40 mmHg for 20 sec) was much less striking thanthe effects of micturition and also indicatedthe absence of autonomic effects. This dif-ference may have been related to the ap-plication of intrathoracic pressure (glottisclosed) as opposed to intra-abdominal pres-sure (glottis open). With the Valsalva ma-neuver, the transmission of increased intro-thoracic pressure to the arteries tends tosupport arterial pressure, and compression ofthe pulmonary vasculature makes maximumuse of this blood reservoir for left ventricularoutput. Pulmonary volume is quickly restoredwith inspiration, however. With micturition,increased intra-abdominal pressure may havea more profound effect on venous returnsince it can be maintained longer withoutdiscomfort and prevents maximum utilizationof the pulmonary blood reservoir.These patients displayed ample clinical

evidence of autonomic dysfunction. Abnor-malities in sweating in cases II and III andanhydrosis in case I, postural hypotension,and a nearly fixed heart are characteristic ofthis disorder. Skeletal muscle wasting andfasciculations were prominent findings, indic-ative of motor nuclear degeneration, and are

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often seen in the Shy-Drager syndrome.1 2, 31, 32The chief symptom in these subjects is

syncope due to arterial hypotension and ce-rebral ischemia as the result of lack ofvasoregulatory function. The patients pre-sented here are particularly interesting be-cause the clinical history suggested thatsyncope and near syncope were frequently as-sociated with exercise, particularly in case I.Syncope was related to quiet standing onlywhen mild dehydration was present (casesII and III). It would seem that patients sus-pected of syncope due to altered autonomicfunction should be given exercise stress toproduce sufficient reduction of the blood pres-sure before other causes are thought oper-ative. The occurrence of syncope with mildhypovolemia may also point to unrecognizedautonomic. dysfunction. Similarly, the con-sistent postmicturition syncope in case I alsoprovided evidence of a vasoregulatory dis-order.

References1. SHY, G. M., AND DRAGER, G. A.: Neurological

syndrome associated with orthostatic hypoten-sion. Arch Neurol 2: 511, 1960.

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Applied Science and Progress

it must be emphasized most strongly that it would be a grievous mistake to thinkthat all practical problems in medicine could be solved more expeditiously by centrallymanaged planning. Numerous examples have been given of instances in which practicalprogress was frustrated until basic observations made without reference to the particularapplied research goal, had been made, after which the practical goal became relativelyeasy of achievement. The genius of science, apart from the enormous power of themethod, lies in the intelligence, the training, and the enthusiasm of its practitioners.There is probably no area of human endeavor in which the "free-enterprise system" hasbeen more successful than in science.-MAUImcE B. VISSCInR: Applied Science andMedical Progress. In: Applied Technological and Medical Progress: A Report to theCommittee on Science and Astronautics, U. S. House of Representatives, By the NationalAcademy of Sciences, 1967, pp. 185-206.


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and RAMON L. LANGEJAMES T. BOTTICELLI, MICHAEL H. KEELAN, JR., FRANCIS F. ROSENBAUM

Syndrome)Circulatory Control in Idiopathic Orthostatic Hypotension (Shy-Drager

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