Journal of Clinical InvestigationVol. 44, No. 6, 1965

Mechanism of Certain Abnormalities of the Circulation tothe Limbs in Thyrotoxicosis *

HERMESA. KONTOS,t WILLIAM SHAPIRO, H. PAGE MAUCK, JR., DAVID W.RICHARDSON,?JOHNL. PATTERSON,JR.,§ ANDALTONR. SHARPE, JR.

(From the Department of Medicine, Medical College of Virginia, Richmond, Va.)

Several studies (1-4) have shown that thyro-toxic patients have increased cutaneous blood flow,presumably for increased heat dissipation. Themechanisms that increase skin blood flow in thyro-toxicosis are not known.

Although it is established that calf and forearmblood flows are increased in thyrotoxicosis (4, 5),it is not known to what extent increased skeletalmuscle blood flow contributes to this augmentationin blood flow. Since skin blood flow in normalsubjects constitutes a considerable portion offorearm blood flow (6) and since skin blood flowis further increased in thyrotoxicosis, the state ofthe circulation to skeletal muscle cannot be esti-mated with confidence from measurements of totalforearm blood flow. Similar considerations applyto the use of total calf blood flow for this purpose(7).

The purposes of the present investigation are:1) to identify the mechanisms responsible for theincreased cutaneous blood flow in thyrotoxicosis,2) to study the circulation of forearm skeletalmuscle in thyrotoxic patients, and 3) to examinethe relationship between the changes in the cir-culation to the limbs and the alterations of thesystemic circulation as a whole in such patients.

Methods

Twenty-three patients with thyrotoxicosis ranging inage from 16 to 68 years (mean age, 36 years) were stud-ied. The diagnosis was based on the clinical symptoms

* Submitted for publication July 23, 1964; acceptedFebruary 25, 1965.

Supported in part by grants H-3361, HTS-5573, andFR 000 16-02 from the National Institutes of Health.

t Address requests for reprints to Dr. Hermes A.Kontos, Cardiovascular Laboratory, Department of Medi-cine, Medical College of Virginia, Richmond 19, Va.

t Occupant of Virginia Heart Association Chair ofCardiovascular Research.

§ Recipient of Research Career Award from the Na-tional Heart Institute.

and signs and was confirmed by the usual laboratoryexaminations (protein-bound iodine and radioactive io-dine uptake by the thyroid gland). None of the patientshad evidence of organic cardiovascular disease. Sixteennormal subjects ranging in age from 22 to 54 years (meanage, 34 years) were similarly studied and served as con-trols. Eleven of these subjects were medical or collegestudent volunteers. The remaining five subjects werepatients that had recovered from minor illnesses. Allstudies were performed in the postabsorptive state in anair-conditioned laboratory (room temperature, 23 to 240C) while the subjects lay recumbent on a table.

Cardiac output was determined by an indicator-dilu-tion method. A known amount of indocyanine greenwas injected suddenly through a calibrated syringe intoan antecubital vein and rapidly propelled into the cen-tral circulation with 10 ml of isotonic saline solution.Dye concentration in arterial blood was measured con-tinuously with a Gilford densitometer. Cardiac outputwas calculated from dye curves after replotting on semi-logarithmic paper. Oxygen consumption rates were de-termined by the timed collection of expired air in Douglasbags for 5 minutes and subsequent determination of itscomposition by the Scholander micrometer gas analyzer(8). Arterial blood pressure was measured with aStatham P23-D strain-gauge. Mean pressure was ob-tained by electronic integration. Systemic vascular re-sistance was calculated as the ratio of mean arterial bloodpressure divided by the cardiac index. Blood flows tothe hand or to the forearm were measured by venous oc-clusion plethysmography using a plethysmograph filledwith water whose temperature was maintained thermo-statically at 32 to 330 C. When forearm blood flow wasmeasured, the circulation to the hand was arrested byinflating a wrist cuff to a pressure well above the patient'ssystolic blood pressure. Arterial blood was obtainedfrom an 18-gauge Cournand needle placed into the brachialartery. Forearm venous blood was obtained from super-ficial and deep forearm veins by retrograde catheteriza-tion with polyethylene catheters whose tips lay in theportion of the forearm enclosed by the plethysmograph.Catheterization of deep forearm veins was carried out ac-cording to the method of Mottram (9). Between samplingof venous blood these catheters were kept patent by theslow infusion of isotonic saline solution. It is knownthat superficial forearm veins contain blood coming fromthe superficial tissues of the forearm, whereas deep fore-arm veins contain blood coming primarily from skeletal

947

KONTOS, SHAPIRO, MAUCK, RICHARDSON,PATTERSON,AND SHARPE

TABLE I

Hand and forearm blood flows and arteriovenous oxygen differences in the forearm in thyrotoxicosis*

Thyrotoxic patients Control subjects p

Hand blood flow, 17.8 :1 1.5 (17) 5.5 i1 0.8 (11) <0.001ml/min/100 ml

Forearm blood flow, 9.3 i 0.7 (23) 2.9 :1 0.3 (11) <0.001ml/min/100 ml

Arterial blood oxygen content, 15.83 i 0.44 (23) 17.30 :i1 1.35 (11) NSml/100 ml

Arterial-deep forearm 5.67 i 0.53 (12) 7.99 i 0.35 ( 9) <0.01venous oxygen difference,ml/100 ml

Arterial-superficial forearm 2.17 i 0.19 ( 8) 3.92 ±t 0.19 ( 5) <0.001venous oxygen difference,ml/100 ml

* All values are mean i standard error. Numbers in parentheses represent the number of patients or subjectsfrom which each mean value was derived.

muscle (10). Since the inflation of a venous collectingcuff is known to alter, for a few seconds, the oxygen

saturation of blood obtained from deep forearm veins(11), sampling from venous catheters was commenced atleast 30 seconds following the last blood flow determina-tion. The oxygen and carbon dioxide contents of bloodsamples were determined by the method of Van Slykeand Neill (12).

The contribution of skin and skeletal muscle blood flowto the total forearm blood flow was determined by meas-

uring forearm blood flow before and after the circula-tion to the skin was completely suppressed by epineph-rine iontophoresis. Epinephrine iontophoresis was car-

ried out by the method of Cooper, Edholm, and Mottram(6) using a current maintained at 20 ma for at least 20minutes. Upon completion of iontophoresis the forearmwas immediately replaced in the plethysmograph, andblood flow determinations were resumed immediately. Ex-periments in which any evidence of significant absorp-tion of epinephrine into the circulation occurred were notincluded in the results. A rise in blood pressure, tachy-cardia, and a postiontophoresis blood flow greater thanthe preiontophoresis value were taken as criteria forsuch absorption (6). In successful experiments the skinof the forearm was uniformly blanched and remained so

until the completion of the experiment. Also in such ex-

periments the blood flow remained constant throughoutthe period of observation. Abatement of iontophoresisduring the experiment was denoted by a continuouslyrising blood flow. Such experiments were rejected. Ob-servations were not extended beyond the forty-fifth min-ute after the end of iontophoresis. Since after suppressionof cutaneous forearm blood flow by this method, theresidual blood flow represents almost exclusively bloodflow to skeletal muscle (6), it was possible to calculatethe oxygen consumption and carbon dioxide productionof forearm skeletal muscle from determinations of bloodflow following epinephrine iontophoresis and the dif-ference of oxygen and carbon dioxide concentrationsin arterial and deep forearm venous blood. In each in-stance two to three sets of arteriovenous differences were

obtained. The results reported are based on experiments

in which the conditions for application of the Fick prin-ciple, e.g., constant blood flow and constant arterial andvenous concentrations of metabolites, were fulfilled (13).The calculation of oxygen consumption and carbon di-oxide production of forearm skeletal muscle describedabove assumes that the concentration of these substancesin the venous blood sampled is representative of all skele-tal muscle enclosed in the plethysmograph (13). Sinceit was not possible to catheterize more than one deepvein in any given forearm, this assumption lacks experi-mental verification.

The effect of intra-arterial atropine administration onforearm or hand blood flows was studied in 12 thyro-toxic patients and in 5 normal subjects. After controlmeasurements of forearm blood flow or hand blood flowwere made, atropine was administered into the brachialartery at a rate of 0.2 mg per minute for a period of 5minutes. The completeness of atropinization was verifiedby the absence of a vasodilator response to the intra-arterial injection of acetylcholine given in 1 ml of iso-tonic saline.

TABLE II

Distribution of forearm blood flow between skinand skeletal muscle in thyrotoxicosis

SkeletalForearm Skin muscle

blood blood bloodName flow flow flow

ml/min/100 ml forearmCBa 6.4 3.5 2.9AL 6.3 3.5 2.8BD 9.1 3.8 5.3LTu 8.3 3.8 4.5RS 7.3 2.5 4.8MS 10.2 2.4 7.8SC 9.5 4.8 4.7

Mean 8.2 3.5 4.7SE 0.6 0.3 0.6

Mean control 2.4 1.1 1.3SE 0.3 0.2 0.1p <0.001 <0.001 <0.001

948

CIRCULATION TO THE LIMBS IN THYROTOXICOSIS

TABLE III

Oxygen consumption and carbon dioxide production of forearm skeletal muscle in thyrotoxicosis*

Name MBF ao2 a-vdO2 aCm2 a-vdID02 V02 VC02

ml/min/ ml/100 ml ml/100 ml ml/100 ml mI/100 ml ml/mini ml/mini100 ml 100 ml 100 ml

CBa 2.9 15.34 6.92 50.74 4.81 0.201 0.139AL 2.8 14.30 6.09 52.77 4.09 0.171 0.115BD 5.3 14.40 4.07 47.80 4.58 0.216 0.243LTu 4.5 14.89 6.46 51.63 4.67 0.291 0.210RS 4.8 16.46 5.86 35.72 3.34 0.281 0.160MS 7.8 15.30 3.80 43.00 3.35 0.296 0.261SC 4.7 18.80 4.72 55.90 2.00 0.222 0.094

Mean 4.7 15.64 5.42 48.22 3.83 0.240 0.175SE 0.6 0.59 0.46 2.59 0.38 0.019 0.024

Mean control 1.3 19.17 9.84 46.63 6.38 0.130 0.083SE 0.1 0.37 0.62 1.62 0.64 0.008 0.007p <0.001 <0.001 <0.001 NS <0.01 <0.001 <0.01

* MBF= skeletal muscle blood flow; ao2 and aCO2 = arterial blood oxygen and carbon dioxide concentrationsrespectively; a-vdo2 and a-vdco2 = arterial-deep forearm venous oxygen and carbon dioxide differences respectively;V02 and Vco2 = oxygen consumption and carbon dioxide production respectively.

Experimental procedure. After completion of arterialand venous punctures a rest period of 30 to 45 minuteswas allowed. Observations were made in the followingorder: hand blood flow, oxygen consumption and cardiacoutput, forearm blood flow, effect of atropine on limbblood flow. In experiments in which the effect of atro-pine on hand blood flow was studied, the order waschanged and hand blood flow was measured last. Inexperiments in which epinephrine iontophoresis wasdone, measurement of oxygen consumption, cardiac output,and in some cases hand blood flow was omitted.

Statistical analysis of the results was done with at test (14).

Results

Hand blood flow, forearm blood flow, and ar-teriovenous oxygen differences in the forearm.Thyrotoxic patients had significantly increasedhand and forearm blood flows (Table I). In bothareas the average blood flow was 320% of thecorresponding mean value for the control subjects.The mean arterial-deep forearm venous and meanarterial-superficial forearm venous oxygen differ-ences were significantly lower than the correspond-ing values for control subjects (Table I).

Distribution of total forearm blood flow betweenskin and skeletal muscle. Epinephrine iontophore-sis of the forearm was carried out successfully inseven thyrotoxic patients and in five control sub-jects. Skin forearm blood flow (difference be-tween forearm blood flow before and after epineph-rine iontophoresis) was increased in all seven thy-rotoxic patients averaging 318% of the mean valuefor control subjects (Table II). Forearm skeletal

muscle blood flow (forearm blood flow after epi-nephrine iontophoresis) was also increased in allpatients studied, averaging 361% of the meanvalue for control subjects (Table II).

Metabolism of forearm skeletal muscle. Theoxygen consumption and carbon dioxide produc-tion of forearm skeletal muscle were determinedin seven thyrotoxic patients and five control sub-jects following epinephrine iontophoresis of theforearm. The mean arterial deep forearm venousoxygen and carbon dioxide differences were sig-nificantly reduced in thyrotoxic patients (Table

12 r

0*C.)

84:0WtiJ

Q,

-iz0

E

8

4

0

ACH ATROPINE ACH

Id~~~~~~~

lb

l1

_I

bIIa,<°

0 2 4 10 12 14 16 18 20

MINUTES

FIG. 1. EFFECT OF INFUSION OF ATROPINE INTO THELEFT BRACHIAL ARTERYONFOREARMBLOODFLOWOF A NOR-MAL SUBJECT. At the arrows marked ACH, 20 Aig ofacetylcholine was injected into the left brachial artery.

949

I

KONTOS, SHAPIRO, MAUCX, RICHARDSON,PATTERSON,AND SHARPS

181- 0-Ii

I.'I\t

* LEFT FOREARMo RIGHT FOREARMx ARTERIAL BLOODA DEEP VENOUSBLOODA SUPERFICIAL VENOUSBLOOD

003f

; RiV.ooo_ f%Pbaoo,3o,

_ ATROPINE t %ACH INFUSION ACH %61

1mgf

6 Yf I I AI lI 1{IT0 2 4 6 8 10 20 22 24 26 28 30 32 37 39

6 B

0opp'o'-'--ooo*0_°Swbp) -OObeo>r@9O pMor"~ °o-0,5oATROPINEINFUSION

Img ACH

I_____________________________I_ I 10 2 4 6 8 15 17 19 21 23 2530 32

MINUTES

FIG. 2. EFFECT OF INTRA-ARTERIAL INFUSION OF ATROPINE ON FOREARMBLOOD FLOW

IN A THYROTOXICPATIENT (SC). A: Atropine was administered into the left brachialartery. Both forearms intact. B: Atropine was infused into the right brachial arteryfollowing epinephrine iontophoresis of the right forearm. At the arrows marked ACH,20 ug of acetylcholine was injected into the left brachial artery in A and into the rightbrachial artery in B. Open circles: right forearm blood flow; solid circles: left forearmblood flow; x = arterial blood oxygen content; open triangles: deep forearm venous bloodoxygen content; solid triangles: superficial forearm venous blood oxygen content.

III). Oxygen consumption and carbon dioxideproduction rates of forearm skeletal muscle were

increased in all seven thyrotoxic patients (TableIII). The mean oxygen consumption and mean

carbon dioxide production rates of forearm skeletalmuscle in thyrotoxic patients were 184% and210%o of the corresponding values for the controlsubjects.

Effect of intra-arterial atropine on hand andforearm blood flows. After the administration ofatropine no tachycardia or change in the size ofthe pupils was observed, indicating that the drugdid not enter the systemic circulation in signifi-cant amounts. The effect of atropine on forearm

blood flow was studied in three normal subjects.Forearm blood flow did not change in two sub-jects (Figure 1), but increased slightly in one.

The increase in forearm blood flow in this sub-ject was accompanied by decrease in the arterial-deep forearm venous oxygen difference, suggestingthat the hyperemia was due to increased bloodflow to skeletal muscle. The administration ofatropine resulted in a significant decrease in fore-arm blood flow in each of seven thyrotoxic pa-

tients studied (Table IV and Figure 2). In fourpatients the decrease in blood flow was presentupon completion of the infusion of atropine. Inthe remaining three patients blood flow decreased

22r A

14

20 k

!4JK

tj to16 ,. -

C:

12

CI-0

NEc

I-

IZC

To

4zoLA.

950

Xwmmmmwm.X mmm. x .Xdmmmmm.x

""...A, 0044... AammummumL

CIRCULATION TO THE LIMBS IN THYROTOXICOSIS 951

TABLE IV

Effect of intra-arterial atropine on forearm blood flow and arteriovenous oxygendifferences in the forearm in thyrotoxicosis*

Before atropine After atropine

Name FBF a-vdo0 a-vso2 FBF a-vdo2 a-vs02

mil/min/ ml/100 ml ml/100 ml mi/mini ml/100 ml ml/100 m"

A. Intact forearmWC 8.2 5.8BD 9.1 6.6DH 8.7 1.80 5.2 4.20EF 9.0 6.62 6.0 6.36LTu 8.3 6.1RS 7.3 5.96 2.10 5.8 5.92 3.52SC 9.5 4.72 1.58 6.6 4.73 3.50Mean 8.6 6.0SE 0.3 0.2

B. Forearm following epinephrine iontophoresisBD 5.3 5.4RS 4.8 4.9SC 4.7 4.5MS 7.8 7.9Mean 5.7 5.7SE 0.7 0.8

* FBF = forearm blood flow; a-vdo2 = arterial-deep forearmvenous oxygen difference; a-vso2 = arterial superficialforearm venous oxygen difference.

* LEFT HANDo RIGHT HAND

I o

0 0

ACH

II I I I of I I I I I 1 1 / .I I I i A I I .

2 4 10 12 14 16 23 25 30 32

MINUTES

FIG. 3. EFFECT OF INFUSION OF ATROPINE INTO THE RIGHT BRACHIAL AR-TERY ON HANDBLOOD FLOWOF A THYROTOXICPATIENT (AL). At the ar-rows marked ACH, 200 ,ug of acetylcholine was injected into the rightbrachial artery.

20

16

12

:t

8

4 L0

ATROPINE ACH0.2 mg /min. I

I

KONTOS, SHAPIRO, MAUCK, RICHARDSON, PATTERSON,AND SHARPE

0

I

r*o.21

0

0

_4 - * .

00

0

3 I I 1 I I-

4 8 12

CARDIAC INDEX L/min./mt

FIG. 4. A: RELATIONSHIP OF FOREARMBLOOD FLOWTO CARDIAC INDEX IN THYROTOXIcOSIS. B: RELATIONSHIP OF

HANDBLOODFLOWTO CARDIAC INDEX IN THYROTOXICOSIS.

over a period of 1 to 3 minutes following the endof atropine infusion. This delay was not due toincomplete atropinization since in these patientsthe effect of acetylcholine was completely blocked(Figure 2). This decrease in blood flow was ac-companied by increase in arterial-superficial fore-

TABLE V

Systemic circulatory alterations in thyrotoxicosis*

Thyrotoxic Controlpatients subjects p

Body surface area, 1.59 :1: 0.04 1.86 :1: 0.06M2

Cardiac index, 7.1 4z 0.6 3.3 4 0.1 <0.001L/min/m2

Heart rate, 109 4 4.8 67 4.6 <0.001beats/min

Stroke volume index, 65.2 :4: 3.8 49.1 ± 2.1 <0.01ml/beat/M2

Mean arterial blood 109 3.7 100 J 3.6 NSpressure,mmHg

Systemic vascular 16.6 4 1.4 31.4 4 2.2 <0.001resistance,mmHg/L/min/m2

Oxygen consumption, 194 4 9.2 125 1 6.2 <0.001ml (STPD)/min/m2

Ratio oxygen consumption 29.1 :h 2.2 39.0 :4 2.6 <0.01cardiac index

*These data were obtained from 15 thyrotoxic patients and 11control subjects. All values are mean standard error. STPD= standard temperature, pressure, dry.

arm venous oxygen difference, but no change inarterial-deep forearm venous oxygen difference(Figure 2 and Table IV). In four thyrotoxicpatients the administration of atropine into thebrachial artery after forearm skin blood flow was

completely suppressed by epinephrine iontophore-sis had no effect on blood flow (Figure 2 and Ta-ble IV). In three of these patients the adminis-tration of atropine into the brachial artery of theopposite limb had resulted in significant decreasein blood flow to the intact forearm. These findingsindicate that the decrease in forearm blood flowfollowing the administration of atropine in thyro-toxic patients was due to decreased skin bloodflow. In two normal subjects and in four thyro-toxic patients, the administration of atropine hadno effect on hand blood flow (Figure 3).

General circulatory alterations. Thyrotoxic pa-

tients had significantly increased cardiac index,heart rate, stroke volume index, and oxygen con-

sumption rate, and significantly decreased systemicvascular resistance (Table V). The cardiac out-put in thyrotoxic patients was increased out ofproportion to the increased oxygen consumptionrate, as indicated by the significantly reduced ra-

tio of oxygen consumption to cardiac index (Ta-

952

A 0

32 r

0

21

'7

"4

i4 '\ 13

P.4

9

5

24 1-r~oO.8 *f.0 P

R4,,

..c

I.

0

S

0ro 16 I-

0

0 4

I | (

8 12

CIRCULATION TO THE LIMBS IN THYROTOXICOSIS

ble V). In thyrotoxic patients the cardiac indexcorrelated well with forearm blood flow (r =0.83) but poorly with hand blood flow (r = 0.21)(Figure 4).

Discussion

Skin blood flow. It is generally accepted thatskin blood flow is increased in thyrotoxicosis (15,16). This view is based on measurements ofhand blood flow (1-3) and on indirect estimatesof total body skin blood flow obtained from mul-tiple skin temperature measurements (4). Thepresent study confirms the increased hand bloodflow in thyrotoxic patients, and in addition itshows that skin blood flow is also increased in theforearm. In our patients the percentile increasein hand blood flow and forearm skin blood flowwas approximately the same, averaging 3.23 and3.18 times the corresponding values for controlsubjects, respectively. These figures agree closelywith the conclusion of Stewart and Evans, whoestimated that total skin blood flow in thyrotoxi-cosis was increased three to four times (4).

The considerable decrease in forearm skin bloodflow following the intra-arterial administration ofatropine indicates that the increase in blood flowto the skin of this part of the body in thyrotoxi-cosis is to a major extent mediated by a cholinergicmechanism. In contrast, the absence of change inhand blood flow following the administration ofatropine suggests that a cholinergic mechanismdoes not play a significant role in the increasedhand blood flow in thyrotoxicosis. The existenceof cholinergic vasodilator fibers to the skin of thehuman forearm is well established (17). Activa-tion of these fibers is primarily responsible for theincrease in forearm skin blood flow that occurs innormal subjects during body heating (17). Incontrast, the increase in blood flow to the skin ofthe hand in response to body heating is due to de-crease in sympathetic vasoconstrictor tone, with-out significant contribution from vasodilator nervefibers (17-20). Thus, the mechanisms mediatingthe increase in skin blood flow in thyrotoxicosisresemble closely the mechanisms responsible forthe increase in skin blood flow in normal subjectsduring body heating. This is not unexpected,since the purpose of skin vasodilatation in thyro-toxicosis is increased heat dissipation. Fox andHilton (21) perfused the subcutaneous tissue of

the human forearm with isotonic saline and foundthat during body heating the concentration ofbradykinin in the perfusate increased. They sug-gested that the local formation of bradykinin re-sulting from sweat gland activity was responsiblefor the cutaneous vasodilatation occurring underthese circumstances. Whether a similar mecha-nism plays a role in the production of increasedforearm skin blood flow in thyrotoxicosis is notknown.

Skeletal muscle blood flow. Previous investi-gations have shown that forearm and calf bloodflow in thyrotoxic patients is considerably in-creased (4, 5). As noted before, in the presenceof increased skin blood flow the state of the cir-culation to skeletal muscle in these areas cannotbe reliably judged from measurements of totalforearm or calf blood flow. That forearm skeletalmuscle blood flow is increased in thyrotoxicosiswas suggested by the finding of reduced arterial-deep forearm venous oxygen difference, and it wasconfirmed by direct measurement following sup-pression of forearm skin blood flow by epinephrineiontophoresis. If we assume that a similar increasein blood flow occurred in other muscles of thebody, the increase in skeletal muscle blood flowis more important quantitatively than the increasein cutaneous blood flow, for skeletal muscle con-stitutes about 40% of body weight. The precisemechanisms by which skeletal muscle blood flowis increased have not been identified. As shownherein, however, oxygen consumption and car-bon dioxide production of forearm skeletal muscleare increased. Thus, skeletal muscle partakes inthe increased metabolism that occurs in most tis-sues of the body in thyrotoxicosis. The augmentedblood flow is very likely related to the increasedmetabolic rate but the mechanism of this rela-tionship is not known. In spite of the increase inoxygen consumption rate of forearm skeletalmuscle, the arteriovenous oxygen difference acrossit was reduced. Thus skeletal muscle met its in-creased oxygen requirements by means of in-creased blood flow rather than by increased oxy-gen extraction. In fact, the increase in blood flowwas greater than that needed to fulfill the increasein oxygen requirements. This suggests the possi-bility that the augmented blood flow is not directlyrelated to the increased oxygen needs. An alterna-

953

KONTOS, SHAPIRO, MAUCK, RICHARDSON, PATTERSON,AND SHARPE

tive possibility is that part of the increased bloodflow is passing through vessels that exchangepoorly with tissues. Evidence obtained fromanimal experiments (22-25) supports the existenceof two types of circulation in skeletal muscle, onetype subserving the nutritional requirements of thetissues and the other exchanging poorly with tis-sue and probably consisting of vessels that passthrough connective tissue septa and tendon (25).

The arterial oxygen content for the entire groupof thyrotoxic patients was not significantly differ-ent from the corresponding value for the controlsubjects (Table I). Some of our patients were,however, mildly anemic. As a result of this thegroup of patients in whomepinephrine iontophore-sis was performed had a significantly lower ar-terial oxygen content than the corresponding groupof control subjects (Table III). Verel and Duff(26) studied forearm blood flow and forearmdeep venous oxygen content in 12 patients withanemia. They found that forearm blood flow wasnormal until hemoglobin concentration decreasedbelow 4 g per ml blood or venous oxygen satura-tion decreased below 15%. It is therefore un-likely that the mild anemia seen in our patientshad a significant effect on forearm blood flow.

Our findings suggest that cholinergic vasodila-tor fibers are not involved in the increase in fore-arm skeletal muscle blood flow in thyrotoxicosis.This is based on the absence of a change in ar-terial-deep forearm venous blood oxygen differ-ence following the administration of atropine andon the lack of change in blood flow in the fourpatients in whom atropine was given followingepinephrine iontophoresis.

General circulatory alterations. It is generallyaccepted that in thyrotoxicosis cardiac output iselevated, heart rate is increased, and systemic vas-cular resistance is reduced. Disagreement existsin regard to stroke volume and arteriovenous oxy-gen difference across the systemic circulation.

In our patients the increase in cardiac ouputwas brought about by increases in both heart rateand stroke volume. This agrees with the find-ings of Bishop, Donald, and Wade (27) and ofGraettinger, Muenster, Selverstone, and Campbell(28). In contrast, in the patients studied byMyers, Brannon, and Holland (29), by Humer-felt, Miller, and Storstein (30), and by Antho-nisen, Holst, and Thomsen (31), stroke volume

was normal, the increased cardiac output being de-pendent entirely on increased heart rate. In thepresent study the arterial-mixed venous oxygendifference, calculated from cardiac output andoxygen consumption rates, was significantly re-duced. This agrees with the findings of Bishopand his colleagues (27) and Graettinger and as-sociates (28), but contrasts with the results ofMyers and co-workers (29), Humerfelt and co-workers (30), and Anthonisen and co-workers(31), who found a normal arterial-mixed venousoxygen difference. In our patients the diminishedarterial-mixed venous oxygen difference was prob-ably related to the diminished arteriovenous oxy-gen difference across skin and skeletal muscle.

Summary

1. Circulatory studies were performed in 23 thy-rotoxic patients and in 16 normal subjects whoserved as controls.

2. Hand and forearm blood flows in thyrotoxicpatients averaged 320% of the corresponding meanvalues for control subjects. Arterial-deep forearmvenous and arterial-superficial forearm venousoxygen differences were significantly reduced inthyrotoxicosis.

3. The distribution of forearm blood flow be-tween skin and skeletal muscle was determinedin seven thyrotoxic patients and five control sub-jects by completely suppressing the circulation tothe skin by epinephrine iontophoresis. Forearmskin blood flow and forearm skeletal muscle bloodflow were significantly increased in thyrotoxicpatients, averaging 318% and 361% of the cor-responding mean values for control subjects.

4. In the patients and control subjects in whomepinephrine iontophoresis of the forearm was car-ried out, the oxygen consumption and carbon di-oxide production rates of forearm skeletal musclewere determined by application of the Fick prin-ciple. In thyrotoxic patients the oxygen consump-tion and carbon dioxide production rates of fore-arm skeletal muscle were increased, averaging184% and 210% of the corresponding values forcontrol subjects.

5. Administration of atropine into the brachialartery had no effect on forearm or hand bloodflows in normal subjects or on hand blood flow inthyrotoxic patients, but resulted in significant de-

954

CIRCULATION TO THE LIMBS IN THYROTOXICOSIS

crease in forearm blood flow in seven thyrotoxicpatients. Atropine had no effect on forearm bloodflow of four patients in whom the circulation toforearm skin was suppressed by epinephrine ion-tophoresis, indicating that the observed decrease inblood flow following atropine infusion in the in-tact forearm was due to decrease in skin bloodflow. These findings suggest that the increasein forearm skin blood flow in thyrotoxicosis ismediated by a cholinergic mechanism and that acholinergic mechanism does not play a significantrole in the production of increased hand blood flowin thyrotoxicosis.

6. In 15 thyrotoxic patients cardiac index, heartrate, stroke volume, and oxygen consumptionrates were increased, whereas systemic vascularresistance and calculated arterial-mixed venousblood oxygen difference were diminished. Therewas a good correlation between cardiac index andforearm blood flow but a poor correlation betweencardiac index and hand blood flow.

References1. Hewlett, A. W., and J. G. Van Zwaluwenburg. The

rate of blood flow in the arm. Heart 1909, 1, 87.2. Stewart, G. N. Studies on the circulation in man.

Harvey Lect. 1912-13, 113.3. Abramson, D. I., and S. M. Fierst. Resting periph-

eral blood flow in the hyperthyroid state. Arch.intern. Med. 1942, 69, 409.

4. Stewart, H. J., and W. F. Evans. The peripheralblood flow in hyperthyroidism. Amer. Heart J.1940, 20, 715.

5. Eichna, L. W., and R. W. Wilkins. Blood flow tothe forearm and calf. IV. Thyroid-activity; ob-servations on the relation of blood flow to meta-bolic rate. Bull. Johns Hopk. Hosp. 1941, 68, 512.

6. Cooper, K. E., 0. G. Edholm, and R. F. Mottram.The blood flow in skin and muscle of the humanforearm. J. Physiol. (Lond.) 1955, 128, 258.

7. Shepherd, J. T. Physiology of the Circulation inHuman Limbs in Health and Disease. Phila-delphia, W. B. Saunders, 1963, p. 3.

8. Scholander, P. F. Analyzer for accurate estimationof respiratory gases in one-half cubic centimetersamples. J. biol. Chem. 1947, 167, 235.

9. Mottram, R. F. The oxygen consumption of humanskeletal muscle in vivo. J. Physiol. (Lond.) 1955,128, 268.

10. Coles, D. R., K. E. Cooper, R. F. Mottram, andJ. V. Occleshaw. The source of blood sampleswithdrawn from deep forearm veins via catheterspassed upstream from the median cubital vein. J.Physiol. (Lond.) 1958, 142, 323.

11. Moreira, M. F., R. F. Mottram, and A. Y. Werner.The effect of venous pressure on the oxygen con-tent of venous blood in the deep forearm veins.J. Physiol. (Lond.) 1956, 133, 255.

12. Van Slyke, D. D., and J. M. Neill. The determina-tion of gases in blood and other solutions by vac-uum extraction and manometric measurement. I.J. biol. Chem. 1924, 61, 523.

13. Zierler, K. L. Theory of the use of arteriovenousconcentration differences for measuring metabolismin steady and non-steady states. J. clin. Invest.1961, 40, 2111.

14. Snedecor, G. W. Statistical Methods, 5th ed. Ames,Iowa, Iowa State College Press, 1956, p. 45.

15. Shepherd, J. T. Physiology of the Circulation inHuman Limbs in Health and Disease. Philadel-phia, W. B. Saunders, 1963, p. 366.

16. Wade, 0. L., and J. M. Bishop. Cardiac Output andRegional Blood Flow. Oxford, Blackwell, 1962,p. 207.

17. Roddie, I. C., J. T. Shepherd, and R. F. Whelan.The contribution of constrictor and dilator nervesto the skin vasodilatation during body heating. J.Physiol. (Lond.) 1957, 136, 489.

18. Sarnoff, S. J., and F. A. Sineone. Vasodilator fibersin the human skin. J. clin. Invest. 1947, 26, 453.

19. Arnott, W. M., and J. M. Macfie. Effect of ulnarnerve block on blood flow in the reflexly vasodilateddigit. J. Physiol. (Lond.) 1948, 107, 233.

20. Gaskell, P. Are there sympathetic vasodilator nervesin the vessels of the hands? J. Physiol. (Lond.)1956, 131, 647.

21. Fox, R. H., and S. M. Hilton. Bradykinin formationin human skin as a factor in heat vasodilatation.J. Physiol. (Lond.) 1958, 142, 219.

22. Barcroft, H., and A. H. Kitchin. Are there arterio-venous anastomoses in the human forearm? Sym-posium sur les interactions arterio-veineuses.Angeiologie 1957, 9 (no. 2), 24.

23. Hyman, C. Physiological implications of a dual cir-culation in muscle. Symposium sur les interac-tions arterio-veineuses. Angeiologie 1957, 9 (no.2), 25.

24. Lambert, J. Reactions vasculaires provoquees dansle muscle strie au repos chez le chien par l'ischemietemporaire experimentale. II. Variations desreponses en fonction de la pression arterielle enamont. Arch. int. Physiol. 1957, 65, 46.

25. Barlow, T. E., A. L. Haigh, and D. N. Walder.Evidence for two vascular pathways in skeletalmuscle. Clin. Sci. 1961, 20, 367.

26. Verel, D., and R. S. Duff. Circulatory adjustments ofvoluntary muscle in anemia. J. app. Physiol. 1958,14, 225.

27. Bishop, J. M., K. W. Donald, and 0. L. Wade.Circulatory dynamics at rest and on exercise inthe hyperkinetic states. Clin. Sci. 1955, 14, 329.-

955

KONTOS, SHAPIRO, MAUCK, RICHARDSON, PATTERSON,AND SHARPE

28. Graettinger, J. S., J. J. Muenster, L. A. Selverstone,and J. A. Campbell. A correlation of clinical andhemodynamic studies in patients with hyperthyroid-ism with and without congestive heart failure.J. clin. Invest. 1959, 38, 1316.

29. Myers, J. D., E. S. Brannon, and B. C. Holland.

A correlative study of the cardiac output and thehepatic circulation in hyperthyroidism. J. clin.Invest. 1950, 29, 1069.

30. Humerfelt, S., 0. Muller, and 0. Storstein. Thecirculation in hyperthyroidism. A cardiac catheteri-zation study before and after treatment. Amer.Heart J. 1958, 56, 87.

31. Anthonisen, P., E. Holst, and A. A. C. Thomsen.Determination of cardiac output and other hemo-dynamic data in patients with hyper- and hypo-thyroidism using dye dilution technique. Scand.J. clin. Lab. Invest. 1960, 12, 472.

956