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STUDIES IN BLOODVOLUME

I. THE BLOOD VOLUMEIN MYXEDEMA,WITH A COMPARISONOFPLASMAVOLUMECHANGESIN MYXEDEMAAND

CARDIAC EDEMA1', 2

By WILLARD OWENTHOMPSON3

(From the Thyroid Clinic of the Massachusetts General Hospital and the Thorndike MemorialLaboratory of the Boston City Hospital)

(Received for publication, April 28, 1926)

I. INTRODUCTIONAND LITERATURE

One of the first things that patients with myxedema notice whenthyroid extract is administered to them, is an increase in water intakeand urinary output. The diuretic action of thyroid substance wasindeed, one of the first effects of its use observed, and was demon-strated as early as 1890 by Leichtenstem (1). Since then severalobservations have been made which support the idea that the thyroidgland is a factor in maintaining the water balance.

Gardella (2) in 1910, and Paladino (3) in 1912, both found increasedviscosity and decreased electrical conductivity of the blood serum indogs and rabbits following thyroparathyroidectomy. A few yearsbefore this, however, Fano and Rossi (4) demonstrated that the vis-cosity of serum, while increased from thyroparathyroidectomy inanimals, was not increased after extirpation of the parathyroids alone.Kottmann (5) and Deusch (6), several years later, and Neuschlosz(7) more recently, reported that increased viscosity of the serumoccurred in patients with myxedema. From refractometric measure-ments, Deusch further concluded that the total protein of the serum is

1 This paper was read at the meeting of the Society for Clinical Investigation inAtlantic City, May 3, 1926.

2This study was aided by a grant from the Proctor Fund of the HarvardMedical School for the Study of Chronic Diseases.

3 Research Fellow in Medicine, Harvard Medical School and MassachusettsGeneral Hospital.

477


increased from 5.3 to 9.1 per cent. Hammett (8) has suggested thatthis interpretatioha should be accepted with reservations in view of thefinding of Peterson, Jobling and Eggstein (9) of a progressive increasein the non-protein nitrogen and proteoses after thyroidectomy inanimals and of ttienne, Richard and Roesch (10) of an increase ofurea nitrogen in the blood in thyroid insufficiency. The increasein all three factors is, however, more marked in experimental myxe-dema and in cretinism than in human myxedema and Deusch's con-clusion that there is high serum protein in myxedema is probablycorrect.

Deusch also found the sodium chloride in serum to be within nor-mal limits in myxedema and observed little change in this respectbefore and after thyroid administration. From this he concludedthat salt and water excretion ran parallel with their removal fromthe tissues and that the water content of the serum was therefore un-changed by thyroid. He concluded that the increase in protein wasan absolute and not a relative one.

In 1917 Eppinger (11) made an important contribution to the sub-ject when he demonstrated that salt solution injected subcutaneouslyand water given by mouth are absorbed more slowly and excreted moreslowly in thyroidectomized than in normal dogs, and more slowly innormal than in thyroid-fed ones. He also observed that in some casesof cardiac and nephritic edema when all known methods of causingfluid elimination had failed, the administration of thyroid substanceproduced marked diuresis. More recently Danzer (12) has reportedthat giving thyroid substance caused a distinct tendency to rapidabsorption in three cases of pleural effusion following lobar pneumonia.The difficulty with such observations is that controls cannot beobtained. Loeb (13) however substantiates this view in a reference tothe fact that Hoover found a collection of a certain amount of fluid inthe peritoneal cavity in guinea pigs suffering from marked inanition,while it was absent in the large majority of animals in which the sameor even a greater amount of inanition was produced through thecombined effects of thyroid feeding and diminished intake of food.

Recently Hammett (8) has shown that loss of the thyroid gland inmale rats 100 days of age, causes a decrease in the water percentage andan increase in the refractive index of blood serum.

478

WILLARD OWENTHOMPSON

An observation of some interest is that of IVilhelmj and Fleischer(14;), (15) that thyroxin fed to normal guinea pigs causes an averagedecrease in surface tension of plasma of 3.7 dynes and that thyroidec-tomy in these animals causes an average increase in surface tensionof plasma of 5.1 to 5.7 dynes. Thyroxin added directly to plasma hadno effect.

Two years ago Hildebrandt (16) made the very important observa-tion that the intravenous injection of 1 mg. of thyroxin in rabbitsafter a hunger-thirst period of 14 to 15 hours caused marked hydremiawith a maximum in the fifth or sixth hour, at which time the totalquantity of blood was usually raised 40 per cent above the normal(as measured by hemoglobin and red blood cell dilution). Parallelto this occurrence there was a large water and salt diuresis. Thenormal red count was reached again after 36 hours.

In support of the idea therefore, that the thyroid gland is concernedin water balance, there are the following observations:

1. Thyroidectomy in various animals causes:a. Increased viscosity of the serum.b. Decreased electrical conductivity of the serum.c. Increased refractive index of the serum.d. Decreased water per cent of serum.

2. Thyroid insufficiency in human beings causes:a. Increased viscosity of the serum.b. Increased refractive index of the serum.

3. Intravenous injection of thyroxin in normal rabbits produces:a. Marked hydremia.b. Pronounced water and salt diuresis.

Thus far no direct observations of the total quantity of circulatingblood or plasma have been made in disorders of the thyroid gland.Since changes in viscosity, refrattive index, electrical conductivityand water percentage of serum, and changes in hemoglobin concentra-tion and red blood cell count may occur without changes in the totalquantity of serum or plasma it is important to learn whether there isa relation between them and disease of the thyroid gland. The factthat in experiments thus far reported the results all point in the samedirection certainly suggests and points to the fact that the serum andplasma are concentrated in myxedema.

479


In the fall of 1923, J began to make observations on the plasmavolume in myxedema. This work was mentioned by Means (17)in his address before the Association for the Study of Internal Secre-tions in May, 1925. Nine patients have been studied, numerousobservations having been made on each one (except patient 3) whilemyxedematous and while receiving thyroid. The cases have consist-ently shown the same results and a report now seems justified.

II. METHOD

The plasma volume method of Keith, Rowntree and Geraghty (18)was used except that brilliant vital red, as suggested by Evans, wassubstituted for vital red and isotonic sodium oxalate as suggested byHooper et al. (19), was used instead of powdered oxalate, to preventclotting. This method is generally recognized as being accuratewithin 5 per cent. In general it proved to be as accurate as this inmy work. Total blood volumes were calculated from hematocritvalues as determined from calibrated centrifuge tubes. Hemoglo-bins, where reported, were done by the Newcomer method. I foundgreat difficulty in matching colors with this hemoglobin method andonly the general trend of the values is of any significance.

In all of the patients the blood was collected in the morning and itscollection was preceded by a hunger-thirst period of 14 to 18 hours.In all except the first three cases it was also preceded by a rest periodof at least one-half hour. In all except the first two cases withdrawalof blood was preceded by a basal metabolism determination done witha Roth-Benedict apparatus.

Only typical cases of myxedema were selected for these observationsand cases of so-called related conditions supposed by some to be ofthyrogenous origin were omitted. Due to the scarcity of untreatedpatients with myxedema, it was necessary to use patients who hadbeen previously treated.

III. THE CONSTANCYOF THE PLASMAAND CALCULATEDTOTAL BLOOD

VOLUMESIN A NORMALINDIVIDUAL

Of thirteen plasma volume observations made of a normal individualover a period of nearly three months, only two varied more than 5 per

480


cent from the average (table 1). All of the calculated total bloodvolumes were within 7 per cent of the average. Blood for these obser-vations was collected in the morning after a hunger thirst period of 14to 18 hours, but was not preceded by a rest period. The resultsserve to illustrate that total plasma and calculated total circulating

TABLE 1

The constancy of plasma and calculated total blood volumes in a normal manAge 42 years, height 166 cm.

Date

1/15/241/21/241/24/241/29/242/ 2/242/ 7/242/15/24

(12:15 p.m.)2/15/24

(1:30 p.m.)2/19/24

(8:40 a.m.)2/27/24

(10: 15 a.m.)2/27/24

(1:30 p.m.)3/23/244/ 6/24

Weight

kg.

61.460.461.462.763.461.160.7

60.7

60.4

60.9

60.9

58.959.8

R.B.C.*

milions

4.84.54.94.3

4.74.6

4.8

4.1

4.0

4.64.6

Hb

per cent

989992859491

100

98

95

99

9493

* In this and the subsequent tables R.B.C.B.M.R., basal metabolism rate.

Hemat-vcrit

per cent

54.258.649.247.250.049.949.4

50.0

48.3

52.0

51.5

47.948.6

Plasma volume Total blood volume

Amount

cc.

2,5852,0802,5552,7752,8002,5202,635

2,480

2,865

2,730

2,755

2,5102,635

Per kilo.gram

cc.

42.234.541.644.344.241.243.3

41.0

47.4

44.9

45.2

42.644.0

Amount

cc.

5,6505,0305,0305,2705,6005,0305,200

4,970

5,550

5,690

5,680

4,8105,125

Per kilo.gram

cc.

92.283.582.084.088.582.385.6

82.0

92.0

93.5

93.3

81.885.7

means red blood cells; Hb, hemoglobin;

blood seem to be fairly constant in the same individual under approdi-mately the same conditions. Several similar results could be cited.

In Lamson's (20), (21), opinion the vital red method is accurate formeasurng plasma volumes, but he states that total blood volumescalculated from hematocrit estimations are not true measures of thetotal quantity of circulating blood because these differ when made on

481


blood from different parts of the body and from the same part underdifferent conditions. He states, however, that, under basal conditions,both plasma and calculated total blood volumes are fairly constantquantities and most of myobservations in myxedema were made underbasal conditions. Only 3 hematocrit estimations vary more than 3per cent from the average of the group (table 1). This is a fairlytypical example. The hematocrit readings of blood drawn before dyeinjection and that on blood withdrawn after dye injection usuallyvaried less than 1 per cent from each other. No claim is made toaccuracy for hematocrits as here determined. They appear, however,to be accurate enough to show gross changes in the volume of cir-culating cells (say 10 per cent and over) under basal conditions.

IV. PLASMAVOLUMECHANGESIN MYXEDEMA

In all of the cases of myxedema, the administration of thyroid sub-stance produced a well marked and permanent increase in the plasmavolume, a decrease in the hematocrit reading and in the red bloodcount. In two of the cases the hematocrit value and red count subse-quently increased due to an increase in the volume and number ofcirculating cells probably as a result of stimulating the bone marrowon administering thyroid extract. As a group, when not taking thy-roid extract the average of the plasma volumes was low-35.4 cc.per kilogram and 1360 cc. per square meter, as compared with normalvalues of 42 to 52 cc. per kilogram and 1500 to 2000 cc. per squaremeter. The significant thing is, however, not the average change butthat observed in each case because the myxedematous level in somewas within the so-called normal limits. The change in these cases was,nevertheless, as great on the average as in the others. Attention iscalled to the fact that the increase in plasma was absolute and notmerely relative due to loss of weight. Even cases 6 and 8 (tables8 and 10), which lost weight when given thyroid extract showed totalplasma increases of 14.0 and 20.9 per cent respectively. It is of inter-est to note that the change in total plasma volume in these two caseswas less, however, than in the other patients who lost less weight. Bothof these patients had slight pitting edema and marked dyspnea onexertion. The possibility of slight cardiac edema masking the myxe-dematous reduction in plasma volume is suggested.

482

WILLARD OVWENTHOMPSON

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THE JOURNALOF CLINICAL INVESTIGATION, VOL. II, NO. 6

488 STUDIES IN BLOODVOLUME

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Patients may show a marked plasma volume decrease on omissionof thyroid extract, with practically no change in weight. This is wellillustrated by case 4.

The percentage increase in total plasma over the myxedematouslevel varied from 14.0 to 35.0 per cent, that in the plasma per kilogramfrom 16.2 to 41.7 per cent, and that in the plasma per square meterfrom 17.1 to 37.7 per cent. The average increases in the three for allnine patients were 22.9, 28.5 and 25.2 per cent, respectively. Withan average basal metabolism increase over the myxedematous levelof 38 per cent the last seven cases showed average percentage increasesin total plasma, plasma per kilogram and plasma per square meter of23.2, 28.9 and 25.2 per cent, respectively.

I have ascertained the average plasma volume and basal metabo-lism figures for each patient both while off and on the administrationof thyroid extract, as well as the gross and percentage increases inthe two over the myxedematous level (table 2) as well as the datacollected on each individual' patient, the order of patients in table 2being preserved throughout (tables 3 to 11).

To prove that the plasma volume increase endures as long as treat-ment is continued and is not dependent on the elimination of excessfluid by diuresis, a study was made of all of the patients in whoma con-trol observation was made before omitting the administration ofthyroid extract; in all of them it was found that a decrease wasobserved after the omission. Two of these patients (cases 4 and 5)had been treated for 14 and 15 months respectively, but in both theomission produced a well marked decrease in plasma volume and sub-sequent administration, a return to the previous level. All patients(except number 3) were followed furthermore, for several monthsafter treatment was begun and in all the increase in plasma volumepersisted.

V. TIME REQUIREDFOR PLASMAVOLUMEREDUCTIONTO OCCURAFTER

OMISSION OF THYROID EXTRACT

The time required for plasma volume reduction to occur afteromitting the administration of thyroid extract varies considerablyfrom individual to indivridual. In all of the cases a well marked changehad occurred within ten days after omission. In patient number 4

496


the level was as low in ten days as it was in the following ten while inpatient number 5 it kept slowly dropping over a period of 5 weeks and,if giving thyroid extract had been withheld longer might have droppedfurther. Plummer and Boothy (22) have estimated that it takes fiftyto sixty days for the effects of a single intravenous injection of thyroxinto wear off. Five of these patients were without thyroid extract forconsiderably shorter periods than this; it is quite possible that thechanges in the plasma would have been more marked had the adminis-tration been withheld for a longer time.

Cases previously untreated might show greater changes, as case 2illustrates. When first seen, she presented the most marked symp-toms of myxedema I have ever seen. Just after she had started9 grains of thyroid extract daily and while her metabolic rate wasstill low, the total plasma was 1850 cc. Her veins were small,difficult to distend and puncture, her blood was extremely viscous andclotted rapidly. The day following the first plasma volume determina-tion, her basal metabolism was -19 per cent. Two days afterwardthe total plasma was 2350 cc. The fact that she took 9 grains ofthyroid extract daily for several days before the first estimatidn ofplasma volume indicates that this value may have been wrong, thatis to say too low. The second estimation two days later, however, ashas been said was less than that subsequently found even after thenon-administration of thyroid extract for six weeks, after treatmentwith it for six months. Under these circumstances the first observa-tion then apparently too low may have been approximately correct.If so, subsequent determinations represent an increase in plasmavolume of at least 62 per cent over the myxedematous level.

VI. RELATION BETWEENPLASMA VOLUME AND BASAL METABOLIC

RATE

A parallelism appears to exist between plasma volume and basalmetabolism (figs. 1, 2 and 3 plotted from the data in tables 6, 7 and 10).

Inasmuch as basal metabolism is a function of surface area, acomparison with plasma per square meter is justified. In interpretingsuch charts, it must be born in mind that there is a 5 per cent error inboth plasma volume and basal metabolic rate determinations and that,therefore, only the general trend of the curves is of significance.

497

RM1RoMI%o g

010 2 3O 8TIME IN DAYS

FIG. 1. CASE OF MYXEDEMANo. 4

Black area in this and subsequent figures denotes the period of thyroid medica-tion. The curves show striking parallelism between basal metabolic rate (B.M.R.)and plasma per square meter. Thyroid extract administration omitted at begin-ning of chart.

)RJ1j~~~~~ Pl~ASMArer sum.c C.

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TIME IN DAYsFIG. 2. CASE OF MYXEDEMANo. 5

These curves also show parallelism between B.M.R. and plasma per squaremeter. Note the slow fall on omission of thyroid extract therapy and rapid riseon administering it. Inasmuch as several B.M.R. observations on 6 grains thy-roid daily ranged from -3 per cent to +3 per cent, one observation of +22 percent on this dose is undoubtedly high and is connected to the others by dotted lines.

493


At the suggestion of Dr. Means, these data of the seven cases havebeen plotted (fig. 4). For each patient represented in figure 4, apoint was plotted for the average without thyroid extract administra-tion and another for the average with treatment; these points havebeen connected with a straight line (fig. 5).

This figure gives at first the impression of a striking parallelismbetween the seven lines. When inspected closely, however, it will

.K '~~~~~~~PlA5MA36ER ..PeTSQ.M.

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TIME IN DAYSFIG. 3. CASE OF MYXEDEMANo. 8

These curves likewise show parallelism between B.M.R. and plasma per squaremeter. Thyroid extract administration omitted about three weeks before thefirst recorded observation.

be observed that there are differences in the reactions of differentpatients. These are related neither to the differences in basal meta-bolic rate nor to those in maintenance dosage of thyroid extract. Theyare probably manifestations of individual variation and representfundamental differences in human constitution. They may belikened to the marked variations in the extent of anhydremia producedby the same dose of insulin in different rabbits of approximately the

499


same weight (Drabkin and Edwards (23)), to the marked variation inthe severity of myxedematous symptoms in different patients withessentially the same reduction in basal metabolic rate and to themarked variation in the amount of thyroid substance required to main-

FIG. 4. B.M.R. VS. PLASMAPER SQUAREMETER. ALL CASES

Observations on case 3 shown by black triangles.Observations on case 4 shown by dots.Observations on case 5 shown by squares.Observations on case 6 shown by circles.Observations on case 7 shown by crosses.Observations on case 8 shown by white triangles.Observations on case 9 shown by pluses.

500

WVILLARD OWENTHOMPSON

tain the normal basal metabolic level in patients with myxedema whoshow about the same reduction in basal metabolism.4

FIG. 5. THE RELATION OF B.M.R. TO PLASMAPER SQUAREMETERIS SHOWNINALL THE CASES

For each case represented in figure 4, a mark has been plotted for the averageB.M.R.-plasma per square meter point when free from, and another during,thyroid extract administration; the two are connected by a straight line.

4 It is not implied that basal metabolism and plasma volume always increasetogether. There are no doubt different types of accelerated and diminishedcellular activity. For example, the oxygen consumption is increased in fever,but evidence thus far collected suggests that the blood is concentrated.

501


VII. THERELATION BETWEENTHEDOSEOF THYROIDEXTRACT5ANDTHE

DEGREEOF PLASMAINCREASE IN THE SAME INDIVIDUAL

It is striking that once the basal metabolism has been restored toits normal level, increases in the dose of thyroid extract up to three and

1 0I

1600~ / -10

Doii lhjrkIsuje (gis30FIG. 6. CASE OF MYXEDEmANo. 5

These curves show the effect on B.M.R. and plasma volume of increasing thedose of thyroid extract beyond the maintenance dose. Each point represents theaverage of at least two observations.

5 Burroughs Weilcome and Company's thyroid extract was used throughout thiswork, except for the first four weeks in case 8, during which Armour's 1 graintablets were used. In the last six patients Burroughs Weilcome and Company'sthyroid preparation was used in 1I grain tablet strength only. In cases 8 and9 oral thyroxin in large doses was used without effect on basal metabolic rate orplasma volume, whereas thyroid extract subsequently produced a prompt andsustained increase in both. Twenty milligrams of thyroxin were injected intraven-ously in case 9, while she was myxedematous. A well marked increase in basalmetabolic rate and plasma volume occurred, the data being recorded in table 11.

502

WILLARD ONENTHOMPSON

four times the maintenance dose produce only slightly greater increasesin plasma volume and basal metabolism than the maintenance dose(figs. 6 and 7). One observes the abrupt change in direction of thetwo lines when the dose is pushed beyond the maintenance dose.

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These curves likewise show the effect on B.M.R. and plasma volume of increas-ing dose of thyroid extract beyond the maintenance dose. The B.M.R. on 6grains daily represents only one observation and is probably high inasmuch as oneof the three B.M.R. observations on 41 grains daily was +23 per cent.

Yet, in spite of little change in plasma volume or basal metabolism,these patients would often complain of precordial pain, palpitationepigastric cramps and dysmenorrhea. One woman (case 7) whose

503


auricles were fibrillating and whose maintenance requirement was74 grains daily had an attack of unconsciousness (probably Stokes-Adams), on two occasions when the dose was increased to 12 grainsdaily. She had had none before and has had none since.

One may compare the difficulty experienced in raising basal metabo-lism and increasing plasma volume once the basal metabolism isnormal with the difficulty encountered in raising both in a normal indi-vidual by giving thyroid extract (table 12). This individual probablybelonged to the so-called "low rate" group of patients. She showedonly a slight increase in basal metabolism and a suggestive slightincrease in plasma volume on taking 44 to 6 grains of thyroid extractdaily. Yet she had precordial pain, palpitation, epigastric pain andsevere dysmenorrhea, all of which disappeared when the administra-tion was stopped.

Data were collected also from a postoperative exophthalmic goitrepatient who may be regarded as approximately normal (table 13).The data begin to be recorded about four months after a subtotalthyroidectomy, that is to say, after the weight had become stationary.Iodine (Lugol's solution) was first given for about 54 weeks. Thebasal metabolism on iodine treatment dropped slightly to a stationarylevel around -5 per cent. Thyroid extract was then administeredin slowly increasing doses over a period of about 24 months. Thepatient was given 134 grains daily for approximately one and one-half months. There occurred a slight increase in basal metabolism(18 points) and possibly a slight increase in plasma volume (1560 ccper square meter to 1670 cc. per square meter). The patient experi-enced no toxic symptoms on 134 grains of thyroid daily a dose suffi-ciently large to produce intoxication in most patients with myxedema.These last two patients illustrate what appears to be a matter of im-portance, namely, variations in the amount of thyroid extract re-

6 It is of interest in this connection that Willius (48) recommends the use ofsmall doses of thyroid extract (1 to 2 grains daily) in the treatment of the Adams-Stokes syndrome and that Aub and Stern (49) report that the daily administrationof 28 grains of Burroughs Wellcome and Company's. thyroid extract for severalweeks produced no cardiac symptoms in a patient with complete heart block, inspite of an increase in basal metabolism to +47 per cent.

504

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Other cases could be cited. These are sufficient, however, to illus-trate that once a patient with myxedema has been given sufficient

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0 '5 -10 15DaL1L ljid Dosam e9

FIG. 8

These Curves present the record of a case of exophthalmic goitre during a periodof thyroid extract therapy beginning four months after a subtotal thyroidectomy(Table 13).

Note that the abrupt initial rise (maintenance dose) seen in figures 6 and 7 islacking.

thyroid to maintain a normal basal metabolism and plasma volume,one is dealing with an essentially normal individual. When the doseof thyroid extract is further increased up to two or four times themaintenance dose, the increases in basal metabolism and plasma vol-

7 It is realized, of course, that post operative patients with exophthalmic goitres,although not grossly myxedematous, may possibly require more thyroid extractbefore they become toxic than normal individuals. This may account in somemeasure for the difference, but probably not completely.

507


ume are proportionately much smaller than those produced by themaintenance dose and are of the same magnitude as the changes pro-duced in both by giving thyroid extract to a normal individual. Thisphenomenon is probably fundamental and seems to be the result ofcalling into play some defense mechanism, some one of the body'sfactors of safety to deal with excess.

VIII. CHANGESIN TOTAL BLOODVOLUME.

In untreated cases of myxedema a well marked secondary anemiawith a hemoglobin of about 60 per cent and a red blood cell count ofbetween 3,000,000 and 4,000,000 is the rule rather than the exceptionand has been emphasized by numerous observers including Minot (24),Emery (25), and recently McKunde (26). She found a decreasein hematocrit values in experimental myxedema in rabbits from 30to 31 per cent to 23 to 24 per cent, and a reduction in hemoglobin of30 to 40 per cent. This reduction in hematocrit value does not repre-sent the total reduction in volume of circulating cells because therewas probably also a reduction in plasma volume. Even if the plasmavolume is concentrated only 15 per cent as the result of thyroidectomy,then an hematocrit reading of 23 really is too high and represents oneof 19.5 based on the original quantity of plasma. If the original hema-tocrit value were 30 this would represent a reduction in volume ofcirculating cells of over one-third and in total blood volume of overone-fifth, reductions which may fairly be assumed.

The reduction in red count and cell volume following the omissionof thyroid extract administration is a slow one; the first response isin fact an increase due to plasma reduction. It is manifestly unfairto keep patients with myxedema off the administration of thyroidextract long enough to allow the red count and cell volume to belowered. There is evidence, however, in the data presented whichallows one to draw justifiable conclusions about changes in total bloodvolume.

For example, consider again case 1 (table 3). Her hematocritreading just after starting the administration of thyroid extract butbefore the drug had had any effect, averaged 26.5, with an averagered count of 3.1 millions. Thyroid extract was administered for about

508


seven months and was then omitted for about six weeks (May 14,1924, to June 27, 1924). During this period the average plasmavolume was 2615 cc. Observations made from July 3, 1924, to Sep-tember 29, 1924, while taking thyroid extract show an average hemato-crit value of 35.6, an average red count of 3.9 millions and an averageblood volume of 4600 cc. Let is be assumed that the plasma volume inthe myxedematous state before she received thyroid extract was thesame as it was when its administration was omitted, namely, 2615 cc.This, with an hematocrit value of 26.5 gives a total blood volume of3560 cc., or 1140 cc. less than the total volume after she had reachedan equilibrium on thyroid -extract treatment. This seems a conserva-tive estimate, since the first two plasma volume observations of 1850and 2350 cc. (although questionable, as stated on page 497) wouldgive still lower total blood volumes for her original myxedematouscondition.

Case 2 (table 4) presents a second example. It was possible towithhold thyroid extract from this patient for a period of over threemonths (January 7, 1924 to April 16, 1924). It will be observedthat although the hematocrit reading increased at first, towards theend of the period it decreased slightly. Then after medication beganagain (April 16, 1924) there occurred following a further decrease,an increase which set in about one month later and gradually becamemore marked during the following four months. If the average of thelast three total blood volumes (March 22, 1924, to April 14, 1924)when he was not taking thyroid extract be compared with theaverage of the last five (August 14, 1924, to September 11, 1924)during its administration, an increase in total blood volume of 1245 cc.will be observed. The data suggest that the original cell volume wasless than when treatment was subsequently omitted, considering thatthe red count on admission averaged between 2.0 and 3.0 millions ascompared with 4.0 millions during the untreated period beginningJanuary 7, 1924. The change of 1245 cc. in total volume is oneactually observed and is probably less than the change that wouldhave been recorded had observations been made before thyroid therapywas begun.

Case 6 had been without thyroid extract for two months when lastadmitted to the hospital. The total volume (5 observations made

509

STUDIES IN BLOODVOLUM1E

from July 29, 1925, to August 7, 1925) averaged 4270 cc. before theadministration of thyroid extract was started August 7, 1925, and the5 last observations, made in the fourth month after starting treat-ment averaged 4895 cc. an increase of over 600 cc.

From such data, together with experimental observations in ani-mals following thyroidectomy, it appears that increases in totalblood volume of one-fourth over the myxedematous level (i.e., 800to 1000 cc. of whole blood in human beings) are not uncommon.

1MTALWEIGHT * e°ASMA

Ko. CC.

T4 3600

68 3300

6? 30000 2 56 63 71

TIME IN DAYSFIG. 9. CARDIAc EDEMA

These curves show increase and decrease in total plasma volume with increaseand decrease in edema (represented by weight curve).

IX. A COMPARISONOF MYXEDEMAAND CARDIAC EDEMA

Myxedema and the edema of heart disease represent two totaliydifferent types of edema and, by comparing them, some light is thrownon the nature of both. In cardiac edema, the excess tissue fluid ischiefly intercellular and the skin pits on pressure. In myxedema theexcess tissue fluid is chiefly intracellular and the skin does not pit onpressure. Cardiac edema may be explained on the basis of an in-creased capillary filtration pressure due to venous congestion (that isto say, this may be the underlying cause of all blood and tissuechanges). Indeed, when one stands at the position of attention for aslong as an hour, the cardiac output decreases, the venous pressure risesand a measurable increase occurs in the diameter of the calf (Field

510


and Bock (27)). Bolton produced marked edema by reducing thelumen of the inferior vena cava to one-third in cats. Myredema, onthe other hand, probably has a much more complex mechanism as aresult of changed osmotic relations between plasma and tissue cells.This subject is discussed later in greater detail.

In cardiac edema as the weight increases the total plasma increases,whereas in myxedema as the weight increases the total plasma de-creases. This is illustrated in figures 9 and 10, where the weightcurves and total plasma volumes are plotted for a case of cardiac edemaand case 5 with myxedema. The data for figure 9 were collected from

WEIG:T* TOTALWEIG4T0-. ~~~PLASMA

KS. CC.

63 2550

61 20

59 250 20 40 45 55

TIME IN CDAYS.


These curves show decrease in plasma volume with increase in weight andincrease in plasma volume with decrease in weight in contrast to those in cardiacedema (fig. 9).

a case of chronic myocarditis which I was fortunate enough to observewhile fully compensated, during the progress of edema and as edemawas subsiding.8

Another point of interest in cardiac edema is that the osmotic8 There is considerable evidence in the literature to support my findings in

cardiac edema. As early as 1884 Oertel (29) taught that in cardiac edema, hydre-mic plethora was present. Stintzing and Gumprecht (30) found hydremia not onlyduring the height of dropsy, but also at the onset. Askanazy (31) concluded fromhis observations that the blood serum was always diluted, dilution depending uponthe extent of the dropsy. Bolton (32) found a well marked increase in blood vol-ume in animals in experimentally produced "dropsy."

511


pressure of the serum as referred to protein is low (Gavaerts (28))whereas the data in myxedema thus far collected suggest that theserum protein is high. Inasmuch as hunger edema is also character-ized by low serum protein and massive pitting edema, Oberndorfer's(1) finding of a markedly diminished weight of the thyroid gland inthis condition appears to be of no consequence from the standpointof etiology of the edema.

X. THE EFFECT OF THYROID ADMINISTRATION ONTHE PLASMAVOLUME

IN CRETINS

A few observations on three cretins have been collected. Two ofthese (aged 4 and 5 years) showed practically no change after takingfairly large doses of thyroid extract for two to four weeks. Thethird case (aged 7 years) showed a 14 per cent increase, in total plasmaafter receiving 3 to 4 grains daily for three weeks. There are, how-ever, not enough data to draw conclusions from. These findingsare interesting in view of those of Hammett (50) that thyroidectomy inmale rats 75 days of age produced much less increase in refractiveindex and much less reduction in water percentage of serum than itdid in sexually mature male rats 100 days of age.

Young rabbits when thyroidectomized show reductions in hemato-crit values which are less marked than those shown by mature rabbits(McKunde). An increase in hematocrit readings on giving thyroidextract has been observed in human cretinism (Talbot (33)).

XI. THE RATE OF DISAPPEARANCEOF INTRADERMALLYINJECTED SALT

SOLUTION IN MYXEDEMABEFOREAND AFTER THYROID

EXTRACTADMINISTRATION.

The Aldrich-McClure intradermal skin test (34, 35) was used.Sodium chloride solution (0.2 cc. of an 0.8 per cent) was injected intra-dermally in two places about 2 cm. apart on the flexor surface of eachforearm a little below the bend of the elbow. The time at which anelevation ceased to be palpable on gently rubbing the finger over thepoint of injection was taken as the end point of the period of absorp-tion. I do not consider the test of much value. Leakage, no matterhow careful the technique, causes variation in the amount of fluid

512


injected. Differences in the depth of injection are unavoidable. Irri-tation of a sensitive skin often masks the end point. I have, however,several observations in four cases under and without the influence ofthyroid extract and I present the averages in each case. They consist-ently show a more prolonged disappearance time before or in the in-terval of thyroid omission than during the period of administration.

Case number Average without thyroid extract Average on thyroid extract

minutes minutes

4 67 405 71 566 122 959 63 44

It is interesting to notice that in all other types of edema Aldrichand McClure found the disappearance time markedly diminished.The wheals usually disappeared in 7 minutes or less over markedlyedematous areas. Although the time was usually greater in non-edematous than in edematous areas of the same patient, the time innon-edematous areas of edematous patients was usually much lessthan the normal of 50 or 50 plus minutes. In a case of nephrosis atthis hospital it was observed that in the legs where edema was markedthe wheals disappeared in 1 to 2 minutes whereas in the arms whereno pitting edema was present the wheals took 12 to 14 minutes todisappear. Obviously this rapid disappearance in edema cannot bedue to capillary absorption for the following reasons:

1. The blood has a low osmotic pressure (as referred to protein) andcan not properly absorb fluid from the tissues. Yet the wheal oftendisappears at 40 to 50 times the normal rate.

2. Differences in the chemical composition of blood sufficient toaccount for differences in disappearance time of 6 to 14 times are notknown to exist.

3. The disappearance time increases as edema subsides, a relationjust the opposite of what one would expect if disappearance were duechiefly to absorption by the blood.

One could account for the differences in disappearance time inmyxedema before and after the administration of thyroid extract onthe basis of changes in the rate of blood flow, assuming that the dis-

513


appearance in this case were chiefly the result of absorption by theblood. Until we know more precisely, however, what the mechanismof disappearance is, it is useless to say more on the subject. Theresults illustrate one more difference, nevertheless, between myxedemaand all other types of edema. Pilcher (36) on injecting codein in-tradermally noticed that the injection wheals disappeared morerapidly than normal in a case of myxedema and in one cretin, aswell as in other types of edema. It is important in such instances,however, not to confuse irritation with diffusion and absorptionphenomena.

XII. DISCUSSION

Magnus-Levy (37) showed that there was accumulation of albumenin the tissues in myxedema and thought that some of the increasewas intercellular. Eppinger (11) assumed that this phenomenonwas the cause of edema in myxedema by virtue of the affinity ofalbumen for water and salt. He inclined to the view, that inedema of this type intercellular albumen was a more importantconstituent than intracellular albumen and based this conclusion onthe fact that when isotonic salt solution was injected subcutaneouslyin myxedematous dogs, protein became mixed with it whereas thisdid not occur in normal dogs. In his opinion protein admixture wasresponsible for slow absorption. Eppinger believed in fact that in-creased tissue albumen accounted for all types of edema. Boothbyet al. (51) confirmed the observation of Magnus-Levy and showedthat the nitrogen-water ratio of the weight lost by one normal andby each of two myxedematous individuals as a result of intravenousthyroxin administration was 1.9, 2.0 and 1.9 per cent respectively.These authors, therefore, concluded that the edema of myxedema' corresponds apparently to an increase in the reserve or depositprotein" and "is an albuminous colloid fluid with a nitrogen-waterratio higher than the average of 1.1 per cent for human bloodserum and identical with that of egg white which contains approx-imately 2 per cent nitrogen, and definitely less than that of musclewhich contains over 3 per cent." They emphasized the fact thaton the contrary the nitrogen content of the edema of cardiac orrenal origin is only 0.05 to 0.001 per cent, a negligible amount.

514


In comparing myxedema with cardiac edema it was suggestedthat the increased tissue fluid in myxedema was probably for themost part intracellular. Tatum (38) has shown that in experimentalcretinism in rabbits,. while there is a varying amount of intercellularserous deposit, the greater changes are in the cells. He demonstratedthat there were hydrophic changes in cells of the heart, liver, kidney,smooth and striated muscle. These experiments then give evidenceto the effect that there may be increased water content of tissue cells.

That the water content of the tissues is increased in myxedema is agenerally accepted fact. Recently McKunde has reported that thewater content of dried fat-free tissue in thyroidectomized rabbits ishigher than normal and that they lose weight and water when fedwith thyroid extract. Hildebrandt has shown that the intravenous in-jection of thyroxin in rabbits causes not only a loss of water from thetissues but also of salt. It is, moreover, generally admitted that thesecretion of the thyroid gland stimulates sodium chloride metabolism.

In myxedema there are then two phases in close association; first areduction in the total quantity of circulating plasma, and second anincrease in water protein, and salt in the tissues. It is my opinionthat both these phenomena are merely by-products of the funda-mental change which thyroid insufficiency produces in the activityand chemical composition of tissue cells.

It is interesting in this connection to refer to the work of Barbourand Hamilton (39), (40), (41) who have demonstrated that coldproduces blood concentration, and heat blood dilution, and that incold anhydremia there is an increase in the water content.of skin andmuscle. They have not demonstrated whether this increased tissuewater is intra- or extracellular. The idea is suggested, however, thatcold and thyroid insufficiency may produce similar types of slowedcellular metabolism and that a by-product of both is probably anincreased osmotic pressure of tissue cells.

Ellinger (42) believes that the influence of thyroid extract on theviscosity of blood serum is independent of the albumen content ofthe latter, and that in this respect its action is similar to that of caffeineand other diuretics.

Loeb (43) reports that Embden and his associates found that thy-roid extract, when added to certain substances increases the rapidity

515


with which the latter pass in vitro through a membrane of frog's skin.He also reports that "Recent experiments in Asher's laboratory haveshown that under the influence of thyroid, methylene blue passes morerapidly from the body fluids into glandular structures in the membranenictitans of the frog. Thyroid extract would thus appear to have aneffect opposite to that of calcium chloride and adrenalin." In view ofsuch reports one must admit that altered permeability of cell mem-branes may play a r6le in the effect of thyroid extract on fluid distribu-tion in myxedema, but it would appear to be a minor role and tobe explicable on the theory that cell membranes share in the generalmyxedematous condition.

Means (17) has well remarked that "However obscure the functionof the endocrine glands may be, we can agree, I think, that they areall concerned in one way or another, direct or indirect, with metabo-lism. .... If the secretions of endocrine glands influence cellactivity, they must also influence the supply of the medium uponwhich such activity depends." Weknow that insulin produces a wellmarked anhydremia, that adrenalin causes some anhydremia and thatpituitrin has a marked effect on water elimination. Krogh (44)indeed thinks that it decreases capillary permeability.

Means also referred to the observation of Bock and Field (45) thatin myxedema the administration of thyroid extract markedly increasedthe minute volume of the heart, initially very low. He referred tothe reduction in the volume of blood and in cardiac output as manifes-tations of the variation in the supply of circulating medium with thedemand. Daly (46) has shown that mere increases in the volume ofblood, other things being equal, increase the cardiac output. Asalready stated, I have observed an increase of 1245 cc. in total circu-lating blood in one patient and have calculated that it must have beenabout this great in another. The value of such increases from thestandpoint of hemodynamics is obvious. It is indeed, quite strikingthat the secretion of the thyroid gland with its marked influence onoxygen consumption should produce such marked changes in the car-riers of oxygen and carbon dioxide. As Barcroft (47) has so well putit "The blood volume should be regarded not as aliquot part of thebody weight but as a physiological variable which is adjusted to thework required of it. . . . ."

516


In brief, the reduction in plasma volume in myxedema is associatedwith an accumulation of albumen, water and salt in the tissues. It isa debatable point as to how much of this increase is intercellular and'how much intracellular. Eppinger's finding of a protein admixturein subcutaneously injected isotonic salt solution in myxedematousdogs, suggests that a considerable part of the increase may be inter-cellular. On the contrary the contrast between myxedema and car-diac edema, together with Tatum's finding of an hydropic conditionof various tissue cells in thyroidectomized rabbits, indicate that thelarger part of the increase may be intracellular. A factor in thesechanges may be diminished permeability of cell membranes. Thefundamental cause of all the blood changes, however, would appear tobe a decrease in the rate of metabolism of tissue cells, with a diminu-tion in the demand for oxygen and carbon dioxide transport. Thedecreased quantity of circulating medium and the reduction in minutevolume of the heart seem to be adaptations of the circulatory systemto this diminished demand. I have suggested that the slowed cellularmetabolism may increase cellular osmotic pressure, but the varioussteps in the process by means of which water is slowly withdrawn fromiplasma and stored up in the tissues, are yet to be worked out.

XIII. SUMMARYAND CONCLUSIONS

In nine patients with myxedema the total plasma volume increasedon the average 22.9 per cent, the plasma per kilogram 28.5 per cent,and the plasma per square meter 25.2 per cent, when given thyroidextract.

From observed and calculated increases in total blood volume, itis estimated that the administration of thyroid extract in myxedemanot infrequently produces total blood volume increases of 25 per cent.

The plasma decrease on omission of thyroid extract and the increaseon administering it, occur much more rapidly than the same changesin the volume of cells. Plasma reduction is usually well marked withinten days after omitting the drug.

A parallelism exists in myxedema between basal metabolism andplasma volume.

Once the basal metabolism has been restored to normal, furtherincreases in the dose of thyroid extract up to four times the mainte-

517


nance dose produce proportionately much smaller increases in plasmavolume and basal metabolism than the maintenance dose.

The plasma volume changes in myxedema are contrasted withthose in cardiac edema in which plasma volume increases with increas-ing edema. Other differences in the two are noted.

In particular I wish to thank Dr. James Howard Means for hisinterest in this work and for help in the preparation of the manu-script. I also wish to thank Dr. Francis W. Peabody for giving meaplace to work while I was a house officer.

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Time Required for Disappearance of Intradermaily Injected Salt Solution.Preliminary Report of Observations, with Special Reference to Cases ofEdema.

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36. Pitcher, J. D.: Amer. Jour. Dis. Child., 1926, xxxi, 77. Wheal Formation inInfants and in Children: I. "In Edema, Cretinism," etc.

37. Magnus-Levy, A.: Ztschr. f. klin. Med., 1897, xxxiii, 269. Untersuchungenzur Schilddruisenfrage; 1904, lii, 201. Ueber Myxodem.

38. Tatum, A. L.: Jour. Exp. Med., 1913, xvii, 636. Morphological Studies inExperimental Cretinism.

39. Barbour, H. G., Hamilton, W. F., Dawson, M. H., and Neuwirth, I.: Amer.Jour. Physiol., 1925, lxxii, 232. Mobilization of Salt and Water beforeSweating, as Determined by the Specific Gravity: Solids Ratio of Bloodand Serum.

40. Hamilton, W. F., and Barbour, H. G.: Amer. Jour. Physiol., 1925, lxxiii, 321.Heat Regulation and Water Exchange. VIII. The Fate of the FluidLeaving the Blood in Cold Anhydremia.

41. Barbour, H. G., and Hamilton, W. F.: Amer. Jour. Physiol., 1925, lxxiii, 315.Heat Regulation and Water Exchange. VII. Evidence that Cold An-hydremia is Due to Loss of Fluid from the Blood Stream.

42. Ellinger, A.: Klin. Wchnschr., 1922, i, 249. Die Angriffspunkte der Diuretica.43. Loeb, Leo: Medicine, 1923, ii, 281. Edema.44. Krogh, A.: NewHaven, 1924, 2nd edition, 156. Anatomy and Physiology of

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xvi, 541. Thyroid Preparations in the Treatment of the Adams-StokesSyndrome.

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