III. Fluctuations in Blood Sugar During Eclampsia: The Relationship Between the Blood Plasma Sugar and the Corpuscular Sugar Variations in Eclampsia as shown by Serial Curves. Preliminary Report*

TITUS

AND

WILLETTS

: FLUC’TU.\‘J’ICNS

IN

IILCOD

SUGAR

DURING

27

IS’LAMI’~Ih

1. In t.he majority of cases of eclampsia there is a tendency toward hyperglycemia. 2. In general the blood-fiugar level remains fairly constant, throughout the disease. 3. As there is no relative hypoglycemia, that, condition cannot be utilized to explain the production of eclamptic convulsions, and these convulsions are not comparable to insulin hypoglycemic convulsions. 4. Following eclamptic convulsions there is a, slight rise 141 blood sugar. 5. A patient may have eclamptic convulsions with the blobd sugar at different levels, and these levels are not. great1.v disturbed by t.he convulsions. REFEREKCEH J. Biol. Chew. 64: 211, 1925. Bet~edict, S. II.: J. Biol. Chenl. Betcedict, S. R.: Ztschr. f. Geburtsh. u. Gyn%k. 71: 544, 1922. Duwa?~, 76: 457, 1928. Beutlain, W.: Canad. M. A. .J. 7: 1057, 1918. Folijl, O., ad Wu, H.: J. W., and Harding, V. J.: Ztsrhr. f. Geburtsh. u. GynLk. 61: J. Biol. Chem. 38: 81, 1919. Hofbauer, J.: Macleod, J. J. R.: 200, 1907. Levy, W. E.: AM. J. OBST. & GYNEC. 12: 866, 1926. 1926. Obata, I., ad Hayashi, T.: Carbohydrate Metabolism and Insulin, London, Arch. f. Gyniik. 109: 80, 1923. Scl~rnidt, H. R., Biakenbach, W., and Jmen, P.: Stcmdrr, H. J., mtl Ra.delet, A. H.: Ztwhr. f. Geburtsh. u. Gyniik. 91: 533, 1907. Sfaatter, H. J.: AM. J. OBST. & GYNEC. Bull. Johns Hopkins Hosp. 38: 423, 1936. Thalhinwr, IV. : Swg. Gynec. Obst. 39: 237, 1924. Titus, P., Hoj$13: 39, 1927. ‘mana, G. L., and Givers, M. H.: J. A. M. A. 74: 777, 1930. Titus, P., Dodds, P., It’a.ltlba,d, B. : Arch. and WiZZftt.s, E’. W.: AM. J. OBST. & GYNW. 15: 3013, 192X. f. Geburtsh. u. Gyngk. 41: 113, f. GvuPk. 116: 68 t 1923 . Vi&N, d. : Monntwhr. 191:i: (For disccrssiorl, SPP pap IJ’;;.)

111. FLIJCTUATIONS

IN BLOOD

THE RELATIONSHIP SUGAR AND THE TIONS BY

PAUL

(Prom

the

SlJGAR

DURING

ECLARIPSIA

:

BETWEEN TIIE BLOOD PLASMA CORPUSCITLAR S;JGAR VARIA-

IN ECLAMPSIA AS SHOWN BY SERIAL CIJRVES. PRELIMINARY REPORT**

TITUS,

Departnwnt

M.D., of

AND

E. W.

Obstetrics

WILLETTS,

alit7 Hospital)

M.D.,

Gyt~ecology,

Nt.

~‘ITTSHURGH,

PA.

Margwrt

Mmrot+aZ

N TWO previous communications’s 2 we reported blood chemistry studies which showed that during the course of an attack of eclampsia, there are wide fluctuations in blood-sugar values in surprisingly short intervals of time, and that it is characteristic for the convulsions to be preceded bg a sharp fall and followed by a rise in blood sugar. Corroborative evidence of this discovery has recently been published by Laferty, Nark and Sweeney3 of Philadelphia. These periods of sudden lowering of blood sugar in eclampsia, which I

being

tory

*This

study conducted

is one of the series by the John C. Oliver

of the St. Margaret

Memorial

of

investigations in Memorial Research

Hospital.

the toxicoses Foundat:on

at

of

the

pwgnancy Labora-

28

THE

AMERIC’AX

JOURNAL

OF

OBSTETRIC’S

AKD

GTNEC’~I.WT

are unlike anything else fauliliar to clinicians except, those due t,o overdosage with insulin. we designated by the term “relative hypoglyceinia ’ ’ Ry this we mean that tll(J levels of hlootl-sugar valncs at which eclamptic convulsions take I)lil(*(’ may bo high 01’ low as conl-

Note brlmrior of whole blood sugar: Period a to a’ sl~ou~s a slight fall in whole blood sugar pwwding the courulsioll, foliowved by slight rise to point b’. Theu thrrc oe~urs from b’ to d a long dewward trend rnnging in twenty-threr minutrs from 133 mg. down to !M mg. followed by the next convulsion. One momeutxry effort toward recovery wxu~s during period b to c but could not ?,e sustained.

TITUS

AND

WILLETTS

: YLUCTUATIONS CASE

SUGAR LEVELS Whole blood Plasma Corpuscles

IN BLOOD

3. FIFTY-SEVEN INITIAL 105 mg. 133 mg. 53 mg.

MINUTES

SUGAR.

DURING

ECLAMPSCA

29

TIME

HIGHEST 121 mg. 156 mg. 13.5 mg.

LOWEST 90 mg. 100 mg. 52 mg.

Period a to b: Recovery of corpuscular sugar content from point of greatest depression, simultaneous with loss of sugar by plasma in period a’ to b’. Period b to c: Fall in corpuscular sugar during which convulsion occurs. Period b’ to c’: No loss and even slight gain in total plasma sugar but plasma graph crossed by whole blood sugar line thus indicating relative loss in plasma sugar content. Period c to d: Restoration of corpuscular sugar content to high level during period (b’ to c’) of relative sugar loss to plasma. Period d to c: Sharp loss in corpuscular sugar during which time convulsion occurs. Period c’ to d’: Influx of sugar to plasma stream. Note behavior of whole blood sugar: Period a’ to b’: one of fluctuation ending in depression and followed by conPeriod Period

c to d: usual d to convulsion:

postconvulsive Moderate

recovery to higher fall in whole blood

sugar sugar.

levels.

pared to “normal” values, but., as said before, almost invariably they follow a sharp fall from some higher level. Because it has been authoritatively shown*’ 5 that the blood-sugar values at which hypoglycemic symptoms may be indnced by insulin injections depend not so much on the actual level of the blood sugar as they do on the rapidity with which that level has been reached in the fall from higher levels, we reasoned that an eclamptic convulsion was analogous and therefore might properly be termed an hypoglycemic reaction, Moreover the rise following the convulsion is similar to that noted in experimental animals dosed with insulin to the point of convulsion. These new blood chemistry findings and conclusions were both consistent and convincing because they accomplished several things; they established the relationship between the convulsions of eclampsia and a disturbance in carbohydra,te metabolism which we had previously postulated; they offered a conclusive explanation for the beneficial effects previously noted in eclampsia from intravenous injections of dextrose; they advanced our knowledge of the etiology of this disease to the extent which we have outlined; and we believe that they also establish a relationship between the toxemias of both late and early pregnancy since we have found similar but, much more slowly attained low blood-sugar values in hyperemesis gravidarum.j A paper by FoshayG on the sugar content of the erythrocytes as an index of insulin action, suggested to one of us (Titus) t.he idea that even more information regarding the etiologic and clinical significance of these fluctuating blood-sugar curves in eclampsia might be gained

frOll1

a

Studg

Of

the

~Or~~LLSC!Lll~l’

SLlgiir

till<1

Of

tlL<’

blOOt1

I)l?lSlll?i

Sllgill

considered separately. This has bern done in the VHSW of three eclnml)tic \vomw not, iucludrd in our twrlic~ scrirs, and suffi~it~nt information has hwn obtained to \VikTr;lllt discussing tllr findings ii1 a ~~rt~lirrrinai*y rrport, from which wc may Ill~llifJ declncticns without attcnildin, 0’ tletinite eonelusion5. Al)l)arrntly it will bf, Ilf~~l?SSil~~ iti tltis stndy as ill ttlf, f~arlif~r oIl(‘s 10 divide cclamldics intr: t\\o lllilin grc;ul)s for c:oinpnrisori ; the slowly l)rogrwsing tylw c:f cwf’h, ant1 the rwl)itll,y prcgwssin, 0. or f’lll~~lillirtillp c*ascs. 1’11fa t\\-0 ViiSf’S itI (‘ll;lI’t 1 ilI‘f’ f~Xrf~llf’llt f~X?tIll~)lf~S Ot’ tll0 IiIttc’I’ iillrl aw strikingly ;Ilil<(l ill ~n;lny of thtzir c~harac~tcristics. Ill tllfw tllf, Ot’ 0111~ il ff’\V IlliIlIltf~S~ \\tllhLY’;lS iTi varif;ws flllCtlliitiOllS ill‘f’ il IllilttP1. thfl others (vitlk, rc’F.‘i. as iI1 (‘llilrt 2. tllcay ill’<’ mort~ :I lf~attf~~ 01’ halE

01’ 1011prt*.

11oLlrs

Natwall?- the inor~~ striking findings ii1.f’ rather thau ttif, slowly prcgressiny ~ast’s,mtl earlier rrprtrd CIII’V~S. t;ENE:K.ZI.

f’I1AHAf’T~lZISTIf’S

()I” 1N

TIIE

EC ‘LAN

M’I~OIX

be note(l iii tllcb swiftly this fact wiis Irott>tl in oui

to

1~1,001~-8L1(:AII

(‘I’I
PSI.\

prison,

\vllol(~ bl ootl-suga 1’ (‘LlI’VC’S art ills0 {)tOttPd fOV tllf’ Sakf’ Ot’ ~Ollland these ~~nfot~ni to thcl g~~nwal cha racteristiw 01’ thaw

sh0w11

iu

Tl1c.

our

cwlicr

papers.

In brirf these tendencies art’ as follows: first, a niarkd tiuetuatioll in blood sugar in short intervals of time ; second, a decided fall pwceding a convulsion; third. as the ~~~~rvousncss and tremor of the ;tpproadiinp convulsion (*onie on, a riw ill blood sugar begins so that thost> specimens taken o~II~ a It~oLllt‘Llt 01’ SO hcforfk it c*onvulsioll ;lctlrally occurred. wvw usually slightly higher than thosth two to thrcy, or folw minutes ltf~folr ; folwtll. this rirv ill blood sugar coiitilkuml after ii convulsion. thrri rithw fluc!tuatetl for a tiiiif~ or subsitlcd to thr lowrr levels pwcetling the next ~orlvulsiotl : fifth, the penc~ral trrid of the hlootl sugar was slowly downward. \VilOl‘l3 1~1‘001) sL~f:AI: SKI’AHA’JEI) DETEH~MIh-ATIONS

INTO

f’OKI’l~TSl’1~L.\1i

DlWIN(;

ANI)

i’LASi\lA

Sl’f;Al<

Ef’LAMI’SIA

In (‘aws 1 and 2, it will hv Ilot that the convulsions OCCLW on tllcb clown s\z-eel) of the eor~~uscular sugar and that this fall continnt3 011 through the period of the convulsion. recovering more sloml~- thall does the plasma sugar. It is true that the plasma sugar usually shows H tlwline before eonvulsions but this is less marked and its rise aftrr the convulsion is almost as striking a phenomenon as is thr fall of the corpuscular sugar before and during a convnlsiou. In these CHSPS(1 and 2) in wtiicli thfl cwrpnscutnr sugar auf1 tllfa

TIT’IJS

AND

WILLETTS

: FLUTCTUATTONS

IN

ISLGOD

SVG;\R

DURING

E(‘LAMPSIA

31

plasma sugar have been separately determined this preliminary study seems to indicate that circulating sugar which is more mobile or most readily available is in the plasma, and that it is not until the corpuscles are deprived of their sugar that a convulsion occurs. We have stated earlier that the convulsion might probably be looked upon as a protective measure in eclampsia. It would seem that following this

CHART

t,m.strd

in

2.-Whole slowly

blood progressing

CASE SUGAR

3.

sugar, case

ONE

HFNDRED

corpuscular

TM~ENTY-FIVE

gg

Period

n to b:

Period

b to

Period of

AND

aud

Sugar

MINUTES

curves

con-

TITHE

LEVELS

Whole blood Plasma Corpuscles

during

plasma sugar of eck5mpsi:l.

this

Depression

e:

Rise

of

d:

Moderate

yfg

of

sugar

sugars

to

safer

most

fall

in

sugxrs

market1 IeVels.

1

fg

in corpuseul:~r T’atieut KIS

curve. rlinic:~lly

-

improve+1

time. c to

followed

by

third

nnd

last

conrulsion

illness. Period

d to

e:

content. Period

e to

f:

Period suddenly Period patient

f

to

g to

h:

postconvulsire

Pronounced g:

checked recovering

Usuxl

fall

Corpuscular by influx Metabolic eonsriousness.

rise, in

sugar equiliibrium

marked

continues

from

in

corpusrulnr

sugar

sugars.

sugar of

especially

fall into

plnsmn stream. being rrstorcd;

sugar

period fluctuations

e to

f

but censiu;:

is ;

terrific muscular upheaval glycogrn is forcibly pull14 out from the liver even to the rxt,ent of exhaus;ting those hrpat,ic reserves not ordinarily affected, to bc poured into the circulation iu response to this demand. In any event there is an increase in the amount of sugar appearing in the plasma, and according to our newest curves these plasma sugar values then subside during the period in which tilt> COYpuscular sugar increases, obviously the result of the replenishment oi the corpnscles from the plasma by which they arc surronndrtl. Case 3 is an example of slowly progressing rclampsia similar to c’crThe fluctuations are not so wide tain of those of our earlier tables. Noreover we cannot demonstrate that nor so violent nor frequent. hypoglycemic fall in whole blood sugar preceding this convulsion JVe brlirve that which was the patient’s third and last such seizure. in this instance our failure to demonstrate this was due to our having taken only two specimens in the entire half hour preceding the convulsion instead of taking them at, five-minute intervals, llaring relaxed our vigilance because t,he patient seemrd to be recovering. This convulsion came as a clinical surprise but it will be not& that following it the cell sugar proved to be fallin g sharply whil(~ tlita plasma sugar was making a moderate gain, the cell sugar then begau to increase rapidly and toward the end of t,hc graph thr equilibrium of all three curves was becoming steadier and more stable at whic*h tim(a the patient was recovrring. Tn a violently active eelamptic, as iu C‘asrs 1 antI 2. the original metabolic disturbance is probably the carbohydrate deprivation which we consider to be the chief etiologic factor iu this disease. Violent falls in blood sugar are naturally followed by strenuous efforts toward recovery to the higher levels and the storm quickly becomes one of great, fluct,uatinp wayrs. During this storm it is reasonable to considel that sugar is torn again and again fmnl the corpuscles only to br restored to them from thr plasma, the process repeating itself until t,he patient either dies or else her stuporous and comatose couditiolt maintains her so absolutely at rest that her metabolic upset again becomes more stable and she recovers, at least from this acute condition. All of these convulsions can usually be stopped abruptly at an) point by the hypodermic administration of morphine and the intravenous administration of hypertonic dextrose solution. .11i view ot these recent findings, the rationale of t,his treatment, hitherto empiric, now appears to be both consist,ent and reasonable. These three patients were thus treated, and all thrcke rccovc~red. POSSIBLE

SIGNIFICANCE

OF

CORPUSCULAR

SUGAR

DEPLETIOX

In commenting on this in connection with insulin hypoglycemic toxemia occurring at varyinn w levels of whole blood sugar, oftentimes

TITUS

AND

WILLETTS

: FLUCTUATIONS

IN

BLOOD

STJGAR

DURING

ECLAMPSIA

33

surprisingly high, Foshay6 says that insulin reactions can occur without hypoglycemia but that they do so simultaneously with the reduction of the corpuscular glucose. He terms this a cytoglycopenia or a status of glucose impoverishment within the cell. IIe says further that it seems highly probable that one of the physiologic actions of insulin on blood is a deprivation or a reduction of the capacity possessed by erythrocytes to contain glucose. The experiments of Car? suggested that this is true also of muscle cells. MacLeods has demonstrated quantitatively that after insulin there is a reduction in the glucose in the leg muscles. Foshay continues “although it is very entertaining to speculate upon what the result would be if this action of insulin occurred in brain cells or other nervous tissue cells, for want of evidence one is not entitled to offer any general theory of the mechanism of the hypoglycemic reaction.” We venture to suggest that this latter may offer a reasonable’ clue to the actual mechanism of eclamptic convulsions. H. D. Lightbody, Director of the Oliver Memorial Research Foundation at this Hospital after reviewing this manliscript makes the following comments on this study: “No attempt has been made to further separate the total cell sugar into ‘true’ and It seems possible ‘apparent’ sugar as does Somogyi (J. Biol. Chem. 78: 117. 1928). that such a procedure might throw some light on the problem. Somo?yi flnds that about one-third of the total corpuscular reducing substance. and about one-twelfth of that of the serum is nonsugar. The present work gives no hint as to whether it is the sugar alone, 01‘ sugar and nonfermentable reducing substance together that are responsible for the decreases shown. and are precursors of uric acid. I suggest that this may be the sowce of that increase in uric acid which is now considered to be a characteristic ‘blood chemistry’ flnding in eclampsia.”

We would say in this connection that such a differentiation would be essential if the relational values between plasma and corpuscular sugar (apparent or true as the case may be) in single specimens only were being considered. In these cases however we plot a curve showing the relationship between a series of corpuscular apparent sugar readings, considered in conju-uction with each other. The same is true of the plasma sugar readings, and the actual numerical relationship of the one series of readings to the other is a relatively minor matter as compared to the behavior of the two curves toward each other. In other words, these graphs could easily be corrected according to the directions of Somogyi, merely by subtracting the proper percentage for nonsugar reducing substance in the plasma and the proportionately greater percentage in the cells in each individual reading. The sole result of this would be to place the graphs somewhat nearer together on the chart, while the general relations throughout the curves would remain identical. The fluctuations would be the same. Briefly, we are much more concerned in these studies with relationships than we are with actual numerical values. LABORATORY

METHODS

In the work reported above all the blood specimens were taken in tubes containing sodium fluoride and thymol as the anticoagulant in order to prevent any change in sugar values (John, II. J.‘), although

in almost every iilstanw the tests w(‘rc made l)roml)tly after slwiniens \VC1’C C!oll~‘ctPct. ‘I‘llt’ lll~~ttlOtl E’Olil1 ikIlt Ct?trl’ioiiiatioiis 01’ WllOt (1 blOc~cl;tIltl 01’ t~t~l~lltil SU~ilI’. ‘r tit’ rt.11 sllgar’ was estimatccl by the following cquatioll : Of’

\Vrl

IVilS

lS<‘t

t’OI’

iltt

l’er cent of t,lootl S,&g” (pc’r cc111 $t’l’,,Inwloln~ Y 1”” rent S,‘I’11111 .--..-. sug:ir, Pn

=

l’er

writ

WII

writ

wll

volume

YU@I

standitld was 1natlr for ract1 Errs11 proulp of specimens tested as we had previously found that the color of standard fatlcs apprrciably during time required for srtting up new groups. In taking specimens it. somc~timrs happened that the quantity ot blood obt,aincd was not enough to permit rising the usual 2 L’.c. quantit!: for the Folin-Wn method on the whole blood plus a similar arno~~llt~ sufEcient for plasma sugar determinations. One of us (IVilletts) fount1 and now suggests as a routine procedure that 0.5 c’.c. of whole blood is quite sufficient ii’ the centrifuge is used instead of the filter for removal of precipit~atecl proteins. This methocl was also used in obtaining the filtrate of the plasma when less than 2 C.C.\\‘a~ to be had. The detail of tllis is merely that the, whole bloocl is centrifugalized for twenty minntcs at aplwoxiniatcly 3000 revolutions per minute. We were able to demonstrate that crntrifugalization for a 1011grlm period is unntwwary because no furthrr packing of’ cells takes place after twenty minutes; whereas ltw timrA is not sufficient for complete packing of cdt>lls. It has been reasonably su,,(l,(wtecl ( Director 1,ightbody i that the practice of collecting different amounts of blood on the same amounts of salt anticoagulant is open to criticism unless it can be shown that this had no material effect on the (a(.11 volumc~. We have askrtl Lightbocly to analyze our figww in this respect and his finclings appear as a separate communication in companion papP1 to this. published hrrrwith. ITis findings offset this possibltl criticism. A frrsh

il

SIT3lMAKI 1. We hare ~)reviously drmonstratrd wide fluctuations in bloodsugar values during cclampsis with thtl convulsions almost invariably prweded by sharp falls in blood sugar. Thwr periods of suddenly lowered values we termed “ rclativc% llypOgl>-ct~Itliil. ” 1’11cst~ findi1lp have been corroborated now by others. IT. These conclusions n-we both wnsistent, and c*onvincing beeauw they accomplishrd several things ; the) cstablishrcl the wlationship between the convulsions of eclampsiw and a disturbance ill oarbohytlrate metabolism which we had previously postulated ; they ofSrrc~tl a conclusive explanation for the beneficial effects prcriousl!~ noted ill cclampsia from intravenous injections of dextrose ; they aclvancecl kno~vledge of the etiology of this disease to the extent which we IIavf’ 0111'

‘TITUS

AND

WILLETTS

: FLUCTUATIONS

IN

BLOOD

SUGBR.

DURING

ECLAMPSIA

35

outlined; and we believe that they also establish a relationship between t.he toxemias of both late and early pregnancy since we have found similar but much more slowly attained low blood-sugar values in hyperemesis gravidarum. III. We now suggest that, fractional blood-sugar values be determined for similar curves during eclamptic seizures, i.e., that the sugar of the blood be determined as blood plasma sugar and corpuscular sugar considered separately. IV. In a preliminary report it may be said : (a) that the circulating sugar which is most mobile or most readily available is in the plasma, and (b) that it is not until the corpuscles are deprived of their sugar that a convulsion occurs (i.e.. on the down sweeps of the corpuscular sugar curve). (c) The first evidence of recovery is an increase in plasma sugar probably obtained from the hepatic stores, (d) after which the plasma sugar values subside as the corpuscu1a.r sugar increases, obviously during replenishment of the erythrocytes from their surrounding plasma. V. It is again pointed out that these fluct.nations as well as the eclamptic convulsions can usually be stopped abruptly at any point b> the hypodermic administration of morphine and the intravenous administration of hypertonic dextrose solutions, now to be utilized as specific rather than empiric therapeutic measures. REFERENC’ES

t us, Paul, Dodds, Paul, ad Willetts, E. W.: Ahl. J. OBST. & GYNEC. 14: 89 ‘:;.>y (2) Titus, Paul, Dodds, Pa%!, and Wil’etts, E. W.: Ant. J. OBST. & &
and

Insulin,

(5) Johns, H. J.: Physiol. 1923. Path. 1015

73: (8) 1:

London, 1926, Longmans, Green and Co., Ltd., p. 196. J. Med. 8~. 172: 96, 1926. (6) Foshay, L.: Am. J. Exper. Therap. 22: 355, (7) Cori, C. F.: J. Pharmacol. J. R.: Physiol. Rev. 1: 008, 1921. (9) John, H. J.: Arch.

Am.

470, 1935. Ma&cod, J. No. 2, 227, 1926.

HIGHLAND BUILDING.