FACTORSAFFECTING THE APPEARANCEAND PERSISTENCEOFVISIBLE CUTANEOUSREACTIVE HYPEREMIAIN MAN1

By W. F. GREENWOOD,2A. C. BARGER, J. R. DiPALMA, J. STOKES, III, ANDL. H. SMITH 8

(From the Department of Physiology, Harvard Medical School, Boston)

(Received for publication October 7, 1947)

Changes in cutaneous reactive hyperemia havebeen used successfully to identify certain local(1, 2) and general (3 to 5) abnormalities of thecirculation. More recently it has been observedthat cutaneous reactive hyperemia is altered con-spicuously in normal subjects by vigorous exer-cise, particularly as the circulatory stress of ex-haustion appears (6). Under these conditionsvenous pressure, cutaneous blood flow, and skintemperature were changing simultaneously andrapidly. Hence it was difficult to understand themechanism by which cutaneous reactive hyperemiamay be altered without more information on thefactors which modify it in the normal subject un-der experimental conditions.

This account describes the effects of environ-mental temperature, skin temperature, elevation ofthe arm, venous pressure, external pressure andepinephrine iontophoresis, on the appearance andpersistence of visible cutaneous reactive hypere-mia. It indicates certain factors which should bekept constant when reactive hyperemia is used asa test to identify changes in cutaneous circulation.

METHODS

Cutaneous reactive hyperemia was produced locally onthe horizontal volar surface of the forearm by placing aweighted plastic ring on the skin for sufficient time toproduce, after removal of the ring, a distinct annularredness of the skin as described by DiPalma et al. (7).The plastic ring itself had an outer diameter of 3.5 cm.,an inner diameter of 2.5 cm., and a total surface area of5 sq. cm. It was attached to the under surface of a 500gm. weight. When resting freely on the skin the weightapplied to the skin immediately beneath the ring a pres-sure equivalent to 73 mm. Hg, i.e., sufficient to collapse

1 The expenses of this investigation were defrayed inpart by a grant from the Life Insurance Medical Re-search Fund.

2Alexander McPhedran Fellow from the Departmentof Medicine, University of Toronto.

3 Student Research Fellow, Life Insurance MedicalResearch Fund.

the minute vessels and to arrest blood flow (8). Directobservations through the transparent ring showed thatthe skin was completely blanched by this pressure. Inthis account the definitions and criteria described byDiPalma et al. (7) will be followed.

"Threshold time" or "threshold" is the least durationof application in seconds required to produce a completehyperemic ring having a width equal to the surface ofthe plastic ring. Applications lasting less than "thresholdtime" produced no visible hyperemia or a patchy incom-plete area of hyperemia which was either narrower orbroader than the ring itself. The end point is undeniablysubjective and its estimation requires certain practice, butwith experience, and under constant conditions, readingscan be duplicated within plus or minus 20 per cent overperiods of several hours. This subjective element wasfinally reduced to a minimum by having one observermake readings without knowing the exact duration ofthe preceding occlusion, the latter being recorded by asecond observer. The juxtaposition of normal skin justinside and outside the ring of hyperemia made compari-sons simpler, more quantitative and more rapid than waspossible with the earlier method of Lewis and Grant (1,9), in which the color of one forearm had to be com-pared with that of the opposite forearm.

"Clearing time" is defined (7) as the time, in seconds,for complete disappearance of that reactive hyperemiawhich has been produced by an occlusion of thresholdduration. Repeated readings of clearing time over shortperiods usually agreed within plus or minus 25 per cent,but occasionally varied more Widely. For this reason itwas found impossible to attribute as much significance tosingle estimations of clearing time as to single deter-minations of threshold.

Uniform lighting, with minimum heating, was obtainedby using either (a) large 40-watt "Daylight" fluorescentbulbs at a distance to illuminate the whole forearm or (b)two small 4-watt bulbs, 5 inches long, one on each sideof the forearm under reflectors.

Environmental temperature was kept constant in mostobservations to within + 0.50 C. by using a constant tem-perature room. Skin temperatures were measured bymeans of iron-constantan silver-soldered thermal junc-tions. The thermal junctions were at first applied underadhesive tape, which covered the junction, but later aspringy celluloid mounting was found more satisfactorybecause the adhesive tape then covered only the wiresleading to the junctions while the junctions themselvesrested against the skin without any covering.

187

W. F. GREENWOOD,A. C. BARGER, J. R. DIPALMA, J. STOKES, III, AND L. H. SMITH

Venous pressure was elevate(of a wide (15 cm.) pneumaticbag long enough to encircle tInstantaneous inflation was a!pneumatic cuff to a large re!brought to the desired pressvenous pressure in several instof venous pressure and pressur

OBSERVAT]

I. Comparison of gross reacand Grant, [9] ), with loemia (DiPalma et al., [a

Lewis and Grant (9) o'the circulation to the entiimore minutes producedwhich persisted, after relefor a period of one-half to tof the occlusion. Thus ociproduced a reactive hypeivisually for 40 to 65 secgraphically for about 25 secthat for both brief and prcvisible redness of the skinsensitive indicator of persicperemia than the plethysmof total forearm volume, wsels of both muscle and skit

e1 14 Aug. 1946Subject- L.H.S.

S Room Temp. - 21C

2 1000z

z 500

o 100

50.= 50 /0a

w_1 5 10

d in the forearm by means Figure 1 shows that, in localized reactive hypere-cuff, containing a rubber mia also, increasing the time of occlusion increased

he upper arm completely. the duration of the local hyperemic response.ssured by connecting the With the arm at or below heart level reactive hy-servoir of air, previouslysure. Direct readings of peremia was absent until the time of occlusion was:ances verified the equality increased to 5 seconds, which was therefore thee in the pneumatic cuff. "threshold" in this instance. Above this threshold

visible reddening of the skin lasted from two toIONS eight times as long as the preceding occlusion.

ltive hyperemia (Lewris This prolonged effect of local occlusion by pres-?calized reactive hyper- sure of the ring can be ascribed to several factors.7]) (1) Because normal and hyperemic skin are ad-

bserved that occluding jacent to each other the contrast afforded by there forearm for one or ring of hyperemia is more accurate than com-a reactive hyperemia parison of one forearm with the other. (2) Thease of the circulation, ring not only arrests blood flow but, through ex-two-thirds the duration ternal pressure, also evacuates blood from theclusion for one minute minute vessel whereas the inflation of a cuff onremia which persisted the upper arm, as done by Lewis and Grant (9),bonds , and plethysmo- leaves within all the minute vessels a certain.onds. It is interesting amount of oxygenated blood and hence, for a)longed occlusions, the given time of occlusion, produces less hypoxiaappeared to be a more than does the weighted ring. Of far less impor-sting mild reactive hy- tance, but still conceivably contributory, may belographic measurement (3) arrest of diffusion of atmospheric oxygenrhich included the ves- through the skin (Goldschmidt and McGlone,n. [101) while compressed by the ring, and (4)-

transitory increase of vasoconstrictor tone due topain produced when an occluding cuff is used(Abramson et al., [11]).

The relative accuracy of long and short appli-cations of the ring under several experimental con-ditions showed that the briefer and repeated de-terminations of "threshold time" were more ac-curate and sensitive than the longer applications,e.g., 5 or 10 minutes. The latter, in fact, produceddepressions in the skin which made accurate read-ings more difficult. Hence for the remaining stud-ies only threshold values were determined. Theclose relation between duration of occlusion andduration of reactive hyperemia showed, however,that this local response is essentially similar to

,, ,mmt , ,1a mmiii that described by Lewis and Grant (9) following500500 1000 the release of an occluding cuff on the upper arm.

FIG. 1. LOGARITHMIC PLOT SHOWINGRELATION BE-TWEEN DURATION OF OCCLUSION AND DURATION OF

REAcTIVE HYPEREMIA, IN ONE SUBJECTSimilar relation was observed in 48 experiments on

three subjects at room temperatures from 170 to 370 C.and with congesting pressures from 0 to 60 cm. water.

II. Effect of environmental and cutaneous temper-atures on reactive hyperemia

Intensification of reactive hyperemia by warm-

ing the skin in a water bath was described by

1I L T

188

FACTORSAFFECTING CUTANEOUSREACTIVE HYPEREMIA

SKINTEMPERATURE-

'C-x- 20

THRESHOLD-SECONDS

*-&- 15

CLEARINGTIME -O

SECONDS--0--

ROOMTEMPERATURE

*C

5

1001

- 8O0

i- 60

40

35

30

- 25

- 20L

rRECUMBENT-

*-.*(t-X-X-

36.7'C

19 Aug. 1946 Subject: J.S. m.

-RECUMBENT -RECUMBET.

XO--** -X ,. 11

q II

4IINI

P A~~~~~~~~~~~~~~~~

26.0 C 17.8 to 15.0 C

I

60 120 180TIME - MINUTES

*- RECUMBENT---

27.00 C

I 1240 300

FIG. 2. CHART SHOWINGEFFECTS OF ENVIRONMENTALTEMPERATUREON THRESHOLD(SOLID DOTSAND LINES) AND ON CLEARING TIME (CIRCLES AND DOTTED LINES) OF REACTIVE HYPEREMIASkin temperature is shown by crosses. Subject recumbent with forearm at heart level during ob-

servations but moving about between observations. Thermal junctions in this experiment coveredwith one layer of adhesive tape.

Lewis and Grant (9). This relation was definedmore quantitatively by determining thresholds andclearing times at environmental temperaturesranging from 170 to 370 C. and skin temperaturesranging from 260 to 370 C. The results of a

typical experiment are shown in Figure 2.At zero time the subject, dressed only in shorts,

had been recumbent for 30 minutes in the con-

trolled temperature room at 36.70 C. Thresholdsand clearing times, skin temperatures and room

temperatures were recorded for 30 or more min-utes. The subject was then allowed to move

about for about 10 minutes. The room tempera-ture was lowered to 26.0° C., the subject againlay down for 30 minutes and observations were

made at this new temperature. In each experi-ment room temperatures of 370, 270, and 170 C.were used in ascending or descending order with a

final observation at 270 C. As indicated in Figure2 threshold and clearing times became progres-

sively longer as environmental temperature was re-

duced. Although observations on three male sub-jects, aged 22 to 33 years, yielded results entirely

similar to those in Figure 2, charting thresholdand clearing times against environmental temper-ature showed wide variations.

However, when threshold and clearing timeswere charted against skin temperature, the effectof tissue temperature on reactive hyperemia be-came much clearer as indicated in Figure 3.Though not always evident in a single subject,the average curves indicate clearly that reducingskin temperature by 50 C. from 370 to 320 C., in-creased average threshold and clearing times by50 per cent or less, whereas a like reduction of50 C., but from 320 to 270 C., increased boththreshold and clearing times three- or four-fold.Under "Discussion" reasons will be given forbelieving that at skin temperatures above 320 C.reactive hyperemia is determined almost solely byaccumulated metabolites, whereas at skin tem-peratures below 320 C. the behavior of the cu-

taneous vessels in reactive hyperemia dependsupon the balance between centrally induced vaso-

constrictor tone and the local and opposing vaso-

dilator effect of metabolites.

360R

189

qd i-40 _

190 W. F. GREENWOOD,A. C. BARGER, J. R. DIPALMA, J. STOKES, III, AND L. H. SMITH

7hRESHOLD2

80 CLEARING TIME G

60-

CLEARINGTIME

SECONDS

4Q-

0 AVERAGE

20- L i

RISub IL.S

.47 35 33 31 29 27 25

SKIN TEMPERATURE-CENTIGRADE

FIG. 3. CHART SHOWINGTHE RELATION BETWEENSKIN TEMPERATURE AND THRESHOLD (ABOVE) AND

CLEARING TIME (BELOW)

Includes observations on three subjects made on rightand left forearms independently by two observers. Thefive lines represent individual observations. The largedots and heavy lines indicate averages along both coor-

dinates of all observations falling within each interval of20 C. from 370 to 260 C.

III. Effect of increased venous pressure on re-

active hyperemia

It was also found that venous pressure hadmarked effects on both threshold and clearingtime, i.e., on the ease with which visible and per-sistent reactive hyperemia could be produced.The results of a typical experiment are shown inFigure 4. At zero time the subject had been re-

cumbent for 30 minutes, with the forearm at heartlevel. Threshold and clearing times having beenrelatively constant for 30 minutes, venous pres-sure was elevated suddenly to 40 cm. H20.Threshold fell gradually over 5 to 20 minutes toone-fourth the control value and clearing timebecame, for a few readings, three times greater,finally stabilizing at about twice the control value.

While clearing time occasionally rose brieflyto, a peak as shown to the left in Figure 4, it wasmore usually elevated merely to a plateau, asshown in the middle and to the right in Figure 4.Results observed in seven subjects are sum-marized in Table I. Elevating venous pressureto 20 cm. H2O lowered threshold in five of sevensubjects and increased clearing time in all. Ve-nous pressures of 30 or more cm. H2O reducedthreshold and raised clearing time in all subjects.On the average these effects became more con-spicuous as venous pressure increased but inindividual subjects this was not always the case(Table I).

Measurements of skin temperature demon-strated the slight cooling of the skin ordinarilyfound during venous congestion but these changeswere far too small to explain the marked changesin reactive hyperemia. A more delicate differen-tial thermopile was also used to detect changes incutaneous blood flow. Congesting pressures of 20and 30 cm. H2O reduced blood flow by a barelymeasurable amount. This reduction seemed fartoo small to explain the markedly reduced thresh-old and increased clearing time, though the actionof gradually accumulating metabolites cannot beexcluded entirely.

Subsequent observations on the effects of posi-tion and of external pressure led to the conclusionthat the appearance and duration of visible reac-tive hyperemia are greatly modified by the degree

TABLE I

Effect of venous pressure on visible reactive hyperemia

Change of threshold Change of clearing timeper cent of control per cent of control

Venous pressure20 30 40 20 30 40

cm. cm. cm. cm. cm. cm.H2O H2O H0O H2O HtO HsO

per per per per per percent cent cent cent cent cent

SubjectDiP. 0 -38 -80 +33 +50 + 16A. C. B. -44 -61 -74 +55 +110 +140A. C. B. 0 -20 -20 +50 +66 +78J. S., III -42 -39 -44 +78 +68 +43J. S., III -40 -40 -40 +67 +46 +69W. F. G. -25 -30 -40 +22 +41 +67L. H. S. -58 -43 -72 + 15 +87 +107

Average change, -30 -39 -53 +46 +67 +74per cent ofcontrol

FACTORSAFFECTING CUTANEOUSREACTIVE HYPEREMIA

CLEARING ; a Room Tmp.: 2arCTIME 6

SECONDS 40---0--- 2b.VIA, .1E 1-N X I20

15THRESHOLD

SECONDS~--' 10

5-

VENOUS 40 40 Ck WATER 30 CM. WATER 20 CM WATER 0

CONGESTION20-----~ -CM. WATER 0 30 60 90 120 150 ISO 210

TIME -MINUTES

FIG. 4. CHARTSHOWINGEFFECT OF VENOUSPRESSUREON THE THRESHOLDAND CLEARING TIME OFREACTIVE HYPEREMIA

29 Ja. 1947\~%M**THRESHOLD Subject: LKH.

30A0XL 0---O CLEARING TIME Temp 3-33.7" to 34.0C

CLEARINGTIME \I

THRESHOLDSECONDS 15 -

ARMELEVATED ARM EVATE

10 20 30 40 50 60 70 ;80TIME - MINUTES

FIG. 5. CHART SHOWINGEFFECT OF ELEVATING THE FOREARMABOVE HEART LEVELAt zero time subject was recumbent with forearm at side. Forearm elevated as indicated on

abscissa, placing test area 30 to 40 cm. above the angle of Louis. In elevated position thresholdsand clearing times were determined by means of apparatus shown by inset.

191

192 W. F. GREENWOOD,A. C. BARGER, J. R. DIPALMA, J. STOKES, III, AND L. H. SMITH

to which the subpapillary venous plexus is dis-tended prior to, and during, reactive hyperemia.

IV. Effect of elevating the forearm (and reducingvenous pressure) on visible reactive hyperemia

Whenthe volar surface of the forearm was hori-zontal at heart level or below, the occluding ringcould simply be laid on the skin. To test theeffect of lowering venous pressure by raising theforearm well above heart level, it was necessaryto mount the plastic ring on the right-angledholder shown by the inset of Figure 5.

With the forearm suspended vertically from thehandgrip "G," the right-angled mounting "M"moved freely on the axle "A." When this mount-ing rested firmly against the skin, the 500-gm.weight "W" pressed the ring "R" against the skinof the vertically placed forearm with a pressure ofabout 73 mm. Hg just as the simple weight andring did in the horizontal forearm. Two smallfluorescent lamps "L" provided uniform lightingin whatever position the forearm might be.

A typical experiment is shown in Figure 5. Atheart level, threshold was 13 to 15 seconds andclearing time averaged 22 seconds. Elevating theforearm as far as possible above heart levelraised threshold promptly and conspicuously butdid not change clearing time significantly. Con-versely, lowering the forearm to heart level re-turned threshold again to the control level. TableII summarizes the results of similar experimentson three subjects. To produce visible hyperemiain the elevated forearm required an occlusion last-

TABLE II

Effect of elevating the forearm on visible reactive hyperemia

Threshold Clearing time

Subject Forearm Forearm Forearm Forearmhori- ele- Change hori- ele- Change

zontal vated zontal vated

sec. sec. per cent sec. sec. per cent

J. S., III 11 21 +91 26 8 +8J. S., III 12 20 +67 21 24 +14L. H. S. 11 16 +45 30 23 -23L. H. S. 11 17 +55 25 24 -4L. H. S. 15 24 +60 22 20 -9W. F. G. 12 20 +67 31 25 -19W. F. G. 10 18 +80 41 26 -37

Average change, per cent +66 -10

ing 66 per cent longer than in the horizontal fore-arm. Despite this longer occlusion, however, theclearing time was not significantly changed; i.e.,the hyperemia remained visible for the usual pe-riod of 20 to 40 seconds in both positions.Changes in skin temperature were again tooslight to explain the observed changes in thresh-old.

V. Effect of external pressure on reactive hyper-emia

The changes in visible reactive hyperemia pro-duced by venous congestion and change of posi-tion suggested that the state of the subpapillaryvenous plexus, i.e., whether distended or collapsed,influences the intensity of skin color in reactivehyperemia as it does normal skin color (Lewis,[12]). Hence external pressure was used to col-lapse the subpapillary venous plexus while re-active hyperemia was induced.

The forearm, supported at heart level, was in-serted into a transparent celluloid chamber througha thin rubber diaphragm which fitted the forarmsnugly but did not congest it. While pressureon the skin was elevated to the desired level (20,40, or 60 cm. H20) the weighted ring could be ap-plied to, and removed from, the skin by hangingit from a rod which entered the distal end of thechamber through a flexible rubber stopper. Thetime of occlusion being varied, threshold and clear-ing times were observed through the transparentcelluloid.

A typical observation is shown in Figure 6.Long rest periods were interpolated at intervalsmerely to avoid the discomfort which developedwhen the forearm was immobilized at heart levelin the chamber for periods exceeding 45 minutes.Increasing the external pressure on the skin andits blood vessels increased threshold but did notchange clearing time. Table III summarizes theresults of three observations on different subjects.External pressures of 20, 40 and 60 cm. H20 in-creased threshold by 53, 78 and 129 per cent, re-spectively, whereas changes in clearing time wereirregular and not significant. Skin temperatureswere measured throughout; changes were toosmall to affect threshold. It appears that visiblereactive hyperemia is more difficult to elicit bothwhen external pressure on the skin is increased

FACTORSAFFECTING CUTANEOUSREACTIVE HYPEREMIA

TRESHOLD1CcSECONDS

7-

6

20 9k0TLAIME IS\TIME15- lc~~~~~~~~~~~~>oo-cJ"

SECONDS--e - 10o REST 0 REST

70 MII 125 MIREXTERNAL 60 40 CM H20 I

H

PRU$SURE 40 20 CM. H20CM. H20 c '

0 10 20 30 40 110 120 130 140 IS0 275 285 295 305 315TIME - MINUTES

Subpet L.RS. - 13 Nov 1946

FIG. 6. CHARTSHOWINGEFFECT OF EXTERNALPRESSUREON THRESHOLDAND CLEARING TIMES

and when venous pressure is reduced somewhat byraising the forearm (Figure 5 and Table II).Decreased filling of the cutaneous subpapillary ve-nous plexus is common to these two proceduresand reduces markedly the visibility of the hyper-emia which follows very brief arterial occlusion.

VI. Effect of epinephrine iontophoresis on re-active hyperemiaThe disproportionately increased threshold ob-

served when room and skin temperatures werereduced (Figure 3) suggested that vasoconstric-tor tone interfered with the dilatation otherwise

TABLE III

Effect of external pressure on reactive hyperemia

Change in threshold Change in clearing timePressure, cm. of

water20 40 60 20 40 60

per per per per per percent cent cent cent cent cent

SubjectW.uF.G. +30 +109 +86 +26 +14 +62L. H. S. +50 +82 +150 -23 -4 -11J. S., III +80 +44 + 150 +24 -12 +15

Average +53 +78 +129 +9 0 +22per cent

produced by metabolites. This could not be con-cluded definitely, however, because of the con-comitant reduction of metabolism in the cooledskin. To produce an increase in the tone of theminute vessels uncomplicated by other factors,epinephrine hydrochloride was introduced into theskin by iontophoresis while reactive hyperemiawas tested repeatedly.

Figure 7 shows the effect of introducing 1:10,-000 epinephrine hydrochloride for 10 minutes froma filter paper electrode 40 sq. cm. in area at 250microamperes (62 microamperes per sq. cm.).Spotty blanching appeared at the anode and itwas impossible to obtain a threshold reactive hy-peremia even though circulation was stopped for2 minutes, or six times the control threshold of18 seconds. Reactive hyperemia was detectedfirst about 11 minutes after the end of iontophore-sis and then it required 2 minutes' occlusion.Clearing times were correspondingly prolonged.Reactive hyperemia returned to normal about 50minutes after the end of iontophoresis. Resultssimilar in every way to Figure 7 were obtainedin three subjects.

In a larger series of subjects the effects oflower concentrations of epinephrine were studied

I193

194 W. F. GREENWOOD,A. C. BARGER, J. R. DIPALMA, J. STOKES, III, AND L. H. SMITH

12

10l

THRESHOLDSECONDS

0

e

6

CLEARINGTIME

SECONDS--o0-

41

2

-10 10 20 30

TIMIE - IN*UTES

FIG. 7. CHARTSHOWINGINCREASEOF THRESHOLDAND CLEARING TIME PRODUCEDBY PRIOR

IONTOPHORESISOF EPINEPHRINE

as shown in Table IV. Iontophoresis was herelimited to 30 seconds with current strength of 36microamperes per sq. cm.4 Even though the cur-rent was lower and the duration of iontophoresiswas briefer, 1: 10,000 epinephrine elevated thresh-old in all subjects by an average of over 200 per

TABLE IV

Effect of epinephrine iontophoresis using 1:10,000to 1:1,000,000 solutions

Num- Total Nmeof Average AverageConcentra- ber num- Numer owexperi- increase increase

tion of of ber of ments showing in ,iincrease df Ihehn cernepinephrine sub- experi- threshold t clteimejects meats od ie

per cent per cent

1: 10,000 9 19 19 (100 per cent) 259 > 87t1:50,000 1 1 19 16 (84 per cent) 171 > 69t1:100,000 11 21 17 percente) 92 151:500,000 9 12 7 (58 per cent) 54 171:1,000,000 5 5 1 (20 percent) 5 0

* The per cent increase was calculated by dividing thesum of the increases by the total number of experiments.Thus with 1:1,000,000 epinephrine, one subject of the fiveshowed a rise of 25 per cent, the others none. The averagerise was 5 per cent.

t Actual value greater than recorded because proceduredid not always allow time for reading full clearing time.

4 These observations were made by J. R. DiPalma atthe Long Island College of Medicine.

cent. A significant effect was observed with con-

centrations down to 1: 500,000. With these lowerconcentrations, however, considerable variabilitywas observed in different subjects and also in thesame subject from day to day, presumably owingto unequal penetration of epinephrine through theskin.

Control observations showed that the simplepassage of current through the skin via electrodessoaked in distilled water or 0.9 per cent NaClsolution either had no effect on threshold or, byproducing redness of the skin (13), made accuratereadings impossible. Nevertheless, epinephrinein sufficient strength always produced blanchingand elevated both threshold and clearing times.It seems certain that these changes were due tothe constrictor action of epinephrine which re-

duced the ability of the minute vessels to respondnormally by dilatation to the metabolites ac-

cumulated when circulation was occluded briefly.

DISCUSSION

The close relation between duration of occlusionand duration of visible redness (Figure 1) indi-

*UNDER t JONTOPHORESISUNDER

THRESHOLD 1:10.000 EPINEPHRIN250 Microsmp.

0 \ area- 40 cm

0 \ Svbject J.S.m37 Not 1946

0~~~~~UNDER

: THRESHOLD

0

!O -

!0 'tMOTTLED BLANCHING

l ~~~ATANODE RkANCHINGEU~~~l~~ALMOSTGONE-

60 7040 50

FACTORSAFFECTING CUTANEOUSREACTIVE HYPEREMIA

cates that the reactive hyperemia produced bylocal compression of the skin resembles the moregeneralized reactive hyperemia produced by Lewisand Grant (9) when circulation to the whole fore-arm was occluded by means of a pneumatic cuffon the arm. Both appear to be due to the localaccumulation of metabolites but the greater sensi-tivity of localized reactive hyperemia made it pos-sible to identify secondary factors which enhanceor diminish the visible response.

The temperature of the skin is known to affectthe degree of vasodilatation produced by arrestingthe circulation for a given time. Lewis and Grant(9) observed, in a limb at 360 C., that plethysmo-graphically recognizable reactive hyperemia oc-curred after occlusions as brief as 5 seconds. Atlower temperatures they found longer occlusionswere necessary but no specific times were stated.Local reactive hyperemia responds in a similarmanner to changes in temperature. Thus whenskin temperature was 370 C. the average threshold(Figure 3) was only 6 seconds; at 270 C. thresh-old was about 30 seconds, a five-fold increase fora difference of 100 C. Average clearing time,i.e., the time required for disappearance of theflush, also increased five-fold when the skin wascooled 100 C.

This change was not uniform, however, through-out the whole range of 270 to 370 C. From 370to 320 C. the average rate of change was low,amounting to a doubling of threshold or clearingtime for a lowering of skin temperature by 10° C.From 320 C. to 270 C. the average rate of changewas much greater, i.e., at the rate of a five- toeight-fold change for a change of 100 C. in skintemperature.

As Lewis and Grant (9) mention, the effect oftissue temperature on reactive hyperemia suggestsof itself that dilatation depends on the metabolicrate of the tissue. A rise of 100 C. usually in-creases the rate of metabolic processes two- orthree-fold. For extremities sympathectomized sixmonths earlier, Freeman (14) found that bloodflow plotted against bath temperature by the Ar-rhenius equation yielded a straight line. The slopeof this line indicates a 2.5-fold change of bloodflow for a temperature difference of 100 C. Inlocal reactive hyperemia, threshold and clearing

time also showed changes of this order when skintemperature was above 320 C.

Below 320 C., however, the rate of change inthreshold and clearing time with change of tem-perature became much greater. In these observa-tions skin temperatures at the critical point, ap-proximately 32° C., corresponded to an averageair temperature of 250 C. Both these tempera-tures agree remarkably well with those at whichFerris et al. (15) observed an abrupt increase ofblood flow in the hand, apparently due to a freeingof the cutaneous vessels from vasoconstrictor im-pulses when conservation of heat was no longerrequired by the thermoregulatory mechanism.On this basis it is suggested that the slow increasein threshold, as skin temperature fell from 37° to32° C., can be explained by a slower accumulationof metabolites. The more rapid increase ofthreshold as skin temperature fell from 320 to 270C. was then probably due (a) to continued slow-ing of metabolite accumulation, and in addition(b) to increasing vasoconstrictor tone. The lat-ter, by resisting vasodilatation, required a largertotal accumulation of metabolites, and hence alonger occlusion time or threshold to produce avisible reactive hyperemia, as well as a longer pe-riod of hyperemia, i.e., clearing time, to removethose metabolites.

Venous pressure proved to be another ex-tremely important modifying factor. When theforearm was kept at heart level, increasing venouspressure (Figure 4) reduced threshold and pro-longed the clearing time. Dependency of the fore-arm had the same general effect. On the con-trary, elevating the forearm (Figure 5) increasedthreshold time definitely above that observed atheart level but had little effect on clearing time.The changes were too great to explain, on thebasis of change in temperature, tone of minutevessels or those small changes in blood flow thatmild venous congestion or change in positionmight produce.

Skin color is largely determined by the amount,and the oxygenation, of the blood in the subpapil-lary venous plexus (12). Thus the depth of skincolor of a whole extremity is less when the ex-tremity is held above heart level than when ithangs dependent. An elevation of venous pressurecan presumably affect the visibility of a given

195

196 W. F. GREENWOOD,A. C. BARGER, J. R. DIPALMA, J. STOKES, III, AND L. H. SMITH

hyperemia in at least two ways: (1) By increas-ing internal pressure in the subpapillary venousplexus, it may make those vessels more easilydilatable by smaller accumulations of vasodilatormetabolites and hence reduce the duration of oc-clusion (or threshold) necessary to produce avisible hyperemia. (2) By widening passively thevessels which comprise the subpapillary venousplexus, an increased venous pressure may makea given hyperemia more easily visible because in-crements of inrushing arterial blood remain in agiven area of skin in greater amount and for alonger time and so change skin color more dis-tinctly. Other things remaining constant bothfactors would not only tend to decrease thresholdbut also to prolong clearing time.

Elevating the forearm, by lowering venous pres-sure, should act in the opposite direction, i.e., in-crease threshold because internal tension is lessand because greater arterial inflow into the col-lapsed plexus would be required to produce avisible hyperemia. A similar prolongation ofclearing time need not occur, however, because thesubpapillary venous plexus tends to empty itselfrapidly when the extremity is elevated. The con-verse also appears to hold. When the subpapil-lary venous plexus was collapsed by applying ex-ternal pressure to the forearm, threshold roseapparently because external pressure made dilata-tion more difficult as well as less easily visible.Clearing time did not change, however, and theeffect was similar to that observed when the fore-arm was simply elevated. In this connection itis noteworthy that as the forearm is progressivelyelevated, venous pressure does not fall to zero butto a plateau between 2 and 5 cm. H20 (16, 17).Correspondingly, the changes in threshold pro-duced by elevating the forearm were limited andsmaller than those that could be produced by ex-ternal pressure. Though clearing time was in-creased by venous congestion, both elevation andexternal pressure had no significant effect. Fromthis it seems probable that small changes in venouspressure modified the visibility of cutaneous re-active hyperemia by mechanical effects on the sub-papillary venous plexus rather than by changes ofarterial blood flow.

The effect of increased tone of the minute ves-sels, while suggested by the studies on tempera-ture, was demonstrated more clearly by epineph-

rine iontophoresis (Figure 7). Temperature,venous pressure and position being constant, epi-nephrine increased both threshold and clearingtime, the former more conspicuously. Theseeffects were very marked as long as visible blanch-ing persisted, but in slighter degree persisted be-yond the period of gross blanching.

Reactive hyperemia is obviously not a simplereaction. Though fundamentally due to the ac-cumulation of vasodilator metabolites, the visibleredness of normal skin can be affected secondarilyby several other factors. Among these are (a)the temperature of the skin which determines therate at which metabolites accumulate during an oc-clusion of the circulation; (b) venous pressure andposition of the extremity which modify the effectof a given occlusion by mechanical effects on thesubpapillary venous plexus and thereby on thevisibility of a given hyperemia; and (c) the tone ofthe minute vessels, either of neurogenic origin, asin cold, or of local chemical origin as in epineph-rine iontophoresis. Because local reactive hyper-emia is affected markedly by modifying vasculartone, it can be used to detect cutaneous vasocon-striction, providing skin temperature and venouspressure in the forearm are known to be constant.The results observed with this method during ex-hausting exercise and other circulatory stressesare reported in another paper (6).

SUMMARY

The factors affecting cutaneous reactive hyper-emia in man were studied semiquantitatively bymeans of a previously described method in whichblood flow in the skin was stopped locally by ap-plying a weighted ring to the volar surface of theforearm. The end points used were (a) the dura-tion of occlusion required to produce a clearly vis-ible ring of hyperemia (threshold) and (b) thetime required for skin color to return to normal(clearing time).

Lowering of tissue temperature produced amoderate increase of threshold and clearing timebetween 370 and 32° C. and a very conspicuousincrease of both between 320 and 270 C. Reasonsare given for ascribing the former to the actionof metabolites predominantly, and the latter toheightened vasoconstrictor tone acting againstthe dilator effect of metabolites.

FACTORSAFFECTING CUTANEOUSREACTIVE HYPEREMIA

Increasing venous pressure by congestion or bydependency of the forearm lowered threshold andincreased clearing time. Elevation of the forearmor application of pressure to the surface of theforearm increased threshold but did not affectclearing time. It appears that these factors act-by their mechanical effects on the subpapillaryvenous plexus and consequently on the visibilityof a given increase of arterial blood flow.

Iontophoresis of epinephrine, by increasing thetone of the minute vessels, increased both thresh-old and clearing time conspicuously.

If venous pressure and skin temperature are

kept constant local reactive hyperemia can beused to detect rapid changes in the tone of theminute vessels of the skin in man.

ACKNOWLEDGMENT

The authors are indebted to Dr. Eugene M. Landis forhelp and criticism throughout the planning, execution anddescription of these studies.

BIBLIOGRAPHY

1. Pickering, G. W., On the clinical recognition ofstructural disease of the peripheral vessels. Brit.M. J., 1933, 2, 1106.

2. DiPalma, J. R., Muss, J., and Foster, F. I., A reac-

tive hyperemia ring test in the study, evaluation,and prognosis of pedal lesions caused by arterio-sclerosis obliterans and arterial embolism. Am.Heart J., 1942, 24, 345.

3. DiPalma, J. R., The circulation in the skin in theshock syndrome; comparison of simple prognosticfeatures of clinical value. J. A. M. A., 1943, 123,684.

4. Herzog, F., Messung der reactiven Erwarmung derHaut zur Funktionsprufung der Arteriolen. Klin.Wschnschr., 1941, 20, 20.

5. von Marsovsky, P., tPber die Funktion der Arteriolenbei dekompensierten Herzkrankung. Ztschr. f.Kreislaufforsch., 1942, 34, 446.

6. Barger, A. C., Greenwood W. F., DiPalma, J. R.,Stokes, J., and Smith, L H. To be published.

7. DiPalma, J. R., Reynolds, S. M. R., and Foster, F. I.,Quantitative measurement of reactive hyperemia inthe human skin; individual and seasonal variations.Am. Heart J., 1942, 23, 377.

8. McLennan, C. E., McLennan, M. T., and Landis,E. M., The effect of external pressure on thevascular volume of the forearm and its relation tocapillary blood pressure and venous pressure. J.Clin. Invest., 1942, 21, 319.

9. Lewis, T., and Grant, R., Reactive hyperemia in man.Heart, 1925, 12, 73.

10. Goldschmidt, S., and McGlone, B., Oxygen absorp-tion through the skin. Effect upon the vascularreactions to stasis and histamine. Proc. Soc.Exper. Biol. & Med., 1932, 29, 827.

11. Abramson, D. L., Katzenstein, K. H., and Ferris,E. B., Jr., Observations on reactive hyperemia invarious portions of the extremities. Am. Heart J.,1941, 22, 329.

12. Lewis, T., Blood Vessels of Human Skin and TheirResponses. Shaw & Sons, London, 1927.

13. Ebbecke, U., tYber electrische Hautreizung. Pfluger'sArch. f. d. ges. Physiologie, 1922, 195, 300.

14. Freeman, N. E., The effect of temperature on therate of blood flow in the normal and in the sympa-thectomized hand. Am. J. Physiol., 1935, 113, 384.

15. Ferris, B. G., Jr., Forster, R. E., II, Pillion, E. L.,and Christensen, W. R., Control of peripheral bloodflow; responses in the human hand when extremi-ties are warmed. Am. J. Physiol., 1947, 150, 304.

16. Carrier, E. B., and Rehberg, P. B., Capillary andvenous pressure in man. Skandinav. Arch. f.Physiol., 1923, 44, 20.

17. Ryder, H. W., Molle, W. E., and Ferris, E. B., Jr.,The influence of the collapsibility of veins onvenous pressure, including new procedure for meas-uring tissue pressure. J. Qlin. Invest., 1944, 23,333.

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