Thorax (1972), 27, 75. Pulmonary capillary blood volume in women: normal values and he effec of oral conracepives ANTHONY SEATON' Deparmen of Medicine, Wes Virginia Universiy Pulmonary capillary blood volume (V0) was deermined in 30 young women, 14 of whom were aking oral conracepives. Duplicae esimaes of V, in he 16 women no aking conracepives showed a significan increase in he second half of he mensrual cycle. Formulae for predicion of V. in women were derived for he firs and second halves of he cycle. V, was shown o be of he same order in women aking conracepives conaining oesrogen and progesogen as in hose in he premensrual phase of he cycle. Possible causes of hese findings and heir relevance o he diagnosis of pulmonary hromboembolic disease are discussed. Oral conracepives appear o have many differen acions on he vascular sysem. On he one hand, hey may cause vasodilaaion (Goodrich and Wood, 1964) and an increase in blood volume (Walers and Lim, 19) while, on he oher, hey may conribue o inravascular coagulaion (Dugdale and Masi, 19; Inman, Vessey, Weserholm, and Engelund, 1970) and endareriis (Irey, Manion, and Taylor, 1970). In he invesigaion of oblieraive disease of he pulmonary vascular bed i has been suggesed ha esimaion of he pulmonary capillary blood volume (Va) may be a helpful diagnosic ool (Nadel e al., 1966). The presen sudy was planned o deermine he normal values for V. in females, and o find if oral conracepive herapy alers hese values. METHODS Thiry women, aged beween 18 and 35 years, were sudied. All were non-smokers or smoked fewer han five cigarees per day. Foureen of he subjecs were aking oral conracepives (oesrogen plus progesogen) a he ime of sudy. The oher 16 were sudied a wo separae imes in he mensrual cyclebeween 7 and 10 days afer and again beweeii 2 and 4 days before he onse of mensruaion. In addiion, nine normal men were each sudied on wo occasions in order o deermine he relaive error of he echniques. The physical characerisics of he subjecs and deails of conracepive herapy are given in Tables I and II. The echniques used were based on hose of McNeill, Rankin, and Forser (1958) using he formula lpresen addrcss: Sully Hospial, Penarh, Glamorgan F 1 /DI= 1/Dm + I OV, derived by Roughon and Forser (1957), where DL=ransfer facor of he lung for carbon monoxide, Dm=diffusing capaciy of he pulmonary membrane, and 0= he reacion rae of haemoglobin wih carbon monoxide in viro. Duplicae deerminaions of DL were made a hree differen alveolar oxygen ensions, using he mehod of Ogilvie, Forser, Blakemore, and Moron (1957) excep ha neon raher han helium was used in he gas mixure. For he low oxygen measuremens, a gas conaining 0.40 carbon monoxide, 0.4% neon, and 21 % oxygen in nirogen was used. For he high oxygen measuremens 0.4% carbon monoxide and 75 0.4 h neon in oxygen was used. The subjecs were sudied in he siing posiion, smokers no being esed unil a leas hree hours afer heir las cigaree. Two single breah manoeuvres were carried ou using he low oxygen gas. High oxygen gas was hen subsiued and he subjecs carried ou wo furher single breah manoeuvres. Finally, wo more measuremens of DL were made using he high oxygen gas afer he subjecs had breahed 100% oxygen for one o wo minues. In all cases care was aken o preven a Valsalva manoeuvre and a leas five minues were allowed o pass beween each es. Neon and carbon monoxide in he gas samples were analysed by a Beckman gas chromaograph and oxygen ension was measured wih an I.L. elecrode. The subjecs' oal lung capaciies were measured in a consan volume body plehysmograph (DuBois e al., 1956) and residual volume was obained by subracion of vial capaciy afer boh volumes had been correced o S.T.P.D. CALCULATIONS Transfer facor was calculaed from he formula of Ogilvie e al. (1957). The reacion rae of carbon monoxide wih haemoglobin, 0, was obained from he formula 1/0=0 33+0'0057 P,o2,
76 where P,o2 is he oxygen ension in he pulmonary capillary. The derivaion of is based on he work of Roughon and Forser (1957) assuming a value for X (he raio of permeabiliy o carbon monoxide of he membrane of he red cell o is inerior) of 25. The pulmonary capillary oxygen ension was esimaed from he expired alveolar oxygen ension (Pco2) from 300 he formula P(o2=(P,o2+5) 301- (McNeill e Di,X 1-23 al., 1958). A formula for regression of 1 /DL on 1/0 was calculaed using he mehod of leas squares. The slope of his line represens 1/V, and he inercep gives he reciprocal of he diffusing capaciy of he pulmonary membrane, Dm. STATISTICAL METHODS In order o compare he resuls in he conrols wih hose in he subjecs aking con- Subjec No. 1 2 3 4 S 6 7 8 9 10 11 12 13 14 15 16 Mean S.D. Age (yr) 18 23 29 23 21 22 28 18 21 25 31 28 19 22-9 4-1 Heigh (in) 62-5 64 63 63 67 605 67 62 65 62 70 70 65-8 3-3 Weigh (lb) (a) (b) 108 108 111 111 1 127 123 123 136 137 101 101 170 172 132 132 135 135 114 111 143 143 143 141 168 170 150 150 166 166 128 128 134-3 134-7 21-5 21-9 a=firs half of mensrual cycle; b=second nal o mensrual cycle Anhony Seaon TABLE I CONTROL SUBJECTS racepive ables, values for DL, VC and D. were divided by he subjec's oal lung capaciy. The groups were hen esed by he es for independen samples, he significan values for a he 5% level for hese daa being equal o or greaer han 2-048. To compare he resuls obained in he conrol group a he wo differen sages of he cycle, he es for paired samples was used. For hese daa he significan value of a he 500 level was equal o or greaer han 2-131. Correlaion coefficiens (r) beween DL, VC and D. and heigh, surface area and oal lung capaciy a S.T.P.D. were calculaed in he conrols a boh sages of he cycle. The values of r showing lineariy bu no a one o one relaionship fall beween 05 and 0 97. The relaive error of duplicae measuremens in he male conrols was calculaed using an analysis of he componens of variaion. (DL) (VC) Toal Lung Lung Transfer Pulmonary Capaciy Facor Capillary Blood a STPD (ml/min/mmhg) Volume (ml) (ml) (a) (b) (a) (b) 2870 5 21-3 60 6-4 2940 25 7 25 8 574 84-7 3110 26-4 229 68-8 75 6 3350 22-4 23-5 57 3 63-2 34 25 4 30 5 81 5 95 7 3440 35.4 34-7 73-4 94.7 3560 30 9 33-3 92-7 96-6 3580 26-9 29-7 74-0 72-6 3590 254 25-9 -3 76-0 36 26-6 30 7 70 3 80-3 3800 23-2 28-8 74-6 106-3 44 29-1 28-7 86-7 96-4 5050 44-4 43 5 138-9 151-7 5300 41-2 38-4 87-3 106-3 5330 41 40 42-4 1190 132-1 54 39.9 46-6 121-7 129-5 3925 30 3 31-7 81-5 95-7 881 7-7 7-7 26-3 24-9 TABLE II SUBJECTS ON ORAL CONTRACEPTIVES (Dm) Membrane Diffusing Capaciy (ml/min/mmhg) (a) (b) 30 7 30 0 45 3 36-2 42-4 32-7 37.9 37-7 36-6 44-7 68-4 56-2 46-2 50-9 50-0 502 39-8 39-5 53 0 49-6 33-4 38-9 44-2 40 3 65-6 60-5 78-7 61-2 63-2 64-1 58 6 72-1 49-6 47-8 13-8 12-3 Typeof Tme Ora Toal Lung DLm Subjec Age Heigh Weigh TCo eracp e C onracepiv Ca acy VC (ml/niin/ No. (yr) (in) (lb) Coaev oaevs aspa (mi/minmm) (m/in Therapy (yr) (ml) mmhg) (m) mmhg) 17 21 61 103 Ovulen-21 1 2790 23-4 68-0 34-5 18 25 60 152 Ovulen-21 3 3110 22-4 78-5 31-1 19 26 63 118 Enovid-E 5 3390 33 9 117-7 47 0 22 63 116 Ovral 0-6 3440 31-3 84-8 52-1 21 19 63 1 Norinyl 1 35 25-5 95-2 34-4 22 24 64 5 149 Orho-Novum 3 35 27-7 71-0 45 3 23 60 5 101 Ovral 0 5 3570 33-2 81-8 55.9 24 24 65 153 Orho Novum 4 3600 26-2 83-9 37-7 25 22 66 135 Ovulen-21 2 30 28-1 97-0 39-5 26 27 63-5 123 Ovral 0-6 3730 37-0 102 4 58-1 27 27 64 123 Orho-Novum 4 3740 31*7 93*5 48-6 28 25 66 113 Orho-Novum 2 5 3790 318 104 3 45 6 29 25 67 163 Norlesrin 2-5 4030 29-4 88-4 43-8 30 23 66-5 127 Ovulen-21 0-6 4380 36-9 103-5 57-6 Mean 23*6 63*8 128 2-2 3590 29-9 90 7 45 1 S.D. 2-6 2-2 19 1-5 377 4-6 13 9 8 85
Pulmonary capillary blood volume in women: normal values and he effec of oral conracepives 77 RESULTS The resuls in he conrol women in he wo sages of he mensrual cycle are recorded in Table I and in he women aking oral conracepives in Table II. When he values for DL, VC, and Dm in he wo sages of he cycle are compared, here is found o be a significan increase in V. in he second half of he cycle (=5 07, criical value for =2.131) while DL and Dm do no vary significanly (=163 and -1-08 respecively). Comparing he subjecs on conracepive herapy wih he conrols, he only significan difference found was in V. correced for oal lung capaciy beween he conrols during he firs half of he cycle and he subjecs on conracepives (Tables III and IV). TABLE III MEAN RESULTS IN CONTROLS AND SUBJECTS ON ORAL CONTRACEPTIVES DL Vc Dm No. Toal Lung Toal Lung Toal Lung of Capaciy Capaciy Capaciy Sub- (ml/min/mm (ml/l) (ml/min/mm jecs Hg/I) Hg/I) Mean S.D. Mean S.D. Mean S.D. Firs half of cycle 16 7 79 105 21-15 2-92 12-73 2-70 Second half of cycle 16 8 09 0-96 24-44 3-49 12-185 Subjecs on pill 14 8-32 0-97 25-30 3-44 12-53 2-02 TABLE IV VALUES-COMPARISON OF CONTROLS WITH SUBJECTS TAKING ORAL CONTRACEPTIVES Conrols Subjecs on Conrols (1s half cycle) v Oral v (2nd half cycle) Conracepives Transfer facor -1-50 -0 65 Pulmonary capillary blood volume -3-58 -0-67 Membrane diffusing capaciy 0-23 -0 47 Criical value for = i 2 048 a 5 % level of significance. From he duplicae measuremens in he male conrols, he relaive error of repeaed deerminaions was found o be 5-6% for DL, 7-3% for Ve, and 11 % for Dm (Table V). The resuls were also found o be repeaable for hree women in whom duplicae measuremens were made a he same phase of he mensrual cycle (Table VI). The relaionships beween DL, VC, Dm and heigh, surface area and oal lung capaciy were esed in he conrols a boh sages of he cycle. The values of r are given in Table VII. The bes predicor of DL, VC, and Dm a eiher sage is oal lung capaciy (a S.T.P.D.). Predicion formule TABLE V DUPLICATE DETERMINATIONS IN MALES DL Vc Dm SUbjec (ml/min.'mmhg) (ml) (ml/min/mmhg) 1 2 1 2 1 2 a 31 2 34-2 101-3 1058 45-1 52-4 b 31-6 34-5 79-5 97-7 52-8 53 1 c 32-5 39 3 122-3 114 4 44-3 59 9 d 35-4 37-6 104-0 91-5 53-7 67-1 e 40-1 39-6 175-0 165-3 48 3 52 4 f 39-3 41-2 123-5 104-0 57-8 68-9 g 43-3 43-5 122-3 140-2 68-2 63-5 h 42-3 45-1 111-5 1210-4 60-5 i 48-7 51*9 163-1 164-8 9 76-7 Relaive error 5-6% 7-3% 11 % TABLE VI DUPLICATE DETERMINATIONS IN WOMEN AT SAME STAGE OF MENSTRUAL CYCLE DL VC Dm Subjec (ml/min/mmhg) (ml) (ml/min/mmhg) F.R. 1 30 7 80-3 49-6 2 31*1 87-5 489 J.S. 1 29-9 74-0 50.0 2 26-9 72-6 50-2 M.P. 1 25-7 70-9 40-0 2 24-9 72-8 37-5 TABLE VII CORRELATION COEFFICIENTS IN CONTROL SUBJECTS Pulmonary Membrane Capillary Diffusing Transfer Facor Blood Volume Capaciy (a) (b) (a) (b) (a) (b) Toal lung capaciy 0-86 0-88 085 0-83 070 0-83 Heigh 0 50 0-58 0 70 0 75 0-22 0 43 Surface area 0-54 0-56 0 74 0 71 0-26 0-44 a= firs half of mensrual cycle. b =second half of mensrual cycle. for hese measuremens based on oal lung capaciy a S.T.P.D. (TLC) are given below: (a) Firs half of he cycle DL=7-42 TLC+±137 (r=0-86) VC=23-17 TLC-7-6 (r=0-85) Dm=10 98 TLC+6-54 (r=0 70) (b) Premensrually DL=7-64 TLC+ 1 70 (r=0-88) VC=234 TLC+3-84 (r=0-83) Dm=11-61 TLC+221 (r=083). DISCUSSION Esimaion of pulmonary capillary blood volume has been suggesed as a mehod for invesigaion
78 Anhony Seaon of occlusive disease of he small pulmonary areries and may be of paricular value in subjecs wih muliple small emboli leading o pulmonary hyperension (Nadel e al., 1966). However, he value of such a es mus depend on a knowledge of he resuls obained in normal subjecs. Alhough a number of auhors have recorded normal values for V. and Dm in heir laboraories (McNeill e al., 1958; Lewis, Lin, Noe, Komisaruk, 1958; Ross, Maddock, and Ley, 1961; Daly, Ross, and Behnke, 1963; McCredie, Lovejoy, and Yu, 1964; and Krumholz, 1966), here has been lile agreemen on he normal range. In paricular, values for Dm have varied very widely in differen series and even in differen paiens in he same series. However, mos auhors find he echniques show good repeaabiliy in he same individual. Bucci, Cook, and Barrie (1961) produced predicion formuke for V. and Dm based on oal lung capaciy, heigh and surface area, finding no essenial difference beween male and female subjecs. The resuls repored in he presen paper show reasonable repeaabiliy in he male subjecs and in he hree female subjecs in whom he es was repeaed a he same ime in he cycle. The values recorded for DL and V, are somewha higher han in oher series. This may be relaed o he use of he body plehysmograph for measuring residual volume, as his does give higher values han helium or neon mehods (Reichel, 19), alhough Daly e al. (1963) used a similar echnique wihou geing such high values. An increase in plasma volume in he lueal phase of he mensrual cycle has been suspeced on he basis of he fall in haemaocri and gain in weigh ha may be found a his ime (Danforh, Boyer, and Graff, 1946). A he same ime in he cycle, venous one is decreased (McCausland, Holmes, and Troer, 1963), his effec also occurring during pregnancy and in subjecs on oesrogen-progesogen conracepives (Goodrich and Wood, 1964). Recenly, i has been demonsraed ha subjecs show an increase in weigh, plasma volume, and cardiac oupu when hey sar aking hese conracepives (Walers and Lim, 19). Vascular changes during he mensrual cycle have been demonsraed direcly in he conjuncival vessels, using sli-lamp microscopy (Landesman, Douglas, Dreishpoon, and Holze, 1953). A his sie vascular dilaaion occurs in he lueal phase of he cycle, followed by increased vasomoion and hen vascular spasm immediaely premensrually. Logan (1967) noiced ha pulmonary capillary blood volume in five normal females was greaer in he second han in he firs half of he cycle, hough he difference was no saisically significan. The presen sudy shows ha here is a significan variaion in V,, hough no in DL or D., hrough he mensrual cycle. In all subjecs sudied save one, an increase in Vc occurred he week before mensruaion and his suggess ha eiher progeserone or is combinaion wih oesrogen is responsible. Confirmaion of his comes from he finding ha V. in subjecs on oesrogen-progesogen ables is also raised compared o conrols sudied in he firs half of he cycle. The increase in V. is no likely o be relaed o an increase in plasma volume, as deerminaion of V. depends on he amoun of haemoglobin raher han plasma in he pulmonary capillaries. In general, here is a sligh drop in haemaocri premensrually (Danforh e al., 1946) which, if i affeced he esimaion of V. a all, would cause an arefacually low resul. A more likely explanaion of he changes observed is ha progeserone, eiher alone or wih oesrogen, causes disension of he pulmonary capillary bed, possibly secondary o an acion on he arerioles or venules similar o ha observed a oher sies (Landesman e al., 1953; McCausland e al., 1963; and Goodrich and Wood, 1964). I is no easy o undersand why hese hormones should have a dual acion on respiraion, acing boh as a respiraory simulan (Goodland, Reynolds, McCoord,andPommerenke, 1953; Doring, Loeschcke, and Ochwad, 1950) and as a pulmonary vasodilaor. Wheher his second effec may conribue o he hypocapnia of pregnancy and of he lueal phase by reducing he physiological dead space is a maer for speculaion. From a pracical poin of view, if a sae of pulmonary vasodilaaion exiss in subjecs on oral conracepives, areriovenous shuns may become opened and cause zones of apparen underperfusion on lung scans which migh be aribued o vascular occlusion. In such circumsances deerminaion of V. should be helpful. If V, is found o be higher han he prediced normal for females in he firs half of he cycle, significan occlusion of he pulmonary vascular bed is unlikely o be presen. On he oher hand, a value for Vc lower han his prediced normal should arouse a srong suspicion of muliple pulmonary emboli. The auhor hanks Mr. Andrew Jacobs and Mr. Rober Reger for he saisical analysis.
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