THE inhalation of radioactive oxygen (0 ir ')

Transcription

1 Regonal Uptake of Radoactve Oxygen, Carbon Monoxde and Carbon Doxde n the Lungs of Patents wth Mtral Stenoss By C. T. DOLLERY, M.B., M.R.C.P., AND J. B. WEST, M.D. THE nhalaton of radoactve oxygen (0 r ') wth external chest countng allows the measurement of regonal ventlaton and oxygen uptake n the lung. 1 The subject nhales a measured volume of ar contanng a mnute amount of oxygen-15 and holds hs breath for 10 to 15 seconds. The ntal peak countng rate s determned by the ventlaton of the core of lung tssue between the counters, and the subsequent fall of counts durng apnea s related to the oxygen uptake. By combnng oxygen-15 wth carbon to form labeled carbon monoxde, the transfer of whch s dffuson lmted, measurements of regonal dffusng capacty per unt of lung volume can be made. 2 Oxygen-15-labeled carbon doxde, whch dffuses very rapdly, allows measurement of regonal blood flow per unt lung volume. 3 The present paper reports the results obtaned by applyng these techncs to patents wth mtral stenoss and the conclusons drawn about the regonal dstrbuton of pulmonary blood flow n ths dsease. Methods Oxygen-15 was prepared by deuteron bombardment of ntrogen molecules n the Medcal Research Councl cyclotron at Hammersmth Hosptal. The target gas, 3 per cent of oxygen n ntrogen, was crculated through the bombardment box and passed rapdly to the adjonng laboratory usng a contnuous flow system. Ths gas was dluted n a secondary system so that the fnal radoactvty was about 5 mc./l. of ar. The radoactvty was montored contnuously n a re-entrant onzaton chamber. For oxygen measurements ths gas was used unaltered, but by use of 2 furnaces all the oxygen could be converted to ether carbon monoxde or doxde as desred. Carbon monoxde was made by passng the radoactve gas from the From the Department of Medcne, Postgraduate Medcal School, Ducane Road, London, W.12, England. Receved for publcaton March 7, 19G0. Crculaton Research, Volume VIII, July I cyclotron over heated charcoal at 900 C. and removng the small proporton of carbon doxde n a sodalme absorber. Carbon doxde was made by passng the oxygen-15 over heated charcoal at 450 C, and convertng resdual monoxde to doxde by passng the mxture over copper oxde at 900 C. The completeness of chemcal converson was checked frequently usng a mass spectrometer to measure oxygen and carbon doxde and an nfra red analyzer to measure carbon monoxde. Oxygen- 15 has a half-lfe of only 2 mnutes and the maxmum radaton dose to the blood or to any part of the body for 6 breaths of 1 L. each was calculated to be less than 400 mllrads. Ths dose s comparable wth that gven to the lung by a lateral chest radograph, and s slghtly greater than the weekly dose, allowed to radaton workers. The patent was seated n a char so that the chest was n a vertcal poston, thus allowng a study of the nfluence of the gravtatonal hydrostatc pressure dfference on the crculaton at the apex and base of the lung. The counters were arranged so that 1 par was postoned anterorly and posterorly over each lung at a dfferent vertcal level on each sde. The radoactve gas was nhaled from a plastc bag attached to a respratory valve box, and after emptyng the bag wth a sngle rapd nspraton, the patent held hs breath for 10 to 15 seconds. The countng rates of the left and rght pars of counters were dsplayed on 2 pen recorders. Most measurements were made usng parallel countng, but some were made wth the counters arranged for concdence countng. Parallel measurements gave hgher countng rates wth less statstcal fluctuaton, whereas concdence countng allowed excellent spatal resoluton, but countng rates were lower and the statstcal fluctuaton greater. The countng postons were referred to the rbs and ntercostal s n the mdclavcular lne, and the left second ntercostal and the rght fourth nter were the postons most frequently used. It was necessary to avod the left fourth nter because the heart often lay wthn the countng feld and labeled blood wthn t nterfered wth the curve. Oxygen-15 s so nearly lnear that, after a background correcton, the rate could be expressed as percentage fall per second of ntal actvty. Carbon monoxde and doxde

2 DOLLERY, WEST Table 1 Mean Radoactve Oxygen and Carbon Monoxde Clearance Rates n Per Cent per Second at the Second and Fourth Intercostal Spaces n Patents wth Mtral Stenoss Patent Rato of Rato of Oxygen-15 rate rates Crbon monoxde rate rates second fourth 2nd/4th second fourth 2nd/4th ".I Pulmonary artery pressure 45/20 40/ /40 115/10 (RV) 60/? 34/12 55/35 Table 2 Mean Radoactve Oxygen and Carbon Doxde Clearance Rates n Per Cent per Second at the Second and Fourth Intercostal Spaces n Patents wth Mtral Stenoss Patent Oxygen-16 rate second fourth Rato of rates 2nd/4th were removed exponentally, and the curves from the pen recorders were replotted on a senlogarthmc graph after correcton for background radaton and radoactve decay. The slope of ths lne n per cent/second of the nstantaneous actvty has been defned as the rate for these gases. Intally, measurements were made on a mxed group of 10 patents who had mtral stenoss of varyng degrees of severty. Later, 7 addtonal patents wth severe mtral stenoss, and wth clncal and radologcal evdence of pulmonary hypertenson and rght ventrcular hypertrophy were selected for carbon doxde measurements. Results The results n tables 1 and 2 show the rates per unt volume at the second and fourth ntercostal s and the rato of the second to the fourth rates. Snce the observed rates are dependent on lung volume, the rato of rates at second and fourth nters has Carbon dox second de rate fourth : Rato of rates 2nd/4th Pulmonary artery pressure 100/45 80/30 28/15 105/70 65/30 80/40 80/45 been used for comparsons between groups. The logarthm of ths rato has been used to acheve a normal dstrbuton for statstcal analyss. In table 3 are shown the geometrc means of the rato of the rates for normal subjects and the 2 groups of patents wth mtral stenoss, and the sgnfcance of the separaton of the means for patents from normals. Radoactve Oxygen Radoactve oxygen rates were measured frst n a group of 10 patents wth mtral stenoss of varyng degrees of severty (table 1) and later n a second group of 5 patents wth severe mtral stenoss selected for the studes wth radoactve carbon doxde (table 2). In most patents, the rato of rates was hgher than the normal mean Crculaton Research, Volume VIII, July 1960

3 PULMONARY UPTAKE OP RADIOACTIVE GASES 767 NORMAL MITRAL STENOSIS NORMAL MITRAL STENOSIS COUNTING POSITION! INTERCOSTAL SPACE Fgure 1 Oxygen-15 rates at the second and fourth ntercostal s; 15 patents wth mtral stenoss compared wth ( normal subjects? fgure of ndcatng a relatvely hgher apcal blood flow n the patents wth mtral stenoss (fg. 1). The frst group of patents had a mean rato of second/fourth rates of 0.96 and the second group a mean rato of 1.38; n both groups, the dfference from the normals was statstcally sgnfcant. Hgh values of the rato of second/fourth rates were partcularly notceable among the patents wth the hghest pulmonary artery pressures. Nne patents had a hgher oxygen-15 rate at the second than the fourth nter, and of these, 6 had a pulmonary artery systolc pressure of 60 mm. Hg or hgher. Sx of the patents studed wth oxygen-15 had a rate rato of less than unty and only 1 of them had a measured pulmonary artery systolc pressure over 60 mm. Hg. Three of these patents had not had a cardac catheterzaton because a short dastolc murmur wth a late openng snap wthout clncal, radologcal or electrocardographc evdence of pulmonary hypertenson suggested that the mtral stenoss was mld. Crculaton Research, Volume VIII, July COUNTING POSITION! INTERCOSTAL SPACE Fgure 2 Carbon monoxde rate at the second and fourth ntercostal ; 10 patents wth mtral stenoss compared wth 7 normal subjects.* Radoactve Carbon Monoxde Measurements Measurements wth carbon monoxde were made only n the frst group of patents (table 1; fg. 2). The mean rato of rates n normals 2 was 0.59 and n patents 1.03 (table 3). Ths dfference s sgnfcant. Although 8 of the 10 patents had fourth rates below the mean normal, 2 5 of them had a hgher rate at the second than the mean normal for ths poston, so that the dffusng capacty of the whole lung would probably be normal. Three patents had rates at both second and fourth s below the mean normal, and n them the whole lung dffusng capacty may have been low. Radoactve Carbon Doxde Measurements When labeled carbon doxde became avalable, measurements were made n 7 patents (fg. 3), all of whom had clncal, radologcal and electrocardographc evdence of severe mtral stenoss wth pulmonary hypertenson (fgs. &A, 4, and 5). In ths group, the rato of second to fourth rates was

4 768 DOLLERY, WEST 3O- NORMAL MITRAL STENOSIS Table 3 Geometrc Means of Ratos of Second to Fourth Inter Clearance Rates for Normal Subjects and Patents wth Mtral Stenoss and Sgnfcance of Separaton of the Means for Patents from Normals < a. < o 2O- Mean Second/fourth nter rate ratos Mtral stenoss Radoactve gas Normals All grades Severe Oxygen 0.45 Carbon monoxde 0.59 Carbon doxde p< p< p< p<0.001 g COUNTING POSITION: INTERCOSTAL SPACE Fgure 3 Carbon doxde rate at the second and fourth ntercostal ; 7 patents wth mtral stenoss and severe pulmonary hypertenson compared wth 5 normal subjects.' 2.32, compared wth the normal rato of 0.30."' Ths dfference s hghly sgnfcant. All 7 patents n the severe group had had a cardac eatheterzaton, and n all except 1 the pulmonary artery pressure was hgh. The low value found n ths patent was surprsng because she was severely ncapactated; there was a strong parasternal lft and on auscultaton a close openng snap wth a rumblng murmur throughout dastole whch suggested tght mtral stenoss. Radographcally the lung felds showed basal ntersttal edema and attenuaton of the pulmonary vessels n the lower zones. These fndngs supported a dagnoss of severe mtral stenoss wth pulmonary hypertenson, and the low pressure found wth the cardac catheter was unexpected and s unexplaned. Dscusson The rate of fall of radoactvty n the feld of the counters s determned by 2 factors: the rate of transfer nto the pulmonary capllary and the rate of removal of the labeled blood from the countng feld. It s possble to set out n a formal manner the factors whch affect the removal of the radoactve gases from the alveolar gas nto the blood, 2 ' 3 but the measured rate depends upon the removal of radoactvty from the countng feld, and thus on how fast the blood leaves the lungs. If the rate of removal were slow compared wth the transfer of carbon doxde from alveolar gas to blood, there would be a plateau on the records before the downstroke. The absence of ths plateau s relable evdence of fast removal of radoactve gas from the countng feld. A further possble objecton s that although some radoactve blood leaves the countng feld very early, the rest s more gradually removed, ether because the blood drans at dfferent rates from dfferent areas of the same feld, or because the contents of the feld are gradually washed out. 3 Evdence aganst ths s that most of the curves are ntally lnear when plotted on semlogarthmc paper. They become curved when recrculaton of radoactve blood occurs after some 10 seconds. Oxygen-15 s not an deal gas for measurng flow because t has a relatvely slow uptake whch makes the measurement of the slope mprecse. The transfer of oxygen-15 from alveol to blood has been examned n detal, 1 and n general the rate s proportonal to blood flow per unt of lung volume. In normal subjects, there s a small alveolar end-capllary gradent at rest and when the dffusng capacty of the lung s reduced, the dffuson barrer may brng about an apprecable lowerng of rate. Carbon doxde does not suffer from ths dsadvantage Crculaton Research, Volume VIII, July I960

5 PULMONARY UPTAKE OF RADIOACTIVE GASES 769 EXPN- IN SPN J j r EXI s : 1 k 1 I T,... at m n Fgure 4A Chest radograph of a patent wth mtral stenoss and severe pulmonary hypertenson (pulmona-ry artery pressure 105/70 mm. Sg). as t s very dffusble and the uptake s rapd and proportonal to the blood flow per unt of lung volume.8 It may seem ncongruous that carbon doxde labeled wth oxygen-15 should be taken up rapdly n the lung, whle a net excreton of ordnary carbon doxde s takng place. The reason s that as the blood s passng along the pulmonary capllary, molecules of carbon doxde are contnually passng n both drectons across the alveolar membrane. The rate at whch carbon doxde leaves the alveolar gas depends upon ts partal pressure, whle the rate at whch t leaves the blood s proportonal to ts local tenson. Thus, the over-all transfer depends on the dfference between the partal pressure n blood and alveolar gas. Snce blood arrvng n the lungs contans no radoactve carbon doxde, any partal pressure of ths gas n the alveol wll nsure ts rapd absorpton. Snce carbon monoxde becomes frmly bound to hemoglobn, t exerts no sgnfcant "back pressure," and transfer across the alveolar membrane s lmted by the dffusng Crculaton Research, Volume VIII, July 1960 k j mm - > TIME 2 SECS. INTERVALS Fgure 4B Carbon doxde curves from the left second nter (top) and the rght fourth nter (bottom). Ordnate represents countng rate. characterstcs of the lung. Ths s also the case for the labeled carbon monoxde, so that the rate s proportonal to the dffuson per unt of lung volume. The frst group of 10 patents was studed wth both oxygen-15 and carbon monoxde so that estmates of regonal flow and dffusng characterstcs could be made. Ths group was taken at random from patents wth mtral stenoss representng all grades of severty. Drect comparson of the rates at the 2 levels shows that 4 patents had a hgher oxygen-15 at the second than at the fourth and the remanng 6 a hgher at the fourth than the second. The

6 T70 " DOLLERY, WEST MITRAL STENOSIS C I 5 O 2 INSPN. EXPN. TIME 2 SECS. INTERVALS Fgure 5 Carbon doxde curve from the left fourth n a patent wth mtral stenoss showng the secondary rse n countng rate as radoactve blood accumulates n the heart. carbon monoxde rates n the same group showed 5 patents wth hgher s at the second than the fourth, and 5 wth the reverse stuaton. Ths contrasts wth the normal second rate whch s lower than the fourth rate n the sttng poston at rest, n the rato 0.45:1 for oxygen-] 5 and 0.59:1 for labeled carbon monoxde. The lower rates near the lung apex n the vertcal chest poston n normals may be the result of gravty effect on the hydrostatc pressure, reducng perfuson. As the pulmonary artery pressure s rased n many patents wth mtral stenoss, the effect of the hydrostatc pressure nfluence would be proportonately less. Ths could account for a change towards more unform perfuson, but would not explan the apparent reversal of the normal rato n severe cases. The most marked ncrease n second rates occurred n those patents wth the hghest pulmonary artery pressures. Snce t was realzed that the oxygen slopes may be nfluenced by regonal changes n dffuson, t was decded to nvestgate a further group of patents wth severe mtral stenoss by usng labeled carbon doxde n whch the rate s faster and dependent purely on perfuson. The second group of 7 cases all showed a hgher carbon doxde rate at the second nter than at the fourth n the rato 2.32:1. Fve of these patents were also studed wth oxygen-15 and ths showed a rato of second to fourth nter rates of 1.38:1. In some patents, the reversal of the rato observed wth labeled carbon doxde was more marked than wth oxygen-15. The dfference between the rato obtaned wth the 2 gases requres further study, but may possbly depend upon reduced oxygen transfer caused by regonal changes n dffuson. Determned by the carbon doxde rate, the blood flow at the level of the second nter was up to 6 tmes hgher than at the fourth nter. Such changes n perfuson are remarkable and must depend upon ntense vasoconstrcton of the lower zone vessels or on organc narrowng, or both. Whle oxygen-15 and carbon doxde rates are dependent on regonal perfuson per unt of lung volume, the rate of carbon monoxde s a measure of the dffuson per unt of lung volume. The hgh carbon monoxde.rate at the second nter n some patents s of the same order as was found n normal subjects after exercse;2 ths suggests that the rased pulmonary artery pressure has the same effect n openng the remanng apcal capllares as does exercse n normals. In some patents, the fourth rate was low wthout an ncrease at the second. These patents may have had a low whole lung dffusng capacty, descrbed n some patents wth mtral stenoss.5 The rate measurements show that the normal dstrbuton of blood flow and dffusng propertes per unt lung volume tends to be reversed n patents wth severe mtral stenoss. Theoretcally, ths could be caused by dmnuton n the regonal blood flow or by ncreases n the regonal lung volume. There s convncng evdence, however, that regonal pulmonary vessel changes parallel the severty of mtral stenoss. Doyle et al.6 observed that arteral narrowng n patents wth mtral stenoss complcated by pulmonary hypertenson was most marked at the base and n the mdzones, whereas the upper zone arteres were often normal. Stener7 showed Avth pulcrculaton Research, Volume VIII, July 1960

7 PULMONARY UPTAKE OF RADIOACTIVE GASES 771 monary aagograms that the upper zone pulmonary vens were grossly dlated and the lower zone vens normal or narrow n patents wth mtral stenoss and very hgh pulmonary artery pressures. Harrson 8 examned lungs (post mortem) from patents wth mtral stenoss and confrmed the dlataton of the arteres n the upper zone and constrcton of those n the lower. He showed that the narrowng of the lower zone arteres was usually regular and even, although focal narrowng also occurred. Our results demonstrate that these changes n the radologcal and pathologcal appearances of the vessels are assocated wth substantal changes n the partton of blood flow. The changes n the lower zone vessels n mtral stenoss are dffcult to explan. The hydrostatc pressure dfference s small n comparson wth the hgh arteral pressure reached n severe cases, and t s dffcult to beleve that t alone can be responsble for the preponderance of vascular changes n the lower zone. Changes n the pulmonary venous pressure may also play an mportant part. Whatever the cause may be the changes are suffcent n some cases to reduce the lower zone perfuson to a fracton of the normal and ncrease t n the upper zone to values near those seen n the normal lower zone. Summary Usng radoactve oxygen (O ls ), carbon monoxde and carbon doxde wth external countng over the chest, t s possble to measure perfuson and dffuson per unt of lung volume. Patents wth mtral stenoss, partcularly those wth hgh pulmonary artery pressures, may show a hgher blood flow through the upper zone of the lung than the lower. Ths dstrbuton of blood flow s the reverse of that found n normal subjects. The observed changes n blood flow are consstent wth the radologcal and pathologcal changes n the pulmonary vascular tree n mtral stenoss. Acknowledgment We should lke to thank the staff of the M.E.G. cyclotron for the use of ther facltes, Mr. P. Buckngham for valuable techncal assstance, and Dr. P. Hugh-Jones and Professor J. McMclael, F.E.S., for nterest and support. Summaro n Interlngua Per medo del uso de radoactve oxygeno (O" 1 ) e mono- e boxydo de carbon, con contaton externe supra le thorace, l es possble mesurnr perfuson c dffuson per mtate de volumne pulmonar. Patentes con stenoss mtralpartcularmente n le presenta de alte pressones pulmonoarteralmonstra frequentemente un plus ntense fluxo do sangune n le zona superor del pulmon que n le zona nferor. Tstc dstrbuton es le contraro de lo que es ncontrate n subjectos normal. Le observate altoratones es congrue con le alteratones radologc o pathologc n le vaseulatura pulnonnr de patentes con stenoss mtral. References 1. DYSON, N. A., HUGH-JONES, P., XEWBERRY, G. 1?., SINCLAIR, J. D., AND WEST, J. B.: Studes of regonal lung functon usng radoactve oxygen. Brt. Med. J. no. 5168, 1: 231, 19G0. 2. DOLLERY, C. T., DYSON, N. A., AND SINCLAIR, J. D.: Regonal varatons n the uptake of radoactve carbon monoxde n the normal lung. J. Appl. Physol. 15: 411, WEST, J. B., AND DOLLERY, C. T.: Dstrbuton of blood flow and ventlaton-perfuson rato n the lung measured wth radoactve carbon doxde. J. Appl. Physol. 15: 405, DYSON, N. A., SINCLAIR, J. D., AND WEST, J. B.: Uptake of oxygen-15 compared wth oxygen-16 n the lung. J. Physol. 148: 17 (Proceedngs), CARROLL, D., COHN, J. E., AND BILEY, R. L.: Pulmonary functon n mtral valvular dsease: Dstrbuton and dffusng characterstcs n restng patents. J. Cln. Invest. 32: 510, DOYLE, A. E., GOODWIN, J. P., HARRISON, C. V., AND STEINER, E. E.: Pulmonary vascular patterns n pulmonary hypertenson. Brt. Heart J. 19: 353, STEINER, E. E.: Badologcal appearances of the pulmonary vessels n pulmonary hypertenson. Brt. J. Sadol. 31: 188, HARRISON, C. V.: Pathology of pulmonary vessels n pulmonary hypertenson. Brt. J. Eadol. 31: 217, Crculaton Research. Volume VIII, July I960