Effect of Oxygen on Pulmonary Vascular Resistance in

Patients with Pulmonary HypertensionAssociated with Atrial Septal Defect

By H. J. C. SWAN, M.B., M.R.C.P., PH.D., HOWARD B. BURCHELL, M.D., PH.D.,AND EARL H. WOOD, M.D., PH.D.

The present studies are concerned with the effect of high oxygen inhalation on patientswith atrial septal defects. The problem of the amount of pulmonary vascular resistanceand the relative contribution of irreversible structural changes and vascular tone may beof important prognostic significance in evaluation of such patients for cardiac surgery.

L OWERED concentrations of oxygen inthe inspired air have been shown to pro-

duce constriction of pulmonary vessels in thecat' 2 and in human subjects.3 4 The reactionof canine pulmonary vessels to hypoxia hasbeen studied by many workers, whose consen-sus appears to favor a constrictor response.However, its variability has caused Lanari-Zubiaur and Hamilton5 to question its biologicsignificance. Conversely, concentrations ofoxygen approaching 100 per cent in inspiredair have been shown to reduce total pulmo-nary resistance in normal man6 and in pa-tients with ventricular septal defect7 and inpatients with patent ductus arteriosus.8The present report concerns patients with

pulmonary hypertension associated with atrialseptal defect, who, in general, fall in an olderage group than do patients with ventricularseptal defect and who may differ from themin the factors underlying the development ofpulmonary hypertension. It will be shownthat in these patients with pulmonary hyper-tension and atrial septal defect, a labile com-ponent of the pulmonary vascular resistancecan usually be demonstrated whether or notthe vascular resistance is increased. Breath-ing high concentrations of oxygen usuallyproduces a decrease in the calculated pressure-flow ratio (vasomotor tone) even in older pa-tients and in those with severe organic occlu-sive changes in the pulmonary blood vessels.

From the Mayo Clinic and the Mayo Foundation,Rochester, Minn. The Mayo Foundation is a part ofthe Graduate School of the University of Minnesota.

Supported in part by research grant no. H3532 fromthe National Institutes of Health, U. S. Public HealthService.

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MATERIAL AND METHODSForty patients with atrial septal defect in whom

the pulmonary-artery systolic pressure exceeded60 mm. of mercury were studied by cardiaccatheterization at the Mayo Clinic between Janu-ary 1, 1955, and December 31, 1957. In 30 ofthese, pulmonary blood flows were determinedwhile they were breathing air and also while theywere breathing concentrations of oxygen that ap-proached 100 per cent. Seventeen of the 30 pa-tients underwent surgical correction of their de-fect, at which time the diagnosis was confirmed.An eighteenth patient was studied following anunsuccessful attempt at operative closure else-where. Of the other 12. 6 were rejected as can-didates for corrective operation on the basis ofsevere pulmonary hypertension, systemic bloodflow significantly exceeding pulmonary blood flowin all 6.' A variety of reasons kept the remaining6 patients from undergoing operation.The age of 1 patient Was less than 20 years; 7,

9, and 10 patients were in the third, fourth, andfifth decades of life, respectively; and 3 patientswere more than 50 years of age.

Seventeen of the patients breathed 95 to 100 percent oxygen via a mouthpiece with wide-bore cor-rugated rubber tubing from a large-volume (ap-proximately 45 L.) spirometer, which incorporateda recirculation pump and carbon dioxide absorberand permitted the measurement of oxygen con-sumption. Thirteen patients breathed oxygen fronta molded rubber mask strapped to the face, whichincorporated a small balloon and into which oxy-gen flowed at a rate sufficient to produce a largeoutboard leak. In this way any tendency for airto be drawn into the face-piece was minimized,and appreciable rebreathing was prevented. Thistechnic, however, did not permit the measurementof oxygen consumption.Pulmonary blood flow was determined by the

Fick principle. Oxygen consumption was deter-mined for all patients while breathing air by meas-uring the volume of gas expired over a 3-minuteinterval and determining the oxygen concentra-tion in a sample of this expired gas by the Haldane

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OXYGEN AND PULMONARY VASCULAR RESISTANCE

method. Midway during the collection of expiredair for determinations of oxygen consumption,blood samples were drawn simultaneously from thepulmonary artery and the radial artery. In allcases records of pulmonary artery and systemicartery pressures were obtained by means of strain-gage manometers at this time. The right atrialpressure was measured from a record obtainedearlier in the procedure.The oxygen breathing was started, and after a

minimal interval of 51/2 minutes (average intervalfor the group: 7 minutes) additional blood sam-ples were withdrawn from the pulmonary andradial arteries. Oxygen consumption was meas-ured in the 17 patients who breathed oxygen fromthe spirometer, and was assumed to have remainedunchanged during oxygen breathing in the others.Recordings of pressure were obtained during theperiod of collection of blood samples while thepatient was breathing 100 per cent oxygen. Thecatheter then was withdrawn to the right atrium,where a further pressure record was obtained.Blood samples were analyzed manometrically

for oxygen content by the method of Van Slykeand Neill,9 and the hemoglobin capacity for oxy-gen was determined by the method of Sendroy10as modified by Roughton and associates.11 Pul-monary blood flow (QQp, L./min.) was calculatedaccording to the formula:

02

(CI)V Cpa)in which 02 is the oxygen consumption in milli-liters per minute and the C's with subscripts indi-cate the oxygen content of pulmonary vein andpulmonary artery bloods, respectively, in milli-liters per liter. In 21 of the 30 cases the arterialoxygen saturation was less than 94 per cent whenthe patients breathed air. One patient from whoma clear history of postoperative pulmonary em-bolism was elicited was found to have a pulmonaryvein oxygen saturation of 93 per cent; but in 6other patients, 4 of whom had significant desatura-tion of systemic artery blood, the saturation ofpulmonary vein blood ranged from 97 to 99 percent. Accordingly, when these values were notmeasured, the assumption was made that the hemo-globin saturation of pulmonary venous blood was98 per cent when the patient breathed air and100 per cent when the patient breathed 99 to100 per cent oxygen, and that 0.3 and 1.8 volumesof oxygen per 100 ml. of blood were present indissolved form under the two circumstances. Thesederived values were used in the determination ofQp.The ratios of pressure to flow referred to as

total pulmonary and pulmonary vascular resist-

ances RP and RPV in dynes sec. cm.-5) were de-termined according to the formulae:

R Ppa X 1332 X 60 d

Qpin which the terms Ppa and Pla represent the meanpulmonary artery and mean left atrial pressures(mm. Hg), the mean left atrial pressure being as-sumed to equal mean right atrial pressure.

RESULTSThe oxygen consumption measured in all 30

patients while breathing air averaged 145 ml.per min. per M.2 Among the 17 in whom itwas measured while they were breathing 95to 100 per cent oxygen, it averaged 143 ml.per min. per M.2 during breathing of air and148 ml. per min. per M.2 during breathingof oxygen.During the period of breathing air and

breathing 100 per cent oxygen, respectively,the average pressures in the pulmonary cir-cuits were 90 and 81 mm. Hg systolic, 37 and34 diastolic, and 55 and 50 mean. The meanpulmonary artery pressure declined in 26cases, was unchanged in 3, and increased inonly 1 (fig. 1). This response apparently wasnot related to the initial levels of pressure.Pulmonary blood flow averaged 4.5 L. per min.per M.2 while breathing air and 5.5 L. permin. per M.2 while breathing oxygen (fig. 1).Generally, larger changes in pressure wereassociated with larger changes in blood flow(fig. 2). Thus the total pulmonary resistance,which averaged 712 dynes sec. em.-5 whilebreathing air, declined to an average of 550dynes see. cm.-5 while breathing 99 to 100 percent oxygen. The average pulmonary vascu-lar resistance declined from 635 to 500 dynessee. cm.-5 with the change of conditions (fig.3). This decline was not demonstrably re-lated to the values for either mean pulmonaryartery pressure or pulmonary blood flow thatwere recorded while the patients breathed airfig. 4). No relation between the ages of thepatients and either the absolute levels or themagnitude of the changes of resistance on

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SWAN, BURCHELL, WOOD

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30 40 50 60 70 80 1 2 3 4 5 6 7 8 9Pulmonary-artery mean pressure Pulmonary blood flow

(air) - mm. Hg (air)-L./min./1M9FIG. 1. Comparison of pulmonary artery mean pressure and pulmonary blood flow values

obtained while breathing air (abscissa) with values obtained while breathing 95 to 100 percent oxygen (ordinate). Note the fall in pressure and increase in flow under latter cir-cumstance.

breathing oxygen could be demonstrated. Theaverage systemic resistance (mean systemic ar-tery pressure divided by systemic blood flow)increased from 1,460 to 1,650 dynes sec. cm.-5during the period of oxygen breathing. Ran-dom changes of considerable magnitude wereseen in right atrial pressures of a few patients.

In 6 cases that included necropsy the statusof the pulmonary vessels was graded inde-pendently according to the severity of struc-tural changes.12 The severity of these organicvascular changes was found to have a positivecorrelation with the pulmonary-systemic re-sistance ratio recorded during breathing ofair and with that recorded during breathingof oxygen. However, in this small group ofpatients no definite correlation was found be-tween the grade of vascular disease and eitherabsolute or relative changes in pulmonaryvascular resistance on breathing oxygen.

DISCUSSIONThese data indicate that in patients with

pulmonary hypertension and atrial septal de-

fect the change from breathing air to breath-ing 100 -per cent oxygen is nearly always asso-ciated with an increase in the flow of bloodthrough the pulmonary circuit and a declinein presdure in the pulmonary artery. Further,since changes in left atrial pressure are minorand random, the increase in blood flow andreduction in pressure indicate that a declinein pulmonary vascular resistance has occurred.Therefore it appears that the pulmonary vas-cular bed in patients with atrial septal defectresponds to this stimulus in a manner similarto that of the pulmonary vasculature in pa-tients with ventricular septal defect or patentductus arteriosus and in normal subjects.Most likely the fall in resistance is due todilatation of pulmonary blood vessels alreadyopen, or to opening of channels that have beenclosed.Assumptions. Three assumptions have been

made concerning the data. First, for thecalculation of pulmonary flow it appears en-tirely reasonable to assume that among the 13patients in whom oxygen consumption was not

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OXYGEN AND PULMONARY VASCULAR RESISTANCE

determined while breathing oxygen it was notless than it had been while they were breath-iig air. Calculated with these values, thechanges in pulmonary flow were of the sameorder of magnitude as in the group of 17 fromwhom the data for both circumstances wereavailable. Since a slight increase of oxygenco01sumJption with the chanlge had been demon-stratedl in that group, the assumption of con-stalicy amiong the 13 actually tends to mini-mize the volume of their pulmonary bloodflows.

Second, in the presence of atrial septal de-fect the close similarity of pressures in the 2atria assumed in this study has been demon-strated by Dexter13 and by others. In thesepatients the differences between mean pulino-iary artery pressures and left atrial pressureswere colisi(lerable, and the defects usuallywere of large size. In only 8 of the 30, how-ever, did the pulmonary flow exceed the upperrange of normal-a fact that implies the flowacross the defect was not great in the majorityof eases under study.The final assnnl-ptioli concerns the values

uised for saturation of pulmnoinary vein blood.Desaturationi of pulmnoliarv vein blood is un-usual inl cases of atrial septal defect.1 Confir-matiomi that the significant desaturation ofsystemic artery blood seen in 21 of the 30l)atients while they were breatmitigr air wasdue to riglit-to-left sliutitimig of venons bloodwas obtained from ili(li(ator dilution curves.Inidee(l, by this technic all the remaining 9Ieatients showed evidence of right-to-leftshulnitingr, though. of milaglitudes too small tobe associated with (lesaturation of systemicartery blood, as is comIIinon in patients havingatrial septal defect without pulmonary hyper-tension.14 In only 1 patient (lid the magnitudeof the right-to-left shunt as demonstrated byrlilutioll curves appear insufficient to accountfor the desaturation of systemic artery blood;and inl this case, as muentiomied earlier, the sat-uration of pulmonary vein blood was found tobe 93 per cent. With the support of meas-nuiements of the saturation of pulmonary veinblood in 6 patients, it w-as assumed that full

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pressed as fractions of values obtained during breath-ing of air. Dashed lines indicate u11c11hanged pressure(abscissa) or flow (ordinate). A rough correlationbetween increase in flow and reduction ial pressure isIreseait.

oxygenation of pulmnonary vein blood oc -curred in all other cases; and the values foroxygen saturations of hemioglobin and theaverage quantities of dissolved oxygen, asfound in normal subjects under conditions ofbreathing air and breathing 100 per cent oxy-tren, were used in the calculations of pulmo-nary blood flow-. Such an assumption couldintroduce a systematic underestimation of pul-inionary blood flow during breathing of air,and hence might permit the estimation of anincrease of pulmonary blood flow in responseto oxygen when no such change in fact oc-curred. As outlined above, the available evi-dence makes this possibility an unlikely one,however; and independemit collaborative dataare provided by the consistent fall in pulino-

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SWAN, BURCHELL, WOOD

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FIG. 3. Decrease in pulmonary vascular resistanceon breathing 95 to 100 per cent oxygen. Note thatthis decrease occurs even in the presence of severe

elevation of pulmonary resistance.

nary artery mean pressure associated with thebreathing of 100 per cent oxygen (fig. 2).Response of the Pulmonary Blood Vessels.

The data are regarded as demonstrating a

decrease in pulmonary vascular resistance as-

sociated with the breathing of 95 to 100 per

cent oxygen in patients with pulmonary hy-pertension and atrial septal defect. Thechange in vascular resistance probably is notconfined to those patients with pulmonaryhypertension, since a decline in total pulmo-nary resistance which averaged 13 per centhas been found in 15 patients who had atrialseptal defect without pulmonary hyperten-sion.15 This response is similar to that seen

in patients having ventricular septal defectwith or without pulmonary hypertension.Further, the change in pulmonary arterypressure usually follows a similar time course,

commencing within 15 seconds of the start ofoxygen breathing and being virtually com-

pleted in 21/2 to 3 minutes, which suggeststhat the underlying mechanism is similar inboth conditions.

Vasoconstrictive Element. The significanceof the present observations lies in the demon-stration of a labile component of the pulmo-nary vascular resistance in patients with atrialseptal defect and pulmonary hypertension,which component is affected by the concentra-tion of oxygen in the inspired air. This ap-

parent ability of the caliber of the pulmonaryvessels to change implies the presence of avasoconstrictive element in the increased vas-cular resistance seen in such patients. How-ever, since similar changes in pulmonary vas-cular resistance occur in normal subjects andin patients having ventricular or atrial septaldefects without pulmonary hypertension-al-though these are more difficult to demonstratebecause of the lower absolute values for pul-monary artery pressures and pulmonary re-sistances-it is not possible to say whether thedegree of tone of the individual smooth-muscle fibers is normal or abnormal.

Studies of the effect of acetylcholine on thepulmonary circulation provide additionalevidence for the contribution of vessel toneto the pulmonary vascular resistance in thepresence of pulmonary hypertension in atrialseptal defect. Harris16 investigated 5 casesof atrial septal defect, in 3 of which pulmo-nary hypertension was severe. Injections ofacetylcholine (average dose for a larger group,2.3 mg.) produced no change in pulmonaryartery pressure. However, when Shepherd andco-workers17 studied the effect of continuousinfusion of 2 to 24 mg. per minute of acetyl-choline in 6 cases of atrial septal defect withpulmon4ry hypertension, both a fall in pul-monary artery pressure and an increase inpulmonary flow occurred. The greatest fallin resistance was observed when acetylcholinewas infused during breathing of oxygen. Mostprobably acetylcholine caused dilatation of thepulmonary blood vessels by direct local ac-tion. The mechanism whereby inspired oxy-gen acts is not known.Development of Pulmonary Hypertension

with Atrial Septal Defect. Pulmonary hyper-tension associated with atrial septal defectdiffers from the hypertension associated withventricular septal defect or patent ductus ar-teriosus in that it appears to be an acquiredcomplication, rather than an immediate hemo-dynamic consequence of-indeed an integralcomponent of the situation arising from-a communication between the pulmonaryartery and aorta or between ventricles

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OXYGEN AND PULMONARY VASCULAR RESISTANCE

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pulmonary artery mean pressure and pulmonary blood flow values obtained during breathingof air. Note absence of any relation between the response to oxygen breathing and the basiclevels of pressure and flow.

which is large enough to equalize pres-

sures between the two circuits from birth. Inour experience,18 as in that of Dexter,13 it isuncommon to find pulmonary hypertension ofthe levels discussed herein associated withatrial septal defect in patients less than 20years of age. In certain patients, however,for reasons not understood, pulmonary arterypressure increases slowly or rapidly duringearly adult life, usually with persistence of anincreased level of pulmonary blood flow. De-velopment of hypertension in the pulmonarycircuit, whether associated with increased pul-monary blood flow or not, is unlike the re-

sponse of normal pulmonary vessels thatdilate, with but a small change in pressure,when the flow through them is increased. Thisdevelopment of pulmonary hypertension inatrial septal defect with a raised pulmonaryblood flow is associated with an increase in

pulmonary vascular resistance from levels be-low the range of normal to values that equalor slightly exceed normal, with a considerableincrease in pulmonary blood flow. Study of

a relatively few patients seen over a periodof 6 to 8 years suggests that once the level ofpulmonary artery systolic pressure is signifi-cantly elevated, it may remain -virtually thesame while the progression of organic changein the pulmonary vessels is manifested onlyby a steady decline in pulmonary blood flow.Why pulmonary hypertension develops in cer-

tain patients and not in others is uncertain.Histologic studies of the small pulmonary ves-

sels of such patients have shown that once pul-monary hypertension is established a distinctmuscular media forms in the arterioles, andthe media of the muscular pulmonary arterieshypertrophies. The progression of suchchanges seems identical to that of the changesin pulmonary hypertension associated withventricular septal defect or patent ductus ar-

teriosus, and hence the similarity of the re-

sponses of these vessels to dilating influencesis not surprising.

Prognosis from the Tests. The prognosticsignificance of the change in pulmonary vas-

cular resistance is uncertain, but the follow-

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SWAN, BURCHELL,7WOOD

ing data suggest that a fall of considerablemagnitude in the pulmonary vascular resist-ance when the patient breathes oxygen indi-cates a greater likelihood of immediate sur-vival following surgical correction. Whilethe mortality among patients with uieonpli-cated atrial septal defect is small19-less thani2 per cent-the finding of pulmonary arterysystolic pressure in excess of 60 mm. Hg, orof total pulmonary resistance in excess of 50per cent of systemic resistance while breathingair, is associated with significant increase inthe rate of surgical deaths.19 Seventeen ofthe patients herein cionsidered underwent op-eration following cardiac catheterization inthis institution. Of the 4 whose ratio of pul-monary resistance to systemic resistance ex-ceeded 0.50, only 1 survived operation; of the13 with ratios of 0.50 or less, 9 survived. Of7 patients in whom the pulmonary vascularresistance during breathing of oxygen ex-ceeded 80 per cent of the value obtained whileI)reathing air, only 2 survived; but of the 10ini whom this ratio was less than 80 per cent,8 survive(l.

In slite of the absence of a correlation be-ween the histologic picture and the change inresistance on breathing oxygen, those patientsill whom the pulmonary vascular bed showsevidence for a greater lability might logicallybe expected to have a less severe degree oforganic pulmonary vascular disease. In suchpatients a more favorable long-term prognosiswith regression of vascular disease might beanticipated. However, the number of follow-up studies is not yet sufficient for solving thisaspect of the problem.

SUMMMARY

l'ul ionary blood flows, and the pressuregraldieiit across the pulmonary vascular bed,were measured in 30 eases of atrial septal de-fect in whom the pulmonary artery systolicpressure exceeded 60 mm. Hg, both while thepatielits breathed air and while they breathed93) to 100 per cent oxygen.The breathing of 95 to 100 per cent oxygen

caused an average increase in pulmonary bloodflow from 4.5 L. per min. per M.2 to 5.5 L. per

mini. per M.2 and an average reduction in pul-monary artery mean pressure from 55 to 50mm. Hg.The average calculated ratio of pressure to

flow (vascular resistance) across the lung de-elined from 635 to 500 dynes see. ell.- Thiswas interpreted to indicate dilatation of theIulmonary blood vessels.

Trhe magnittude of the clhante ini vascularresistance oii breathing 93 to 100 per cent oxy-(ren was not related to the initial level of pul-nioiary- pressure or of pulnlonary blood flow,nor to the resistanice -values determnined whenbreathiny air.

In a small group of patients for whoml histo-logic sections of the lungs lbecamie available,the chailge in resistailce ol breathing oxyrgencould not be related to tile sv(erity of thevascular disease. Those patients ill whom theI)reathinll of oxygcl(l (aaused the greater(le-('limle in resistaiie ha(l a higher ol)erative sur-vival rate.

SUMAIIA1IO IN INTLRLINGUALe fluxos de sailguille puhmnollar e le diffe-

rentias de tension trans le vasculatura pulumo-nar esseva mesurate in 30 patientes dOll defee-tos del septo atrial in qui le teilsion systolicdel arterias pulmonar eeedeva 60 mnn de Iigtallto quando illes respirava aere como etianmquanldo illes respirava inter 93 e 100 procento de oxvg(eiio.Le respiration de inter 93 e 100 pro cento

de oxygeilo causava u11 auginenlto lme(lie dclfluxo de sanlguine pulilonar de iliter 4,3 1/min/M2 a 5,5 1/min/u12 e U11 re(luctioll lllediedel tension pulmono-arterial medie de inter 3)mm de Hg e 50 mm de Hg.

le calculate )roportioll lledtli de telsio a

fluxo (= resistenitia vascular) trans le pulmnonidescendeva ab 635 a 500 dyna/see/em-5. Istoesseva interpretate conmo indication (Ie tin dila-tatioll del vasos de saritruille pulmnonar.

lie nlagllitude del alteration ill le resisteitiavascular, resultante del respiration de inter95 e 100 pro cento de oxygenio ilon esseva re-lationate al nivello illitial (dl tension p)1l11no-nar o del fluxo de sanguine pulmonar e no10al valores del resisteiltia determiniate quandoaere esseva respirate.

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In un micre gruppo de patientes ab quisectiones histologic del pulmones devenivadisponibile, le alteration del resistentia per lerespiration de oxygeno non poteva esser rela-tionate al severitate del morbo vascular. Lepatientes in qui le respiration de oxygenocausava le plus grande reduction del resisten-tia se distingueva per le plus alte procentagesde superviventia al intervention chirurgic.

REFERENCES1. VON EULER, U. S., AND LILJESTRAND, G.: Ob-

servations on the pulmonary arterial bloodpressure in the cat. Acta physiol. scandinav.12: 301, 1946.

2. DUKE, H. N.: Site of action of anoxia on thepulmonary blood vessels of the cat. J. Phys-iol. 125: 373, 1954.

3. FISHMAN, A. P., MCCLEMENT, J., HIMMEL-STEIN, A., AND COURNAND, A.: Effects ofacute anoxia on the circulation and respira-tion in patients with chronic pulmonarydisease studied during the "steady state."J. Clin. Invest. 31: 770, 1952.

4. MOTLEY, H. L., COURNAND, A., WERKO, L.,HIMMELSTEIN, A., AND DRESDALE, D.: Theinfluence of short periods of induced acuteanoxia upon pulmonary artery pressures inman. Am. J. Physiol. 150: 315,1947.

5. LANARI-ZUBLAUR, F. J., AND HAMILTON, W.F.: Effect of unilateral anoxia on pulmon-ary circulation. Circulation Research 6: 289,1958.

6. BARRATT-BOYEs, B. G., AND WOOD, E. H.:Cardiac output and related measurementsand pressure values in the right heart andassociated vessels, together with an analy-sis of the hemodynamic response to the in-halation of high oxygen mixtures in healthysubjects. J. Lab. & Clin. Med. 51: 72, 1958.

7. MARSHALL, H. W., SWAN, H. J. C., AND WOOD,E. H.: Effect of breathing oxygen on pul-monary artery pressure and pulmonary vas-cular resistance in patients with ventricularseptal defect. Unpublished data.

8. BURCHELL, H. B., SWAN, H. J. C., AND WOOD,E. H.: Demonstration of differential effectson pulmonary and systemic arterial pressureby variation in oxygen content of inspired

air in patients with patent ductus arteriosusand pulmonary hypertension. Circulation 8:681, 1953.

9. VAN SLYKE, D. D., AND NEILL, J. M.: Deter-mination of gases in blood and other solu-tions by vacuum extraction and manometricmeasurement. J. Biol. Chem. 61: 523, 1924.

10. SENDROY, J., JR.: Manometric determination ofhemoglobin by the oxygen capacity method.J. Biol. Chem. 91: 307, 1931.

11. ROUGHTON, F. J. W., DARLING, R. C., ANDROOT, W. S.: Factors affecting determina-tion of oxygen capacity, content and pres-sure in human arterial blood. Am. J. Phys-iol. 142: 708, 1944.

12. HEATH, D., AND EDWARDS, J. E.: The pathol-ogy of hypertensive pulmonary vasculardisease: A description of six grades ofstructural changes in the pulmonary arterieswith special reference to congenital cardiacseptal defects. Circulation 18: 533, 1958.

13. DEXTER, L.: Atrial septal defect. Brit. HeartJ. 18: 209, 1956.

14. SWAN, H. J. C., BURCHELL, H. B., AND WOOD,E. H.: The presence of venoarterial shuntsin patients with interatrial communications.Circulation 10: 705, 1954.

15. WEIDMAN, W. H.: A study of hemodynamicalterations associated with atrial septal de-fect. Thesis, Graduate School, University ofMinnesota, 1956.

16. HARRIS, P.: Influence of acetyleholine on thepulmonary arterial pressure. Brit. Heart J.19: 272, 1957.

17. SHEPHERD, J. T., SEMLER, H., HELMHOLZ, H.F., AND WOOD, E. H.: The effects of infu-sions of acetylcholine on pulmonary vascu-lar resistance in patients with pulmonaryhypertension and congenital heart diseasewhile breathing air and oxygen. Unpub-lished data.

18. WEIDMAN, W. H., SWAN, H. J. C., DUSHANE,J. W., AND WOOD, E. H.: A hemodynamicstudy of atrial septal defect and associatedanomalies involving the atrial septum. J.Lab. & Clin. Med. 50: 165, 1957.

19. MCGOON, D. C., SWAN, H. J. C., BRANDEN-BURG, R. 0., CONNOLLY, D. C., AND KIRKLIN,J. W.: Atrial septal defect: Factors afect-ing the surgical mortality of operation.Circulation 19: 195, 1959.

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H. J. C. SWAN, HOWARD B. BURCHELL and EARL H. WOODHypertension Associated with Atrial Septal Defect

Effect of Oxygen on Pulmonary Vascular Resistance in Patients with Pulmonary

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1959 American Heart Association, Inc. All rights reserved.

75231is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TXCirculation

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