Effects of Acute Hypoxia on the Pulmonary Vascular

Transcription

1 Effects of Acute Hypoxi on the Pulmonry Vsculr Bed of Ptients with Acquired Hert Disese With Specil Reference to the Demonstrtion of Active Vsomotion By PAUL N. YU, M.D., GERALD GLICK, M.D., BERNARD F. SCHREINER, JR., M.D., AND GERALD W. MURPHY, M.D. Downloded from by on September 23, 218 THE EFFECTS of brething low oxygen (cute hypoxi) on the pulmonry cireultion in norml subjects nd in ptients with vrious crdiopulmonry diseses hve been reported by mny workers.'-8 In generl, during the period of cute hypoxi the pulmonry rteril pressure nd the pulmonry blood flow usully rise, while the pulmonry wedge or left tril pressure is unchnged or slightly incresed. In most instnces there is n increse in the clculted pulmonry vsculr resistnce, since the mgnitude of rise in the pulmonry rteril to left tril pressure grdient usully is proportiontely higher thn tht in the pulmonry blood flow. Bsed upon the ugmenttion in the pulmonry vsculr resistnce during cute hypoxi, it hs been generlly ssumed tht decresed lveolr oxygen tension invokes ctive constriction of the pulmonry vessels. Chnges in the vsculr resistnees, however, cn result simply from pssive distention or nrrowing ssocited with proportionl increse or decrese in both the volume of blood nd distending pressure within the vessel. Therefore, the mesurement of pulmonry vsculr resistnce lone my not necessrily reflect chnge of cliber of the vessels.9' 1 Active vsoconstriction of the pulmonry vsculr bed in mn during cute hypoxi would be more relibly demonstrted if one could From the Crdiopulmonry Lbortory, Deprtment of Medicine, University of Rochester School of Medicine nd Dentistry, nd the Medicl Clinics of Strong Memoril nd Rochester Municipl Hospitls, Rochester, New York. Supported in prt by grnts-in-id from the Ntionl Hert Institute, U. S. Public Helth Service (H 3966 C3), the Monroe County Hert Chpter, the Hochstetter Fund, nd the Ernest L. Woodwrd Fund. Circultion, Volume XXVII, April show decrese in pulmonry blood volume with n ttendnt rise in pulmonry vsculr pressures. To our knowledge, no such clinicl studies hve been reported in the literture except for our preliminry dt in five cses included in previous communiction." The purpose of this pper is to report our further observtions on the effects of cute hypoxi on the pulmonry vsculr bed nd to demonstrte the presence of ctive vsomotion of the pulmonry vessels in ptients with cquired hert disese. Methods nd Clinicl Mteril All ptients underwent right hert12 nd trnsseptl left hert ctheteriztion,13 14 with ctheter plced in the min pulmonry rtery nd nother ctheter in the left trium. The zero level for right hert pressure ws tken 6.5 enm. below the sternl ngle; for the left hert pressure, 8.5 cm. below the sternl ngle. A no.-18 Cournnd needle ws inserted into brchil rtery nd connected to cuvette densitometer.* Indietordilution curves were inscribed from the brchil rtery fter indocynine green (Crdiogreent) ws injected sequentilly into the pulmonry rtery nd the left trium, s deseribed by Milnor nd ssocites.'5 The two injections were usully ccomplished within 2-minute period, nd the order of injection ws rndomized. The smpling rte ws.7 to.8 ml. per second, nd ech curve ws inscribed on direct writing recorder.t All trcings were corrected for "ded spce" time from the rteril needle to the densitometer which ws pproximtely 2 seconds. The "centrl" blood volume is tht volume between the min pulmonry rtery nd the brchil rtery, including ll temporrily equidistnt *Obtined from Gilford Instrument Lbortories, Inc., Oberlin, Ohio. t Obtined from Hynson, Westcott nd Dunning, Ine., Bltimore, Mrylnd. t Obtined from Texs Instruments, Inc., Houston, Texs.

2 542 YU ET Al. 5 r.a AKUlAiLj D)l Ar. IIiInFY linuta I Llin / min hll'la l M2 4/ 7" /* 5' 4 PULMONARY BLOOD VOLUME (ML/M2 ),/ / / S.D.: 14.9 / / // /1 /,' / /, / */,X'~~~~@ L1J,9I 2 ~ ~ ~ ~~~ N 2- // / X' / / '~~ //, / / Downloded from by on September 23, 218 L A INJECTION rwigure 1 Vlu4es of crdic indexces derived from the PA curves re plotted ginst those drerived frorn the corresponding LA curves obtined frtom the ptients of the present series. There wvs good greement between the vllues derived from the two sets of curves, nd no systemtic error WCbS obser*ved. The solid linbe indictes identity, nd the two dotted lines repgresent the boundrie's of difference of 4-1 per cent. brnches. It ws clculted by the Stewrt-Hmilton method16 from the product of the crdic index nd the men trnsit time from pulmonry rtery to brchil rtery. CBV =CI *TM (PA -BA) where, CBV ="centrl" blood voluime (MI./M.2) CI crdic index (Ml./M.2/see.) TM (PA_-BA) = men trnsit time in seconds from PA to BA The pulmonry blood volume is the volume with-,in the pulmonry rteries, pulmonry cpillries, nd pulmonry veins. It ws clculted from the crdic index multiplied by the men trnsit time from min pulmonry rtery to left trium. PBV =CI [TM (PA-BA) -TM (LA_- BA)] where, PBV =pulmonry blood volume (MI./M.2) TM(LA_ BA) = men trnsit time in seconds from LA to BA The volume withiin the left trium, left ventricle, nd rteril components, left tril to brchil rteril volume, ws clculted s follows: LA to BA volume = CI * Tm(LA -BA) As hs be-en previously reported from this lb- loo r I I I t DETERMINATION Figure 2 Duplicte determintions of pulmoncry blood volume in series of 16 ptients. The solid line indictes identity, wheres the two dotted lines represent the boundries of difference of + 1 per cent. ortory, there ws good greement between the vlues of crdic index derived from indictordilution curves following pulmonry rteril injection nd those following left tril injection.1" In 84 determintions obtined from 4 ptients, the correltion coefficient ws high (r =.9), nd there ws no systemtic error (fig. 1). In the clcultion of blood volume, therefore, the men vlues of the crdie index derived from the pired indictor-dilution curves were used. The reproducibility of the method hs been demonstrted in nother series of 16 ptients on whom duplicte determintions of pulmonry blood volume were mde fter period of 1 to 15 minutes. The stndrd devition of the duplicte determintions ws 14.9 ml./m.2 (fig. 2). In given ptient, mesurement of pulmonry blood volume differing by 5 ml./m.2 from the control vlue ws considered significnt. In the sme series of ptients the stndrd devition of duplicte determintions of centrl blood volume ws 31.4 ml./m.2. Therefore, difference of 1 ml./m.2 or greter between the control nd experimentl vlues ws considered significnt. In the erly prt of our study the rteril blood withdrwn for indictor-dilution curves ws not re-infused into the ptients. Therefore, when multiple curves were inscribed, the totl blood loss during the procedure would be considerble. Recently, the blood hs been returned to the ptients Circultion, Volume XXVII, April 1963

3 HYPOXIA AND PULMONARY VASCULAR BED 543 Downloded from by on September 23, 218 fter inscription of ech dilution curve, nd the totl blood loss hs been miniml. As suggested by Milnor nd ssocites,15 the men distending pressure in the pulmonry vessels ws clculted by verging the men pulmonry rteril nd men left tril pressures. Since, during inhltion of 12 per cent oxygen, only miniml ltertions in the intrpleurl pressures hve been observed in mn,7' 8 the chnge in intrvsculr distending pressure my be considered resonble estimte of chnges in "trnsmurl" pressure. The rteril blood oxygen ws nlyzed by the mnometric method of Vn Slyke nd Neill.17 Eighteen ptients, 16 with vlvulr hert disese nd two with crdiomyopthy, were included in this study. Among the 16 ptients with vlvulr hert disese, eight hd predominnt ortic vlvulr lesions, nd eight hd predominnt mitrl vlvulr lesions. There were 12 men nd six women, rnging in ge from 17 to 51 yers. During the control period, while the ptients were brething room ir, pulmonry rteril, left tril, nd brchil rteril pressures nd the electrocrdiogrm were recorded simultneously. In most instnces pulmonry wedge pressure ws lso recorded either prior to or simultneously with left tril pressure. Dilution curves were inscribed fter sequentil injections of the indictor into the pulmonry rtery nd the left trium. Subsequently, rteril blood smples were obtined for gs nlysis. During the period of cute hypoxi, the ptients inhled 12 per cent oxygen in nitrogen through mouthpiece for 1 to 14 minutes, nd the minute ventiltion nd respirtory frequency were constntly monitored. Between the eighth nd twelfth minutes of inhltion of low oxygen, recording of pressures, inscription of indictor-dilution curves, nd smpling of rteril blood were repeted. In five cses simultneous pulmonry wedge nd left tril pressures were recorded. The bove protocol ws crried out in 16 ptients (cses 1 to 16). Three ptients (cses 12, 17, nd 18) were studied fter prolonged period of cute hypoxi (for t lest 16 minutes) nd fter removl of considerble mount of blood (35 ml. or more). In three ptients (cses 1, 15, nd 16) studies were mde during cute hypoxi before nd during infusion of cetyleholine into the right ventriele through the proximl lumen of double lumen ctheter, while the tip of the ctheter ws plced in the min pulmonry rtery. In ddition, second no.-18 Cournnd needle ws inserted into the left femorl rtery for continuous recording of systemic rteril pressure. During the infusion of cetyleholine the pulmonry rteril, left tril, nd femorl rteril pressures, minute ventiltion, Ci.-cultion, Volume XXVII, April 1965 nd respirtory frequency were continuously recorded. The infusion rte ws regulted t 2 to 4 mg. per minute in order to produce n pprecible reduction of the pulmonry rteril pressure without inititing cough or ffecting the femorl rteril pressure or ventiltory rte. Results The hemodynmic responses nd chnges in "centrl" blood volume nd in pulmonry blood volume during inhltion of 12 per cent oxygen by 16 ptients re summrized in tble 1. The following chnges were observed during cute hypoxi. Arteril oxygen sturtion declined significntly from control men vlue of 94 per cent to men vlue of 74 per cent (p <.1). The chnges in pulmonry vsculr pressure nd pulmonry blood volume were not directly relted to the mgnitude of decline of systemic rteril oxygen sturtion. The crdic index incresed slightly from 2.75 L./min./M.2 to 3.6 L./min./M.2. There ws significnt increse in the hert rte (p <.2), while stroke index showed no consistent chnge. The men pulmonry rteril pressure incresed 5 mm. Hg or more in 1 of 16 ptients. The increse in men pulmonry rteril pressure for the whole group ws sttisticlly highly significnt (p <.1). In generl, those ptients with n elevted resting men pulmonry rteril pressure mnifested greter rise thn those with norml resting pressures. The men left tril pressure did not chnge more thn 4 mm. Hg, except in one ptient (cse 16) who showed rise of 6 mm. Hg. In the five ptients in whom the pulmonry wedge nd left tril pressures were recorded simultneously, the difference between the two never exceeded 2 mm. Hg. In two, the pulmonry wedge pressures were slightly higher thn the left tril pressure, wheres in three the opposite ws noted. The pulmonry distending pressure incresed in 13 of 16 ptients (p <.1), with n increse of 3 mm. Hg or greter in six. In the entire series no consistent chnge ws observed in the men brchil rteril

4 544 YU ET AL. 6 ~> ^1,4.o o-1 CC CD " --I 1t- C CC C> (X 1 C- Co Cq CoCY OC]in C,-iO Oc CC G, C C C- C] C] CC CC n c C CC to V- V 1- CA m co CC r4 CC- 1-c] c OV V x cmt cq cq 1- cc LO Lo i c C] q O dq Ci Cil Vc C C r.1 cli CA CA t ci OC< - D r-q e4 1t- CC In 4C 1- 'I 1L- V 1- C CC I- 1- r- e m m,' C-: I.q CCi L- CC o H C] C i Cl.. o rc V- -t ooi (:. V IC 4 -di r- C] r--~ - CA CQ C] -- 1 co 4 C c; 6 si r c; cyi iq C l CC C] r-- r-- r- r- co dlvq C ecoc -cs -I t- toic Cv C C OC VI+ Cc 1-in 1-V C -It - CC Co O 1- o ]: C S; C C C]A 5 C] IC r- C q C;,q q,.q r CA H H H > CO Lo U r-iin CA C]i E c- 14 A I P4 't Co -tl Cl t- m O> o OI IC :S IsCD oo IC IC'~t CC CDC 1-1-V AGt C 5 U o _L C! C> H O O C] D CLI C] C - m G-. In C o O LO LOZ r--r-- r-q rq I r-- C C]V CC CLC I C] Vt CC V) t I rh r- r-- r-- r- CiCO C]C C]CC C] C]; C] m C] Ci C CQ1 to 1VD cl *1 cq ci 71 Downloded from by on September 23, 218 r-q 4v r-.4 r ce E-4 rt oi P- Z.% Ci 4sQ 1t- CD tg - Oq B~ u C.._._ o V.4; OCD C L ]>oo t- "i c t C i CAJ C1. lld IIf: Cl3 GS CA CA l LO csi (o t o CD o 1- G C; O k O O V;l GICICX OI "lcc 1>t t- -li CC c C Ii ldq- C]C] C]C] V C] CC C] CC s.4o C L O CCtCCS: 6 t!a Ci L5 6 icn O to ~ %= o~l C] Ht Vc": 1- C] ~ t- -" -If TV -i I C] *1-qG - ) CQ+ CCC m CO m ]l C] ) t- V 1t- t1 esocccv C CO CO C O Vc OeC o m. ~.~.... * 4 i i l.~ l *~ c CC CCCC CAC] C]CC 9CC 1- V Vi~ 4-i ic~ 1-CC.CC CC..* * * m 1 - PFqco ~ C] cl ;4r t-l' s1 R o ~ "4.i mc r- in t' C- t S; o CA- 1-t GJ CIG q m G3 to GCCo CJ CA G C o t- V1- O CCOt_ m co C5> O CCV mo C co Vo 1- ic] Ci c r ft,i ~ ::~C] t IC 1Cqtor O GJ V C] C] CC CC ~~ *_;@ r. u )._ >~ CD H-q U Go " CD C I I Go V- C] CC '14 IC C 1 t- - C] C "d to iq ri T4 r r" r Circultion, Volume XXVII, April 1963

5 HYPOXIA AND PULMONARY VASCULAR BED 545 H Downloded from by on September 23, 218 m cli O o ci t- 1-. It.46O LO = (X m r-- V lfc t- CA ; oc (eo fo' G ; V O r- Cl1 C'J] C l ( Cl m to C] v CO Co -'t o CO 1s ~C o ~ C] o 6( (, r x o OIc o Z) "Il e% V r-- C * C Cl~~~~~~~~l C1 C O LoO COO L-O) V CO 1 C C CO O V ~ C C- PC Ce ;.4 CeC 5+c C C, v +C1, Q C e~ O PCe s n Co S o: S * Q Ce 5i c H3 m 2 2 e;; 22 Ce4. m S o t S e Circultion, Volume XXVII, April 1963 c ) CC. o~~p d Ce~.H SVNXo~~~~~C ih c s w. Ce. Ce._ pressure. Pressure trcings nd the electrocrdiogrm recorded continuously during the period of cute hypoxi in cse 9 re illustrted in figure 3. The pulmonry vsculr resistnce incresed significntly for the whole group (p <.2), with n increse of more thn 25 per cent in seven of 16 ptients. According to our previous dt, the rnge of vrition of pulmonry vsculr resistnce for two successive determintions in series of 2 ptients ws + 25 per cent. Devition beyond this limit between the control nd experimentl periods is considered significnt.18 It is relized, however, tht when the control vlue of pulmonry vsculr resistnce is low, such chnge my well be scribed to technicl error. In ll seven ptients who developed significntly incresed pulmonry vsculr resistnce, there ws n increse in both pulmonry rteril nd pulmonry distending pressures ssocited with decresed or unchnged pulmonry blood volume. In three other ptients (cses 1, 3, nd 9), however, while rise in both pulmonry rteril nd pulmonry distending pressures ws once gin ssocited with significnt reduction in the pulmonry blood volume, the pulmonry vsculr resistnce showed either s1ight decrese or no chnge. There ws significnt decrese in the men trnsit time from the pulmonry rtery to the left trium (p <.5). Although for the whole group the " centrl " blood volume showed smll but sttisticlly significnt decrese (p <.5), only three ptients showed fll of greter thn 1 ml./m.2 The pulmonry blood volume showed significnt reduction in eight ptients, nd essentilly no chnge in the remining eight. For the whole group, however, the chnge ws sttisticlly significnt (p <.1). When the chnges in both pulmonry distending pressure nd pulmonry blood volume re tken into considertion, n increse in pulmonry distending pressure ws ccompnied by significntly decresed or unchnged pulmonry blood volume in 13 p-

6 546 YU ET AL. Downloded from by on September 23, 218 Figure 3 Continuously recorded trcings of femorl rteril (FA), left tril (LA), nd pulmonry rteril (PA) pressures nd electroccrdiogrm in cse 9. Note tht during the period of brething low oxygen there ws significnt rise in pulmonry rteril pressure despite slightly decresed femorl rteril pressure nd n unchnged left tril pressure. In this cse, during cute hypoxi, significnt decrese in the pulmonry blood volume ws observed. The rrow indictes the beginning of hypoxi. Numbers t the top represent minutes of hypoxi. Circultion, Volume XXVII, April 1965

7 HYPOXIA AND PULMONARY VASCULAR BED 547 Downloded from by on September 23, 218 g % Zz~ - O CONTROL * ACUTE HYPOXIA 5 1O PAm+ LAm Figure 4 The chnges in pulmonry distending pressure (PAm + LAm)/2 re plotted ginst those in pulmonry blood volume during inhltion of low oxygen. In 13 of 16 ptients n increse in pulmonry distending pressure ws ccompnied by 'X decresed or unchnged pulmonry blood volume. These discordnt chnges in the pressure-volume reltionship re convincing evidence of ctive vsoconstriction of the pulmonry vsculr bed. Open circles represent control vlues; blck dots represent vlues during cute hypoxi. tients (fig. 4). In one ptient (ese 15) there ws significnt decrese in pulmonry blood volume, despite no chnge in pulmonry distending pressure. In the remining two ptients (cses 2 nd 6), no significnt chnge in either pulmonry distending pressure or pulmonry blood volume ws observed. In the three ptients who received cetylcholine, the elevted pulmonry rteril pressure induced by cute hypoxi could be promptly lowered by this gent. The pulmonry rteril pressure ws significntly lower during combined cute hypoxi nd cetylcholine infusion thn during cute hypoxi lone. The reduction occurred within the first 2 minutes of infusion. When n cetylcholine infusion ws dded to hypoxi, the pulmonry blood volume incresed significntly in two ptients nd remined unchnged in the third. In one ptient (cse 1) when the cetyleho- Circultion, Volume XXVII, April C I (L /min / MV12) - 2. I. - 1 H R (bets / min ) - 9 e8 FA 1 (mm Hg) PA 4 (mm Hg) 3 L 2-1 LA 2 (mm Hg) L 1-35 PBV - 3 (mi/m2) [ 25 L 2 U * M. B. # I 31 EI rigure 5 Crdic index (CI), hert rte (HIR), femorl rteril (FA), pulmonry rteril (PA), nd left tril (LA) pressures nd pulmonry blood volume (PBV) in cse 1 during (I) control period, (II) period of cute hypoxi, nd (III) combined cute hypoxi nd cetylcholine infusion. During cute hypoxi there ws significnt rise in pulmonry rteril systolic (upper circle), distolic (lower circle), nd meen (br) pressures. A concomitnt decrese in pulmonry blood volume ws observed. When n cetylcholine infusion ws dded to hypoxi, there ws significnt decrese in pulmonry rteril pressures ssocited with n increse in pulmonry blood volume. A slight increse in both crdic index nd hert rte ws noted during cute hypoxi with or without cetylcholine infusion. There ws no pprecible chnge, however, in either femorl rteril or left tril pressure. These chnges demonstrte tht ctive vsoconstriction of the pulmonry vessels induced by cute hypoxi could be reversed by the ctive vsodiltion produced by cetylcholine. line infusion ws terminted but hypoxi continued, the pulmonry rteril pressure

8 548 YU ET AL. Downloded from by on September 23, 218 eq cx co ) C. 3-Q C. C.) C.) D P PA _ m k 4 o o IV,.1 x. CI to CC CO CO CC cc CC CC t- to * o o o q ol ec ICI1 = ll lzpc -t 6 t CD (:: ; t: 16 'I o rl Cl.. C l r>..- oodo s r n:s oocccn * o. C. C+. oic ' l m r-- r-.)> ) o o c t'-m IC ClCl- 1. ICI IC k C> C* * Cl C C t6 t Cl,- 4 cc 4CC Cl Cl m C>* S t 4 Cl H,-,- Cl Cl CNI N~ X X H o so Q +cq CO Cl C ClI CA Cl C1 Co ICD CC CC Cl CO CC r-4i = C-(= CC~ ICV GQ C1 * - cl t- t- O C *- Lo C In COOO *.tcol ṣ r1i 1- r--l 1:Ct to C oo OO - to m CD 1 r4 to C] ci 44o cici t,t-c CoC e ' *)e Do r2 O ; C._ Cd p Cl E-OC; x * Ct-It ~CCc tzc'r t 17 Cl'r-. -1 Ct ~ ~ ~ ~ ~ ~ ' * X CD o * t s s CI Cs.H v o OC; t. e 3 * C ) '4 '4igL H il , F4 o; O gin rose. No definite chnge in the brchil rteril pressure ws observed. These chnges re summrized in tble 2, nd the dt obtined from cse 1 re depicted in figure 5. In three ptients (cses 12, 17, nd 18), the inhltion of low oxygen ws continued for more thn 16 minutes, nd during the period of cute hypoxi multiple indictordilution curves were recorded with removl of more thn 35 ml. of blood in ech cse. Towrd the end of the study in these ptients, the response of the systemic rteril nd pulmonry rteril pressures ws entirely different from tht observed when the period of cute hypoxi ws less thn 15 nminutes nd loss of blood ws less thn 15 ml. There ws striking reduction in the men brchil rteril pressure, mounting to 35 mm. Hg or more in ech cse. A decrese ws lso noted in crdic index, hert rte, pulmonry rteril, nd left tril pressures. The clculted peripherl vsculr resistnce ws sinificntly decresed. The pulmonry blood volume ws reduced in two ptients nd remined unchnged in the third. The chnges in pulmonry vsculr resistnce nd in men trnsit time from the pulmonry rtery to the left trium were inconsistent. These findings re presented in tble 3. Discussion Technics employing simultneous'9 or sequentil15 injections of indictors fford the only current direct pproches to the ssessinent of blood volume chnges occurring exelusively within the lungs. Interprettion of the results must be mde with n pprecition of the potentil errors involved. These hve been reviewed in detil elsewhere.", 15, However, two points should be emphsized. First, there is the possibility of non-uniform mixing of indictor in the left trium. This my be relted to the position of the ctheter, the time of injection during the crdic cycle, the vritions in the flow rte through the left trium nd the turbulence within it, the ctul volume of the left tril chmber, the effects of mitrl insufficiency, the presence of Circultion, Volume XXVII, April 196S

9 HYPOXIA AND PULMONARY VASCULAR BED 549 Downloded from by on September 23, 218 tril rrhythmi, etc. Thus, vrible frction of the left tril volume my be included in the pulmonry blood volume. Secondly, n unvoidble potentil source of error reltes to the uneven pulmonry blood flow tht is known to occur in the lungs of ptients with mitrl vlvulr disese. It is theoreticlly possible tht s the result of poor mixing of indictor in slowly moving pools, or s the result of non-mixing in stgnnt blood pools, the estimted pulmonry blood volume my be erroneously high or low.1" 21 The results of the present study confirm previous reports by other workers nd from this lbortory tht short-term hypoxi in mn induces n increse in pulmonry rteril pressure nd pulmonry vsculr resistnce with little or no effect on pulmonry wedge, left tril, nd systemic rteril pressures. The elevted pulmonry distending pressure in the fce of decresed or unchnged pulmonry blood volume is convincing evidence of the presence of ctive constriction of the pulmonry vsculr bed, s result of ugmented tone of the pulmonry vessels. We feel tht the evlution of discordnt chnges of the pressure-volume reltionship in the pulmonry vsculr bed is fr better nd more relible index of ctive vsomotion thn the ltertion in the clculted pulmonry vsculr resistnce. This contention is supported by the dt obtined from three of our ptients (cses 1, 3, nd 9) in whom ctive vsoconstriction occurred during cute hypoxi, despite slight decrese or no chnge in clculted pulmonry vsculr resistnce. From the present study it is not certin in wht segment of the pulmonry vsculr bed ctive vsoconstriction hs occurred. As pointed out by other workers, pulmonry cpillries probbly re not contrctile vessels, since they lck musculr component.8 The bsence of pressure grdient from the pulmonry wedge position to the left trium speks strongly ginst ny significnt sphincter ction by pulmonry veins in mn Nevertheless, since pulmonry veins contin bout 53 per cent of the blood in the pulmo- cd E- o-4 O 2 c 22 t e 2 D CH m C Q) P., 8 = ;4 LO~ t- in In > 1- N c] e H m cs Cq C q LO C C '- 1'-sD ~t tc,i o CC CC '--q ~14 4 C-I 14 -q,-i C]- C] P4,- C] o 1 ~> CA "II It r- C -I 4 r r H ci C _1.1 :4 d m -: "I ; A; ro P: I' 4J( OE E D -._ Q-)._. 2. O7r 2 V P "A m CO = O' kr.oed Ce 1 Co Co r--c-q rq lo CA CI CA Z C]i 1- = LO C] q C]H cc C C" m C O es m tso o te ~c C C 1 ci (., co c ci 4 CC 2 CA2 C] c] CA C C] C] CC C] C] C in5 ~o 1 CS:O2 ) 2 C C] '-H C] ~~~1 ~1 ]CCA o/ CC 1 f \ 4-.:- ; 2 2. > r.co t II.. A- Circultion, Volume XXVII, April 1968

10 Downloded from by on September 23, nry vsculr bed,24 it is resonble to speculte tht during cute hypoxi mild contrction of the pulmonry veins my still occur with n pprecible chnge in the volume but no chnge in venous pressure. Such constriction would increse venous return to the left trium, but, in the presence of compensted hert, the venous pressure would not be expected to rise. It should be pointed out, however, tht in cttle25 nd in dogs26 hypoxi my indeed induce pressure grdient between the pulmonry wedge position nd the left trium s consequence of sphincter mechnism locted either within the pulmonry veins or t their junction with the left trium. Since the pressures in the left trium nd in the pulmonry wedge position did not chnge significntly, the bulk of the evidence obtined in the present study indictes tht cute hypoxi in these ptients produces its most pronounced effect on pressure by its ction proximl to the pulmonry rteries. The inerese in pulmonry rteril or distending pressure ws generlly most impressive in those ptients who hd pre-existing pulmonry hypertension. This ugmented chnge could not be ccounted for by ny unusul degree of incresed pulmonry blood flow. In these ptients some degree of pulmonry vsoconstriction probbly ws lredy present. During cute hypoxi ny dditionl constriction of the pulmonry rterioles would result in disproportiontely greter increse in the vsculr pressure nd resistnce thn in those ptients without pre-existing pulmonry hypertension. Utilizing indictor-dilution curves, other investigtors hve shown inconsistent chnges in " centrl" blood volume during hypoxi.3'27 However, since the volume so determined hs included blood within vrible portions of the right nd left hert, in ddition to tht in the pulmonry bed, it is conceivble tht criticl chnges in blood volume within the lungs my hve been obscured by chnges in vrious crdic chmbers or in the rteril component. Our present studies hve shown, in fct, tht YU ET AL. in severl ptients the pulmonry blood volume decresed significntly even though the " centrl" blood volume showed n increse or no pprecible chnge. In experimentl nimls some workers, using rdioisotope methods, demonstrted n increse in pulmonry blood volume during cute hypoxi Recently, mny investigtors hve reported the effects of cetylcholine on the pulmonry circultion in norml subjects nd in ptients with crdiopulmonry diseses.3' 37 It is generlly greed tht in norml subjects with incresed pulmonry rteril pressure induced by cute hypoxi nd in ptients with moderte degree of pulmonry hypertension cetyleholine does hve vsodilting effect. Our recent study of this gent in five ptients hs provided evidence tht it does, indeed, produce ctive vsodiltion of the pulmonry vessels.1" This ctive vsodiltion ws mnifested by significnt reduction in the pulmonry rteril nd pulmonry distending pressure ssocited with n increse in the pulmonry blood volume during infusion of this gent into the pulmonry circultion. The results of the present study hve confirmed the erlier studies reported by Fritts nd ssocites32 nd hve further demonstrted tht cetyleholine my counterct nd reverse vsoconstriction of the pulmonry vessels induced by cute hypoxi. When n cetyleholine infusion ws dded, we noted considerble reduction of pulmonry rteril nd pulmonry distending pressures, despite n increse or no chnge in pulmonry blood volume. These results strongly suggest tht the ugmented tone produced by hypoxi ws countercted by the ctive vsodiltion cused by cetyleholine. With prolonged hypoxi, prticulrly fter removl of considerble mount of blood, ctive vsomotion of the pulmonry vessels ws no longer demonstrble. Rther, uniform decrese in both systemic nd pulmlonry rteril pressures ws observed. This reduction ws not necessrily due to severe degree of rteril oxygen desturtion, since none of Circultion, Volume XXVII, April 1963

11 HYPOXIA AND PULMONARY VASCULAR BED 551 Downloded from by on September 23, 218 these three ptients hd sturtion of less thn 7 per cent during the inhltion of the low oxygen. Almost 2 yers go, Breroft nd Edholm38 noted similr chnges in mn nd even vsovgl-like rections during cute hypoxi combined with phlebotomy. They interpreted these chnges on the bsis of profound peripherl vsodiltion nd incresed blood flow to the skeletl muscles. In the present study we hve demonstrted decrese in systemic rteril pressure s well s in crdic index. The clculted peripherl vsculr resistnce ws reduced. Fishmn nd ssocites4 lso noted the tendency of the elevted pulmonry rteril pressure to fll towrd the initil levels in mny of their ptients s brething t low levels of oxygen ws continued. We believe, therefore, tht the ctively induced rise in pulmonry rteril pressure seen erly in the course of cute hypoxi my be superseded by fll of this pressure when the period of cute hypoxi is prolonged. The reduction in pulmonry rteril pressure is secondry to systemic hypotension, which my supervene when hypoxi is continued too long. Finlly, we wish to emphsize tht the interprettion of these dt should be restricted to ptients with ltered pulmonry circultion secondry to cquired hert disese. Although it is possible tht similr results would be obtined in subjects with no crdiopulmonry disese, ctul verifiction must wit further study.. Summry nd Conclusions The present study ws undertken to investigte the nerly simultneous chnges in pulmonry blood flow, volume, nd pressures during cute hypoxi in 18 crdic ptients. Indictor-dilution curves were inscribed from brchil rtery fter rpid sequentil injections of Crdiogreen into the min pulmonry rtery nd the left trium (trnsseptl technic). Pulmonry blood volume ws estimted from the product of crdic output nd men trnsit time from the pulmonry rtery to the left trium. The distending or "trnsmurl" pressure ws clculted by verging Circultion, Volume XXVII, April 1963 the men pulmonry rteril nd the men left tril pressures. During cute hypoxi the presence of ctive vsoconstriction ws demonstrted by n increse in the pulmonry distending pressure ssocited with decrese or no chnge in the pulmonry blood volume. The increse in the pulmonry distending pressure ws minly due to n ugmented pulmonry rteril pressure, no pprecible ltertion in the left tril pressure being noted. Acetyleholine infused into the pulmonry circultion my counterct the hypoxic vsoconstriction nd euse ctive vsodiltion, despite the continution of hypoxi. The vsodilting effects were evidenced by decrese in pulmonry distending pressure nd n increse in pulmonry blood volume. When the period of cute hypoxi ws prolonged nd considerble mount of blood ws removed, there ws uniform reduction of pressures in both systemic nd pulmonry circuits ssocited with decrese in pulmonry blood volume. These chnges were probbly due to peripherl vsodiltion, decresed venous return, nd diminished crdic output. Acknowledgment We re indebted to Dr. Arthur Dutton, Associte Professor of Rdition Biology nid Scientist (Sttistics), Atomic Energy Project, University of Rochester, for his help with the sttisticl spects of this study. We would like to thnk Miss Mry Ellen Lindsy, Miss Ann Grtiot nd Mr. Wddell Johnson for their technicl ssistnce, nd Mrs. Pul Robbins nd Mrs. Bonnie Sollie for their secretril id. References 1. MOTLEY, H. L., COURNAND, A., WERKo, L., HIMMELSTEIN, A., AND DRESDALE, D.: Influence of short periods of induced cute noxi upon pulmonry rtery pressures in mn. Am. J. Physiol. 15: 315, WESTCOTT, R. N., FOWLER, N. O., SCOTT, R. C., HAUENSTEIN, V. D., AND MCGUIRE, J., JR.: Anoxi nd pulmonry vsculr resistnce. J. Clin. Invest. 3: 957, DOYLE, J. T., WILSON, J. S., AND WARREN, J. V.: Pulmonry vsculr responses to short-time hypoxi in humn subjects. Circultion 5: 263, FISHMAN, A. P., MCCLEMENT, J., HIMMELSTEIN,

12 Downloded from by on September 23, A., AND COURNAND, A.: Effects of cute noxi on the circultion nd respirtion in ptients with chronic pulmonry disese studied during the " stedy stte. J. Clin. Invest. 31: 77, SIEBENS, A. A., SMITH, R. E., AND STOREY, C. F.: Effect of hypoxi on pulmonry vessels in mn. Am. J. Physiol. 18: 428, Yu, P. N., BEATTY, D. C., LovEjoY, F. W., JR., NYE, R. E., JR., AND Joos, H. A.: Hemodynmic effects of cute hypoxi in ptients with mitrl stenosis. Am. Hert J. 52: 683, FISHMAN, A. P., FRITTS, H. W., JR., AND COURNAND, A.: Effects of cute hypoxi nd exercise in the pulmonry circultion. Circultion 22: 24, FISHMAN. A. P.: Respirtory gses in the regultion of the pulmonry circultion. Physiol. Rev. 41: 214, DUKE, H. N.: Observtions on the effects of hypoxi on the pulmonry vsculr bed. J. Physiol. 135: 45, BURTON, A. C.: Reltion between pressure nd flow in the pulmonry bed. In Pulmonry Circultion. Ed. by W. Adms nd I. Veith. New York, Grune & Strtton, Inc., OAKLEY, C., GLICK, G., LURIA, M. N., SCHREINER, 13. F., JR., AND YU, P. N.: Some regultory mechnisms of the humn pulmonry vsculr bed. Circultion 25: 917, Yu, P. N., LOVEJOY, F. W., JR., Joos, H. A., NYE, R. E., JR., AND MCCANN, W. S.: Pulmonry circultory dynmics in ptients with pulmonry emphysem. J. Clin. Invest. 32: 13, Ross, J., JR., BRAUNWALD, E., AND MORROW, A. G.: Left hert ctheteriztion by the trnsseptl route. A description of the technic nd its pplictions. Circultion 22: 927, BROCKENBROUGH, E. C., BRAUNWALD, E., AND Ross, J., JR.: Trnsseptl left hert ctheteriztion. A review of 45 studies nd description of n improved technic. Circultion 25: 15, MILNOR, W. R., JOSE, A. D., AND MOGAFF, C. J.: Pulmonry vsculr volume, resistnce nd complince in mn. Circultion 22: 3, HAMILTON, W. F., MOORE, J. W., KINSMAN, J. M., AND SPURLING, R. G.: Studies on the circultion. Further nlysis of the injection method nd of chnges in hemodynmics under physiologicl nd pthologicl conditions. Am. J. Physiol. 99: 534, VANSLYKE, D. D., AND NEILL, J. M.: Determintion of gses in blood nd other solutions by vcuum extrction nd mnometric mesurement. J. Biol. Chem. 61: 523, YU ET AL. 18. Yu, P. N., NYE, R. E., LOVEJOY, F. W., JR., SCHREINER, B. F., JR., AND YIM, B. J. B.: The effects of intrvenous hexmethonium on pulmonry circultion in ptients with mitrl stenosis. J. Clin. Invest. 37: 194, DOCK, D. S., KRAUS, W. L., MCQUIRE, L. B., HYLAND, J. W., HAYNES, F. W., AND DEXTER, L.: The pulmonry blood volume in mn. J. Clin. Invest. 4: 317, MoRI, T. W., AND GoTT, F. S.: The centrl circulting blood volume in norml subjects nd ptients with mitrl stenosis. Am. Hert J. 61: 74, GLICK, G., SCHREINER, B. F., JR., LURIA, M. N., AND YU, P. N.: Determintion of crdic output by mens of rdioisotope dilution technic. Prog. Crdiovsc. Dis. 4: 586, BURCH, G. E., AND ROMNEY, R. B.: Functionl ntomy nd "throttle vlve" of the pulmonry veins. Am. Hert J. 47: 58, LITTLE, R. C.: Volume pressure reltionships of the pulmonry-left hert vsculr segment. Evidence for "vlvelike " closure of the pulmonry veins. Circultion Reserch 8: 594, LANDIS, E. M., AND HORTENSTINE, J. C.: Functionl significnce of venous blood pressure. Physiol. Rev. 3: 1, TSAGARIS, T. J., KUIDA, H., AND HECHT, H. H.: Evidence for pulmonry venoconstriction in Brisket disese. Fed. Proc. 21: 18, RIVERA-ESTRADA, C., SALTZMAN, P. W., SINGER, D., AND KATZ, L. N.: Action of hypoxi on pulmonry vsculture. Circultion Reserch 6: 1, FRITTS, H. W., JR., ODELL, J. E., HARRIS, P., BRAUNWALD, E., AND FISHMAN, A. P.: Effects of cute hypoxi on the volume of blood in the thorx. Circultion 22: 216, AVIADO, D. M., JR., CERLETTI, A., ALANIS, J., BULLE, P. H., AND SCHMIDT, C. F.: Effects of noxi on pressure, resistnce nd blood (P32) volume of pulmonry vessels. Am. J. Physiol. 169: 46, AVIADO, D. M.: The phrmcology of pulmonry eircultion. Phrmcol. Rev. 12: 159, HARRIS, P.: Influence of cetyleholine on the pulmonry rteril pressure. Brit. Hert J. 19: 272, WOOD, P., BESTERMAN, E. M., TOWERS, M. K., AND MCILROY, M. B.: Effect of cetyleholine on pulmonry vsculr resistnce nd left tril pressure in mitrl stenosis. Brit. Hert J. 19: 279, FRITTS, H. W., JR., HARRIS, P., CLAUSS, R. H., ODELL, J. E., AND COURNAND, A.: Effect of cetyleholine on the humn pulmonry circu- Circultion, Volume XXVII, April 1968

13 HYPOXIA AND PULMONARY VASCULAR BED 553 ltion under norml nd hypoxic conditions. 33. J. Clin. Invest. 37: 99, SODERHOLM, B.,. AND WERK6, L.: Acetylcholine nd the pulmonry circultion in mitrl vlvulr disese. Brit. Hert J. 21: 1, SHEPHERD, J. T., SEMLER, H. J., HELMHOLZ, H. P., JR., AND WOOD, E. H.: Effect of infusion of cetylcholine on pulmonry vsculr resistnce in ptients with pulmonry hypertension nd congenitl hert disese. Circultion 2: 381, CHIDSEY, C. A., FRITTs, H. W., ZOCCHE, G. P., HIMMELSTEIN, A., AND COURNAND, A.: Effect of cetylcholine on the distribution of pulmonry blood flow in chronic pulmonry emphysem. Mllttie Crdiovsculri 1: 15, STANFIELD, C. A., FINLAYSON, J. K., LUEIA, M. N., CONSTANTINE, H., FLATLEY, F. J., AND Yu, P. N.: Effects of cetylcholine on hemodynmics nd blood oxygen sturtion in mitrl stenosis. Circultion 24: 1164, BATEMAN, M., DAVIDSON, L. A. G., DONALD, K. W., AND HARRIS, P.: A comprison of the effect of cetylcholine nd 1 per cent oxygen on the pulmonry circultion of ptients with mitrl stenosis. Clin. Sc. 22: 223, BARCROFT, H., AND EDHOLM,. G.: On the vsodiltion in humn skeletl muscle during posthemorrhgic finting. J. Physiol. 14: 161, Downloded from by on September 23, 218 Giovnni Bttist Morggni, the Founder of Pthologic Antomy In deling with the rhythm of the pulse, Morggni recognized two kinds of interinittency. One kind ws of long durtion nd of serious nture, which he considered due to hypoxi; this ws the kind of disor4er with which Lncisi, ccording to his own testimony, ws fflicted. Morggni lso recognized nother type of intermittency, in which the intermission ws brief; this is illustrted by the cse of the distinguished professor of physic t Bologn, who hppened to discover tht' once in while his pulse ws intermittent. Morggni's dvice ws to tell this ptient to tke his finger off his wrist nd not to inquire too nxiously bout his condition. The dvice ws followed, nd resulted in complete recovery.-c. G. TEDESCHI, M.D. Giovnni Bttist Morggni, The Founder of Pthologic Antomy: A Biogrphic Sketch On the Occsion of the 2th Anniversry Of The Publiction Of His "De sedibus et cusis morborum per ntomen indgtis." The Boston Medicl Qurterly 12:122, Circultion, Volume XXVII, April 1963