SEVERAL studies have suggested the possibility

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1 Relatin Between Lung Vlume and Pulmnary Vascular Resistance By DANIEL H. SIMMONS, M.D., PH.D., LEONARD M. LINDE, M.D., JOSEPH H. MILLER, M.D., AND EONALD J. O'REILLY, SEVERAL studies have suggested the pssibility f a causal relatinship between changes in lung vlume (LV) and changes in pulmnarj' vascular resistance (PVR). 1 " In general, data indicate that an increase in LV abve nrmal results in increased PVR. 1 On the ther hand, there is relatively little infrmatin n the effect f decreasing LV belw nrmal. Cletta was the first t suggest that decreased LV might als result in elevated PVR, giving a "U-shaped" curve relating resistance t LV, but his data were nt cnclusive. 2 Burtn and Patel recently presented data indicating that this relatinship held fr the saline-perfused lung f the pen-chest rabbit. 3 Simmns and Hemingway 1 bserved markedly increased PVR fllwing inductin f pneumthrax in clsedchest dgs, als cnsistent with Cletta's hypthesis. Because the effect f bth increased and decreased LV n PVR had never been investigated simultaneusly in the intact animal, the present study was undertaken. Methds Tn experiments were cnducted n mngrel dgs (. t 2.4 Kg.) anesthetized with 25 mg./kg. f sdium pentbarbital intravenusly, with small additinal dses as needed. Nrmal ventilatin was maintained with a Starling respiratin pump (psitive-pressure breathing), small dses f intravenus succinylchline chlride being given fr muscle relaxatin. The inspired gas was pure xygen t prevent hypxia and its effects n cardiac utput and pulmnary vascular Frm Wadswrth Hspital, Veterans Administratin Center, and the Departments f Physilgy, Medicine, and Pediatrics, University f Califrnia Medical Center, Ls Angeles, Califrnia. Supprted by grants frm the Ls Angeles Cunty Heart Assciatin and the American Heart Assciatin. Received fr publicatin Nvember 2, 19. M.D. resistance (PYR). The lungs were hyperinflated with a pressure f apprximately 3 em. H2O every 15 minutes, t prevent distributin abnrmalities and resultant changes in acid-base status. Pressures were measured with electrical pressure transducers frm an arbitrary zer cm. abve the dg's back. Differential pressures were determined directly, using differential transducers. Mean pressures were btained by electrical integratin. The fllwing pressures were determined directly: (1) pulmnary artery pressure (PAP), using a cardiac catheter inserted thrugh the external jugular vein; (2) left atrial r pulmnary venus pressure (LAP), using a cardiac catheter inserted thrugh the femral artery; (3) pulmnary vascular pressure gradient (PVPG = PAP-LAP), using bth cardiac catheters and a differential pressure transducer; (4) intratracheal pressure (ITP) ; (5) intrapleural pressure (IPP), using a Harvard pleural cannula inserted thrugh the furth interspace t the right f the sternum; () transpulmnary pressure (TPP = ITP-IPP) ; () distending pulmnary artery pressure (DPAP = PAP-IPP), which is the effective distending pressure r "transmural pressure" f majr pulmnary arteries; and (S) distending left atrial pressure (DLAP = LAP-IPP), the effective pressure distending the left atrium r pulmnary veins. Mean femral artery pressure (FAP) was measured with a mercury manmeter, and the experiment was discntinued if a drp f ver 25 per cent ccurred. Cardiac utput (CO) was measured by the dye-dilutin technique, using cardi-green dye and a Clsn cuvette densitmeter. Duplicate determinatins differed less than 5 per cent, n the average. Withdrawn bld was reinfused t minimize bld-vlume changes. The fllwing determinatins were made anaerbically n arterial bld: (1) ph at 3 C, with a Beckman mdel GS ph meter; (2) pco 2, calculated frm ph and CO 2 cntent (Van Slyke) by the Hendersn-Hasselbalch equatin; and (3) xygen saturatin by a standard spectrphtmetrie technique. Pulmnary vascular resistance was calculated in arbitrary units by dividing PVPG (in cm. H 2 O) by CO (in L./min./Kg.). Circulatin Research, Vlume I, March

2 4 SIMMONS, LIDE, MILLER, O'REILLY END-EPIRATORY PULMONARY VASCULAR RESISTANCE AND CARDIAC OUTPUT AT NORMAL AND DECREASEO LUNG VOLUME (EP.*I9) PVR cm.h2 l/min./kg. LUNG VOLUME CO ml./min /kg. Figure 1 Apparatus fr varying end-expiratry pressure at the utlet f the Starling respiratin pump t change the functinal residual capacity. Measurements were made at zer end-expiratry pressure (zer EEP) and at smaller and larger lung vlumes btained with negative r psitive end-expiratry pressures f 15 em. f water at the same respiratry rate and tidal vlume (fig. 1). Thirty minutes were allwed fr equilibratin after each change in EEP. The rder f measurements at zer, negative, and psitive EEP was varied in different experiments t btain an rthgnal system and eliminate effects f the supine psitin and duratin f anesthesia. Examinatin f the final data revealed n cnsistent tendency fr changes in PVR with time. Eight experiments were cnducted using all three end-expiratry pressures and lung vlumes. Tw mre experiments were cnducted in which six sets f measurements were made at alternate zer and negative EEP. One f these is graphically presented in figure 2. In evaluating the respnses, changes were calculated frm the values at zer EEP, and the significance f the changes was determined by standard statistical techniques. The change in LV r functinal residual capacity (FRC), when starting either negative r psitive EEP, was calculated by the fllwing: equatins: With zer EEP: ~ _ Tidal vl., in ec. TPP TPP ' ^ ' At negative r psitive EEP: AFRC = C (EEP. EEP 2er ). (2) HOURS Figure 2 Cmparisn f PVR and CO at nrmal and decreased lung vlumes in ne experiment. Increase in PVR and decrease in CO with time, nted here, icas nt fund in ther, similar experiments. In these equatins, (C) signifies lung cmpliance, and (TPP ex 1 ) and (TPP inbp ) signify transpulmnary pressure at the end f expiratin and inspiratin. Results The principal results are summarized in table 1 and are graphically pltted against changes in LV in figure 3. Pulmnary Vascular Resistance Of measurements f PVR at decreased LV, 12 were higher than at nrmal LV, ne was unchanged, and ne was lwer. The mean increase was 24 per cent. In bth experiments with rapid alternatin between zer and negative EEP, PVR was higher at the smaller lung vlume each f the six times it was determined (fig. 2). At increased LV, PVR increased in every case; average increase was.12 per cent. Cardiac Output "With negative EEP, CO increased in 12 f cases; the mean increase was statistically significant. CO decreased in every case at psitive EEP. Pulmnary Vascular Pressures PAP and LAP decreased significantly with negative EEP and increased significant^ Circulatin Research, Vlume I, March 191

3 LUNG VOLUME AND PULMONARY RESISTANCE 4 with psitive EEP. as ne wuld expect. Hwever, the effective distending pressure (r transmural pressure), which is the difference between abslute vascular pressure and intrapleural pressure, did nt change in the same manner. "With negative EEP, mean DPAP and DLAP bth increased, the frmer significantly. In the case f psitive EEP, there was an increase in DPAP and a slight decrease in DLAP, but neither f these changes was statisticalh- significant and therefre neither culd accunt fr the increased PVR at increased r decreased LV. The mean pressure gradient between pulmnary artery and pulmnary vein increased significantly with bth negative and psitive EEP. Functinal Residual Capacity Mean decrease in FRO with negative EEP was 32 per cent f the predicted nrmal f 25 ml./kg. ; s mean increase with psitive EEP was 5 per cent. Intratracneal Pressure Mean intratracheal pressure was 3.3 cm. H 2 O fr psitive-pressure breathing at zer EEP. With negative EEP, this decreased t -.2, and with psitive EEP it rse t Measurements were therefre made under cnditins f slight psitive-pressure breathing at zer EEP, high psitive-pressure breathing at psitive EEP, and negative-pressure breathing at negative EEP. Femral Artery Pressure There were n significant differences between FAP measured at zer and at negative EEP. On changing t psitive EEP, there was a slight drp in seven experiments and a small increase in ne. The mean change was nt statistically significant. Arterial ph Arterial ph drpped an average f. units (.2 t.1; during psitive EEP breathing and rse an average f. units (. t.12) during negative EEP in fur experiments. These changes are cnsistent with the metablic acidsis assciated with psitive-pressure breathing (unpublished b- Circulatin Retearch, Vlume I, March 191 MEAN HEMODYNAMIC CHANGES WITH ALTERED LUNG VOLUME A PVR cm.h 2 O ml./min./kg A CO ml./min./kg. -2 A DPAP cm. H 2 ADLAP cm.h 2 A GRADIENT cm. H AFRC,% Figure 3 Summary f results. Changes (&) in pulmnary vascular resistance (PVR), cardiac utput (CO), distending r transmural pulmnary artery pressure (DPAP), left ill rial pressure (DLAP), and pressure gradient frm artery t vein are pltted fr decreased, nrmal, and increased FRC. The mean per cent changes in FRC are indicated n the abscissa. The mean abslute value fr each parameter at nrmal FRC is given alng the dtted line. Significant deviatins frm zer F.EP are indicated liy slid circles. serratins f R. Y. Fs, R. II. Settlage, and D. II. Simmns). Arterial pco» Arterial pco 2 did nt change significantly, decreasing an average f 2.4 mm. Hg with psitive EEP and. mm. Hg with negative

4 4 SIMMOS, LINDE, MILLER, O'EEILLY Summary f Results (Ten Experiments)' Table 1 Mean S. E. N Mean S. E. Mean S. E. N PVR in./kg.) e! } }.9 PAP ft LAP Nrmal lung vlume (zer EEP), abslute values Change.9 ft* DPA Change with decreasedi lung vlume (negative EEP) - 1.9} +4.3} +.5} ft* DLA Grad +3.}. with increased lung vlumes (psitive EEP) +11.} +5.4} } O IPP } 11 +.} ITP } } 1.5 FRC 43 cc %}.4 + 5%} 2. *CO = cardiac utput; PAP =; pulmnary artery pressure; LAP = left atrial pressure; gradient PAP- LAP; PVR. = gradient/co; DPAP = effective distending pressure, pulmnary artery; DLAP = effective distending pressure, left atrium; IPP = intrapleural pressure; FRC = functinal residual capacity; S.E. = standard errr f mean; jst = number f measurements. \Changes in FRC stated in per cent f nrmal predicted FRC. }Change frm value at zer EEP significant (P<.5). EEP in fur experiments. This indicates that the prcedures had n effect n minute ventilatin. Arterial Oxygen Saturatin Oxygen saturatin varied between 99. and 11.2 per cent in determinatins made during the varius respiratry prcedures. Discussin Of special interest is the effect f negative and psitive EEP n PVR. With increased LV, PVR rse in each f eight experiments t almst triple the cntrl value. Of the measurements made in 1 experiments at decreased LV, PVR rse in 12, decreased in ne, and remained unchanged in ne; the mean increase, apprximately 25 per cent, was statistically significant. These data indicate that pulmnary vascular resistance increases with bth increased and decreased LV under the cnditins f these experiments. These results were nt due t decreased distending pressures f pulmnary vessels secndary t changes in pulmnary bld flw (i.e., CO) and therefre must be ascribed t changes in the gemetry f sme part f the pulmnary vasculature assciated with the change in lung vlume itself. It is pssible that neurhumral factrs may cnditin the respnse. These data indicate that the relatin between PVR and lung vlume in the intact animal is a U-shaped curve, as suggested by Cletta 2 and as fund in the pen-chest preparatins by Burtn and Patel, wh failed t cnfirm the finding fr the islated lung. 3 As previusly indicated, there is cnsiderable data frm several types f preparatins cnfirming that PVR increases as LV increases abve nrmal. Increased PVR assciated with decreased LV is als cnsistent with the changes ccurring after inductin f pneumthrax 1 and with the mai-ked and rapid drp in PAP and PVR f newbrns n taking the first breath. 9 The bserved increases in PVR culd nt be due t the mechanical effects f psitivepressure breathing r the resultant changes Circulatin Research. Vlume I, March 191

LUNG VOLUME AND PULMONARY RESISTANCE 49 in CO, since psitive-pressure breathing primarily affects the S3'stemic circulatin and has n direct effect n the pulmnary circulatin, 1 " 12 and since n

5 LUNG VOLUME AND PULMONARY RESISTANCE 49 in CO, since psitive-pressure breathing primarily affects the S3'stemic circulatin and has n direct effect n the pulmnary circulatin, 1 " 12 and since n significant changes in the large-vessel distending pressures resulted frm changes in CO. Our data indicate that the increase in PVR with decreased LV is cnsiderably less than that fllwing increased LV. Hwever, the change in LV with psitive EEP was mre than duble that with negative EEP, s that a greater change in PVR might be expected n this basis alne. Calculating the increase in PVR per unit change in LV, the effect f psitive EEP is still much greater than that f negative EEP. Part f this remaining difference ma}' be ascribed t the fact that psitive-pressure breathing was used in this study rather than spntaneus breathing. Decreased venus return and decreased flw at increased LV results in lwering f the distending pressure f pulmnary vessels and increasing f their resistance t flw. With spntaneus breathing, the respiratry effect n flw at increased LV wuld be reversed, 3 and resistance wuld therefre prbabty be lwer than ur bserved values. Increased PVR with decreased LV in this study is cnsiderably less than that nted fr a cmparable degree f lung cllapse fllwing pneumthrax, 1 prbably because f ppsite effects f the prcedures n venus return ' and cardiac utput and cnsequent ppsite effects n effective distending pressure f the pulmnary vessels. 15 The effect n PVR, independent f the artifacts f either experiment, might lie smewhere between the values bserved in this study and in the pneumthrax study. Since PVR rse with bth increased and decreased LV, even thugh distending pressures f majr pulmnary vessels were cnstant r increased, ne must ascribe the increased PVR t either: (1) decreased distending pressure f small vessels lying deep in the lung parenchyma and nt expsed t IPP; (2) decreased distensibility f pulmnary vessels, which might then have a smaller diameter in spite f increased distending Circulatin Research, Vlume I, March 19G1 < z tr VESSELS LUNG VOLUME Figure i One pssible explanatin f V-shaped curve relating PVR and LV, n the basis f knivn changes in resistance. PVR is cnsidered the sum f resistances in small vessels (increasing with increasing LV) and in large vessels (decreasing with increasing LV). pressure; r (3) a change in vessel gemetry which wuld increase the turbulence f pulmnary bld flw and thereby increase resistance. Nr is it necessary t pstulate the same ne f these mechanisms fr increased PVR at bth decreased and increased LV. There is evidence that the increased PVR at increased LV is due t a decrease in caliber f small vessels f the lung because f a decrease in their effective distending pressure. Schleier perfrmed calculatins indicating that the majr PVR is in the small vessels. 1 Irwin et al. presented cnfirming histlgical evidence 1 and demnstrated that these vessels lie in alvelar septa and are therefre expsed t alvelar pressure. One can demnstrate that fr either nrmal respiratin r psitive-pressure breathing, the transmural r distending pressure in these vessels and their diameters must decrease as the lung distends. This is brne ut by the bservatin that the vlume f bld in the smaller lung vessels decreases as LV increases. 2 1Si 19 - There is evidence fr tw mechanisms by which PVR might rise with decreased LV. First, Burtn and Patel demnstrated a change in gemetry f arteriles ("gnarliness") with lung cllapse, which appears

6 4 SIMMONS, LIDE, MILLER, O'KEILLY capable f causing increased resistance t flw in this area. 3 Secndly, Macklin 1 and Hwell, Permutt, and Prctr 19 demnstrated that the vlume f bld in the larger pulmnary vessels decreases as LV decreases belw nrmal, indicating a prbable decrease in diameter and increased resistance t flw. Bth arterilar gnarliness and large-vessel cllapse might cntribute t increased PVR at decreased LV; there are n data by which t judge their relative imprtance. If decreased diameter were the factr increasing resistance at decreased LV, a U-shaped curve f PVR might be described if ne cnsidered verall PVR as the sum f resistance in large and small vessels (fig. 4). As Burtn and Patel pinted ut, 3 increased PVR at belw-nrmal LV culd be due either t passive changes in gemetry f pulmnary vessels r t reflex increases in vasmtr tne. That the changes are passive is suggested by the effect f pneumthrax n PVR 1 and by the pen-chest data f Burtn and Patel, since their ligatin f the pulmnary artery in all prbability interrupted the nervus supply t the vessels. 3 As expected, cardiac utput decreased with psitive EEP, the usual result f increased intrathracic pressure in the anesthetized dg. The fact that CO was higher with negative EEP and negative-pressure breathing (mean intratracheal pressure = 1.5 cm. H 2 ) than at zer EEP shuld nt be takeu t indicate that negative-pressure breathing in itself increases CO. It is likely, instead, that the slight psitive-pressure breathing at zer EEP leads t reductin in CO, as cmpared with spntaneus breathing, while negative-pressure breathing has n effect n CO. 12 ' " Burtn and Patel have pinted ut tw reasns fr cnfusin in evaluating effects f varius prcedures n PVR. 3 These are: (1) the fact that PAP has been used as a measure f the driving frce f bld acrss the pulmnary circulatin, while this measure shuld in fact be pressure drp frm pulmnary artery t vein, i.e., PVPG; and (2) the fact that the pressure passively distending pulmnary vessels has been assumed t be the intravascular pressure, rather than the effective distending pressure r transmural pressure. This study pints ut a third pssible surce f cnfusin, namely, variatin in lung vlume frm ne study t anther. Summary Ten experiments were cnducted n anesthetized dgs ventilated with a Starling pump and breathing xygen. While tidal vlume, respiratry rate, and arterial ph and pco were kept cnstant, lung vlume was varied by using either a negative, zer, r psitive end-expiratry pressure, leading t average changes in lung vlume f 32,, and +5 per cent. Pulmnary vascular resistance (PVR) increased with either decreased r increased lung vlume, indicating that the relatinship between resistance and lung vlume is a U-shaped curve. Since the transmural distending pressures f large pulmnary vessels either increased r remained unchanged during these prcedures, changes in PVR cannt be ascribed t changes in systemic circulatry dynamics, such as cardiac utput. It was nted that cardiac utput increased with negative end-expiratry pressure (effectively, negative-pressure breathing) and decreased with psitive end-expiratry pressures (effective]y, psitive-pressure breathing), as previusly reprted. A hypthesis is presented fr explaining the U-shaped curve relating resistance and lung vlume. References 1. SIMMONS, D. H., AND HEMINGWAY, A.: Pulmnary circulatin fllwing pneumthrux and vagtmy in dgs. Circulatin Eesearcli : 93, CLOETTA, 31.: Im weleher Respiratinspkase ist die Lunge am besten durchblutet? Arch, exper. Path. u. Pharmakl. : 4, BURTON, A. C, AND PATEL, D. J.: Effect n pulmnary vascular resistance f inflatin f rabbit lungs. J. Appl. Physil. 12: 23, 195S. 4. EDWARDS, W. S.: Effects f lung inflatin and epinephrine n pulmnary vascular resistance. Am. J. Physil. 1: 5, BRECHEE, G. A., AND HUBAY, C. A.: Pulmnary bld flw and venus return during spntaneus respiratin. Circulatin Research 3: 21, Circulatin Research, Vlume I, March 191

7 LUNG VOLUME AD PULMONARY RESISTANCE 41. DUOMARCO, J., ESTABLE,.T. J., RIMINI, E., DE BOEVEAl', S. C, AND GlAMBRUO, C. E.: Accin de ls nivimients respiratris sbre lii pequena circulatin. Rev. argent, eardil. : 3 39, MEAD, J., AND COLLIER, C.: Relatin f vlume histry f lungs t respiratry mechanics in anesthetized dgs. J. Appl. Physil. : 9, SIMMONS, D. H., AD HEMINGWAY, A.: Functinal residual capacity and respiratry nitrgen excretin f dgs. J. Appl. Physil. : 95, :>. DAWES, G. S.: Pulmnary circulatin after birth. In Pulmnary Circulatin, edited by \V. R. Adam, and I. Veith. ew Yrk, Grime & Strattn, BOWDITCH, H. P., AD GARLAND, G. M.: Effect f the respiratry mvements n the pulmnary circulatin. J. Physil. 2:, MALONEY, J. V., JR., AND WHITTEBERGER, J. TJ. : Direct effects f pressure breathing n the pulmnary circulatin. Ann. ew Yrk Acad. Sc. : 931, 395. li'. LINDE, L. M., AND SIMMONS, 1). II.: Effect f psitive pressure breathing n pulmnary hemdynamics. T be published in J. Appl. Physil.. KlI.BIRN, K. H., AND SlEKER, H. O. : Effect Of cntinuus psitive and negative pressure breathing n intrathracic hemdynamics in man. Circulatin 1: 41, HOLT, J. P.: Effect f psitive and negative intrathracic pressure n cardiac utput and venus pressure in the dg. Am. J. Physil. 2: 594, BORST, H. G., MCGREGOR, M., WHITTEBERGER, J. L., AND BERGLCND, E.: Influence f pulmnary arterial and left atrial pressures n pulmnary vascular resistance. Circulatin Research 4: 393, SCHLEIER, J.: Der Energieverbrauch in der Blutbahn. Arch. ges. Physil. 13: 12, TRWIN, J. \V., BCRRAGE, W. S., AIMAR, C. E., AND CHESTNUT, K. \V., JR.: Micrscpical bservatins f the pulmnary arteriles, capillaries, and venules f living guinea pigs and rabbits. Anat. Rec. 119: 391, MACKLIN, C. C.: Evidence f increase in the capacity f the pulmnary arteries and veins f dgs, cats, and rabbits during inflatin f the freshly excised lung. Rev. Canad. de Bil. 5: 199, HOWELL, J. B. L., PERMCTT, S., AND PROCTOR, D. F.: Effect f lung inflatin upn the pulmnary vascular bed f excised dg lungs. Pd. Prc. 1: 4, 195. Circulatin Research, Vlume I, March 1OG1

CONDITIONS characterized by the presence

CONDITIONS characterized by the presence Cardiac Functin in Experimental Mitral Stensis By F..1. HADDY, M.D., A. L. FERRIN, M.D., D. W. HANNON, M.D., J. F. ALDEN, M.D., W. L. ADAMS, M.D., AND I. D. BARONOFSKY, M.D., PH.D. The results f S5 cmbined