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Wauthy, P. (2004). Evaluation du couplage ventriculo-artériel pulmonaire: études expérimentales et applications cliniques (Unpublished doctoral dissertation). Université libre de Bruxelles, Faculté de Médecine – Médecine, Bruxelles.

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Université Libre de Bruxelles Faculté de Médecine

Evaluation du couplage ventriculo-artériel pulmonaire Etudes expérimentales et applications cliniques

Pierre Wauthy

Thèse présentée en vue de l’obtention du titre de Docteur en Sciences Médicales

2004

Am J Physiol Heart Cire Physiol 284: H1625-H1630, 2003.

First published January 16, 2003; 10.1152/ajpheart.01023.2002.

Single-beat estimation of right ventricular end-systolic pressure-volume relationship

Serge Brimioulle,^ Pierre Wauthy,® Patricia Ewalenko,^ Benoît Rondelet,^

Françoise Vermeulen,* François Kerbaul,* and Robert Naeije*

^Laboratory of Physiology, Free University of Brussels, B-1070 Brussels; ^Department of Intensive Care, Erasme Hospital, B-1070 Brussels; ^Department of Cardiac Surgery, Brugmann Hospital, B-1020 Brussels; and ^Department of Anesthesiology, Bordet Jnstitute, B-lOOO, Brussels, Belgium Submitted 2 December 2002; accepted in final fonn 14 January 2003

Brimioulle, Serge, Pierre Wauthy, Patricia Ewalenko, Benoit Rondelet, Françoise Vermeulen, François Ker- baul, and Robert Naeije. Single-beat estimation of right ventriculEir end-systolic pressure-volume relationship. Am J

published January 16, 2003; 10.1152/ajpheart.01023.2002.—

Assessement of right ventricular (RV) contractility firom end- systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR tind contractility can be determined without metisuring RV vol­

ume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (Pmax) was pre- dicted from isovolumic portions of RV pressure during eject- ing beats and compared with Pmax measured during the first beat after pulmonary artery clamping. In RV pressure-vol­

ume loops obtained from RV pressure and integrated pulmo­

nary arterial flow, end-systolic elastance (Ees) was assessed as the slope of Pmox-derived ESPVR, pulmonary artery effec­

tive elastance (Ea) as the slope of end-diastohe to end-systolic relation, and coupling efficiency as the Ees-to-E» ratio {E^J Ea)- Predicted Pmax coirelated with observed Pmax (r = 0.98 ± 0.02). Dobutamine increased Ees from 1.07 to 2.00 mmHg/ml and Eea/Ea from 1.64 to 2.49, and propranolol decreased Eee/Ea from 1.64 to 0.91 (ail P < 0.05). After adrenergic blockade, preload réduction did not affect Ecs, whereas hyp- oxia and arterial constriction markedly increased E„ and somewhat increased Eeo due to the Anrep effect. Low preload did not affect E^JE^, and high afterload decreased E^JE^- In conclusion, in the right ventricle 1) Pmax can be calculated from normal beats, 2) Pmax can be used to détermine ESPVR without change in load, and 3) Pmax-derived ESPVR can be used to assess ventricular contractihty and ventricular-arte- rial coupling efficiency.

contractility; preload; afterload; pulmonary hypertension;

hypoxia

LEFT VENTRICULAR CONTRACTILITY is

commonly defined by the end-systolic pressure-volume relationship (ESPVR) (15, 16, 24). In the right ventricle (RV), the concept of ESPVR is also valid (8, 20) but it is difficult to apply in practice. The major problem is the difficulty in mea­

suring instantaneous RV volume in vivo. In 1988, Kass

(13) summarized the limitations of available methods and mentioned the potential of conductance volumetry.

Although not completely validated for measurement of instantaneous volume, conductance has been used re- peatedly to generate pressure-volume loops in animais and humans (34). The method remains difficult and time consuming and is therefore predominantly used as a research tool (31). A second problem may be the identification of end systole on triangle-shaped RV pressure-volume curves. Several investigators (9, 20) determined ESPVR from end-ejection pressures and volumes, but end éjection and end systole are known to occur at different times in the RV. Finally, the ESPVR is generally obtained during a transient change in preload or afterload, but such maneuvers may affect sympathetic tone and myocardial contractility and may not be acceptable in patients.

We therefore propose a method to assess right ven­

tricular ESPVR without measuring instantaneous RV volume and without changing preload or afterload (Fig.

1). Part of this method has been validated for the lefl ventricle (26, 27). It assumes that the ESPVR is the same in ejecting and isovolumic beats, and that the maximal pressure of an isovolumic beat (Pmax) can be extrapolated from normal ejecting beats. We investi­

gated whether RV Pmax can also be predicted from normal ejecting beats to détermine ESPVR and to dérivé RV end-systolic elastance (Ees), pulmonary ar­

tery effective elastance (Ea). and ventricular-arterial coupling efficiency as the £es-to-Ea ratio (Ees/EJ. We further investigated whether Ees reflects RV contrac­

tile changes induced by dobutamine and propranolol, and whether it is affected by changes in RV preload or afterload.

METHODS

Préparation. The experiments were done in accordance

with the “Guiding Principles in the Care and Use of Animais”

approved by the American Physiological Society. Details of our préparation hâve been published previously (4). Briefly, 28 mongrel dogs (mean wt 24 kg) were anesthetized with sufentanil (10 pg/kg iv) and a-chloralose (80 mg/kg iv), fol-

The costs of publication of this article were defirayed in part by the

H1626

Fig. 1. Principle of single-beat end-systolic pressure-volume rela- tionship (ESPVR) détermination. The ESPVR is assumed linear and alterload indépendant. Trace ABCDA is the pressure-volume curve of a normal ejecting beat, with end diastole in point A and end- systole in point C. In a traditional approach, a progressive increase of afterload at same preload yields the end-systolic points /, J, and K, and the ESPVR is defined as the CIJK line. In the présent approach, the computed maximal pressure of an isovolumic beat at same preload (ABLBA) yields the end-systolic point L, and ESPVR is defined as the CL line.

lowed by infusions of sufentanil (1 p.g-kg“^-h“*) and oi-chlo- ralose (20 mg-kg“^-h“^), and ventilated with 40% O

and 5 cmH20 end-expiratory pressure. RV pressure was monitored with a micromanometer cathéter (Mülar Instruments; Hous­

ton, TX) and instantaneous pulmonary blood flow with a transit-time ultreisonic flow probe (Transonic Systems;

Ithaca, NY). Cardiac output and RV éjection fraction were measured with a fast-response thermodilution pulmonary artery cathéter (Baxter-Edwards; Irvine, CA) (30). A clamp was placed around the pulmonary artery upstream from the flow probe, ~ 1 cm away from the pulmonary valve. The chest was closed but no attempt was made to restore négative pleural pressure. Hypoxie pulmonary vasoconstriction was enhanced by aspiiin (20 mgTcg iv) (4).

Protocol. In the first pari; of the study, flow and pressures

were recorded during several beats befbre and during the first beat after the proximal pulmonary arlery was clamped (Fig. 2). In each dog, the procedure was repeated at each combination of nonnal or low preload and normal or high afterload with normal or low or high myocardial contractility (12 combinations). Preload was decreased by inflating a beil- loon in the inferior vena cava to reduce venous return. After­

load was increased by reducing the inspired oxygen to 10% to cause hypoxie pulmonary vasoconstriction. Contractility was increased by dobutamine (5-10 p.g-kg”'-min”^ iv) and de­

creased by propranolol (1 mg/kg iv). In the second part of the study, flow and pressures were recorded to déterminé ESPVR and to assess RV contractility and coupling efficiency. Con- tractihty, preload, and afterload were modified by the same procedures as before. Because we found flow réduction and hypoxia to cause sympathetic stimulation, we also increased the afterload by constricting the proximed pulmonary artery and assessed the effects of flow réduction, hypoxia, and constriction before and after a- emd p-adrenergic blockade with phentolamine (2 mg/kg iv + 50 p.g-kg“^-h“‘) and pro­

pranolol (2 mg/kg iv) (4).

Data analysis. Ventricular and arterial components of cou­

pling, E

and E

averaged consecutive beats. First, RV end-diastolic volume

was calculated as the ratio of stroke volume to éjection fraction (end-diastolic volume does not affect E^

or Ea', see

discussion).

The decrease of RV volume during systole was computed by intégration of the instantaneous pulmonary arterial flow, assuming that blood flowing through the prox­

imal pulmonary artery was ejected from the RV. Second, the RV pressure-volume loop (limited to isovolumic contraction, éjection and isovolumic relaxation) was constructed from instantaneous RV pressure and volume. Third, Pmax was determined by fitting the équation P = a + fe-sin ic-t + d), where P is pressure and t is time, to RV pressure values before the maximal first dérivative of pressure development over time (dP/d/) and after minimal dP/d( (Fig. 3, left) (26).

Coefficients a-d were computed by a least-squsue nonlinear fitting routine by using the Levenberg-Marquardt procedure.

Pmax was obtained as Pmax = a + 2b. Fourth, the ESPVR line was drawn from Pmax down and tangent to the pressure- volume curve, i.e., from predicted isovolumic beat end systole to actual ejecting beat end systole (Fig. 3, right) (27). The arterial effective elastance line was drawn from end systole to end diastole. Fifth, E^

was computed as the slope of the ESPVR line, and Ea as the absolute slope of the arterial elastance line (17).

Statistics. Results are expressed as means ± SE. Predicted

and observed values were compared by corrélation analysis.

Changes in contractihty, preload, and afterload were tested by analysis of variance and analysis of contreists. P values

<0.05 were accepted as indicating statistical significance.

RESULTS

Pmax prédiction. Observed Pmax values were obtained in 136 of the 144 instances. Failures were related to prématuré beats triggered by the clamping procedure.

Predicted Pmax values were obtained in 114 instances.

Failures were mainly related to RV pressure tracing artifacts due to cathéter knocking against the ventric­

ular Wall at low preload or during dobutamine infu­

sion. The automated fitting procedure failed in eight instances. Overall, 106 pairs of values were available for corrélation analysis. In each dog, a strong corréla­

tion was observed between observed and predicted

Fig. 2. Exaraple of proximal pulmonary arterial (PA) clamping pro­

cedure. The beat recorded just after the clamping is isovolumic, as verified by the absence of flow in the artery, and begins at the same end-diastolic volume and pressure (press) as the normal ejecting beats. RV, right ventricular.

AJP-Heart Cire Physiol • VOL 284 • MAY 2003 • vvww.ajpheart.org

SINGLE-BEAT RIGHT VENTRICULAR ESPVR

H1627 Table 1. Effects ofdobutamine and propranolol on right ventricular-arterial coupling

Time, msec Volume, ml

Fig. 4. Example of corrélation between Pma», measured when the

Baseline Dobutamine Propranolol

Flow, 1/min 2.8 ±0.3 4.0 ±0.6* 2.4 ±0.2

HR, beats/min 89±9 99 ±13 103 ±7

P.„ mmHg 103 ±5 118 ±10* 83 ±4*

Ppa, mmHg 15 ±2 18 ±2* 15 ±3

fies, mmHg/ml 1.07 + 0.11 2.00 ±0.23* 0.94 ±0.11- fia, mmHg/ml 0.86 ±0.12 0.91 ±0.14 1.24 ±0.20

Ees/Ea 1.64 ±0.39 2.49 ±0.51* 0.91 ±0.20*

Fig. 3. Détermination of ventricular end-systolic elastance (£ea) and arterial effective elastance (£a). Left: end-systolic pressure of an isovolunaic beat is computed by sine wave extrapolation from the ejecting beat by using pressure values recorded before maximal first dérivative of pressure development over time (dP/df) and after min­

imal dP/d/. Right-, this maximal RV pressure of isovolumic beats (Pma») value is drawn on the RV pressure-volume diagram. The ESPVR line is drawn from Pma» down and tangent to the pressure- volume curve, i.e., from predicted isovolumic beat end systole to actual ejecting beat end systole (defined by the contact point of pressure-volume curve and ESPVR line). The effective arterial elas­

tance line is drawn from end systole to end diastole. Ees is the slope of the ESF’VR line, and £a is the absolute slope of the arterial elastance line.

Pmax ir = 0.98 ± 0.02, P < 0.001). Régression lines had intercepts of 1 ± 2 mmHg and slopes of 0.87 ± 0.06 (Fig. 4). Predicted Pmax thus consistently overesti- mated observed Pmax by —15%.

Baseline and inotropic changes. Baseline hemody- namics and blood gas values were normal (Table 1). E^s was 1.1 ± 0.1 mmHg/ml, E^ was 0.8 ± 0.1 mmHg/ml, and EeJE^ was 1.6 ± 0.4. Dobutamine increased car-

Values are means ± SE, n = 12. HR, heart rate; P,», systemic arterial pressure; Pp„ pulmonary arterial pressure; E^,, right ven­

tricular end-systolic elastance; E^, pulmonary arterial effective elas­

tance. *P < 0.05

VS.

diac output and systemic arterial pressure. It in­

creased Eee to 2.0 ± 0.2 mmHg/ml, did not affect E^, and increased EeJE^ to 2.5 ± 0.5. Propranolol did not change cardiac output and decreased systemic arterial pressure. It did not affect Eee or £a significantly, but decreased EeJE^ to 0.9 ± 0.2.

Preload and afterload changes. Venous retum réduc­

tion decreased cardiac output and ail intravascular pressures and increased heart rate (Table 2). It did not affect Ees, increased £a from 0.6 ± 0.1 to 1.3 ± 0.2 mmHg/ml, and decreased E^JE^ from 2.0 ± 0.3 to 1.1 ± 0.2 mmHg/ml. E^s tended to increase in dogs with moderate hypotension and tachycardia due to barore- ceptor-induced adrenergic stimulation. It tended to de- crease in dogs with severe hypotension and tachycar­

die, possibly due to decreased coronary flow. Aller adrenergic hlockade, venous return réduction still de­

creased cardiac output and pressures, hut no longer had an effect on heart rate, Ees, £a. or E^JE^- Hypoxia increased pulmonary arterial pressure and cardiac out­

put (Table 3). It increased Ses from 1.0 ± 0.1 to 1.3 ± 0.2 mmHg/ml and E^ from 0.7 ± 0.1 to 1.1 ± 0.2 mmHg/ml and did not affect E^JE^- After adrenergic blockade, hypoxia still increased Ees, but decreased EeJEa from 1.4 ± 0.2 to 1.1 ± 0.1 mmHg/ml. Pulmo­

nary artery constriction increased pulmonary arterial pressure and decreased cardiac output (Table 4). It increased E^

from 1.2 ± 0.2 to 2.0 ± 0.4 mmHg/ml and Ea from 1.0 ± 0.1 to 2.6 ± 0.5 mmHg/ml and decreased EaJEa from 1.6 ± 0.5 to 0.9 ± 0.1. After adrenergic

Table 2. Effects of venous return réduction on right ventricular-arterial coupling

Before Adrenergic Blockade After Adrenergic Blockade Baseline Réduction Baseline Réduction Flow, 1/min 3.6 ±0.3 2.3 ±0.2* 2.9 ±0.2 1.9 ±0.1*

HR, beats/min 87 ±7 127 ±10* 94±5 98 + 5

Pee, mmHg 90 ±4 69 + 6* 76 ±5 58 + 4*

Ppa, mmHg 16 ±1 12 ±1* 17 ±1 11 ±1*

fie», mmHg/ml 1.03 + 0.09 1.07 ±0.13 0.94 ±0.09 0.93 ±0.10

H1628

Table 3. Effects ofhypoxia on right ventricular-

arterial coupling

Before Adrenergic Blockade

After Adrenergic Blockade Baseline Hypoxia Baseline Hypoxia Flow, 1/min 3.5 ±0.2 4.6 ±0.3* 2.8 ±0.2 3.2 ±0.2 HR, beats/min 84 ± 6 128 ±11* 89±5 103 ±6

P,„ mmHg 91 ±4 93±5 74±5 71±4

Ppa, mmHg 16 ±1 25 ±2* 16 ±1 25 ±2*

Et,, mmHg/ml 0.96 ±0.10 1.32 ±0.20* 0.93 ±0.10 1.23 ±0.10*

Et, mmHg/ml 0.68 ±0.09 1.08 ±0.16* 0.89 ±0.12 1.20 ±0.11*

EtJE, 1.74 ±0.22 1.53 ±0.32 1.39 ±0.24 1.08±0.11*

Values are means ± SE; n = 16. *P < 0.05 vs. baseline.

blockade, constriction still increased £es and decreased EJE^.

DISCUSSION

RV pressure-volume curves. Right ventricular pres- sure-volume curves and ESPVR were first reported by Maughan et al. (20), in an isolated heart préparation and with a method avoiding any assumption of ventric­

ular shape. Compared with the left ventricle, the au- thors noted the lower pressures, the triangular shape of the curves, and the time lag between end systole and end éjection (20). Later, ESPVR and maximal élas­

tance were determined in vivo from pressure-volume curves obtained by cineradiography, radionuclide ven- triculography, and sonomicrometry. These methods, however, were limited by geometrical assumptions, sampling frequency, and/or amount of needed calcula­

tions (13). More recent studies were done with conduc­

tance volumetry in animais (10, 11, 19, 31) and hu- mans (3, 33). The method is not easy to apply in the RV and remains predominantly used as a research tool (31). We determined RV volume changes by integrating flow measured in the proximal pulmonary artery with a widely validated ultrasonic method. As seen in Fig. 3, the resulting pressure-volume curves are quite compa­

rable to those reported by Maughan et al. (20).

ESPVR afterload independence. In the left ventricle, afterload independence of ESPVR was initially re­

ported by Suga et al. (25) and confirmed by Maughan et al. (21) using linear ESPVR. In subséquent studies, ESPVR was commonly found linear (2, 7, 14, 23), but sometimes found curvilinear with a decreased slope at high preload (7, 14, 18) or at high afterload (23, 28).

Noda et al. (23) reported that curvilinearity was small, particularly if afterload changes were of limited ampli­

tude. Kass et al. (14) concluded that despite curvilin­

earity, Ees determined throughout limited load ranges could accurately assess inotropic State. Taking curvi­

linearity into account. Van der Velde et al. (28) found only nonsignificant effects of afterload on ESPVR slope. Accordingly, the authors (1, 27) who investigated the myocardial contractility with methods assuming ESPVR afterload independence reported significant and consistent results in patients. Ail of the above- mentioned studies involved the left ventricle. In the RV, the afterload independence of ESPVR has been

investigated only by Maughan et al. (20) using isolated hearts and linear ESPVR. ESPVR slopes in isovolumic beats were found to be once flatter (2.26 vs. 2.60 mmHg/ml) and once steeper (2.68 vs. 2.50 mmHg/ml) than in ejecting beats. Recalculations firom their indi- vidual data (20, Table 2) show similar end-systolic pressures in ejecting and isovolumic beats at end- systolic volumes of 40 ml (83 ± 7 vs. 85 ± 7 mmHg) and 60 ml (135 ± 11 vs. 138 ± 11 mmHg). This resuit suggests that RV ESPVR is the same for ejecting and isovolumic beats, and thus is afterload indépendant in the investigated volume ranges.

Pmax prédiction. In isolated hearts, Sunagawa et al.

(26) determined by Fourier analysis that the pressure- time relationship of a left ventricular isovolumic beat is very close to a sine wave. Accordingly, they found a good corrélation between Pmax observed during an iso­

volumic beat and Pmax predicted by sine wave extrap­

olation from the isovolumic parts of an ejecting beat.

The same assumption could be incorrect in the RV, due to its crescent shape and its asynchrone contraction pattern, or not be true in vivo due to ventricular inter- dependence or pericardial constraint. We therefore ver- ified the assumption for the in vivo RV with the use of ejecting and isovolumic beats beginning at the same end-diastolic volume. We found excellent individual corrélations between observed and predicted Pmax (^ = 0.98 ± 0.02). Predicted Pmax overestimated observed Pmax, a finding that we had anticipated. The lower Pmax during our “isovolumic” beats was attributed to the pulmonary valve opening and to minimal éjection from the RV into the pulmonary artery up toward the clamp- ing device. In this situation, observed Pmax should be lower than predicted Pmax, and the différence should increase in proportion to the generated ventricular pressure. This is exactly what we observed. These results suggest that predicted Pmax is very close to the Pmax of a true isovolumic beat. The single-beat method used in the left ventricle (27) can thus also be used in the RV to détermine the ESPVR and assess the inotro­

pic State.

Baseline and inotropic changes. Baseline RV JSes val­

ues were ~1.1 mmH^ml, in keeping with values of 1.2 mmHg/ml reported in dogs vdth sonomicrometry (12).

Ea was —0.7 mmHg/ml, reflecting the low pulmonary arterial pressure and résistance. E^JE^ was —2, which Table 4. Effects of pulmonary artery constriction on right ventricular-arterial coupling

Before Adrenergic Blockade

After Adrenei^c Blockade Baseline Constriction Baseline Constriction Flow, 1/min 3.4 ±0.3 2.8 ±0.3* 2.3 ±0.2 1.9±0.2

HR, beats/min 98± 12 116±11* 91 ±8 100-^8

P,o, mmHg 88±7 76±9 70±9 58±9

Ppa, mmHg 18 ±2 29 ±3* 17 ±2 18 ±2

Et,, mmHg/ml 1.18 ±0.17 1.99 ±0.38* 0.81 ±0.09 1.09 ±0.16*

Et, mmHg/ml 0.99 ±0.12 2.63 ±0.50* 1.03 ±0.16 2.39 ±0.40*

Eea/Eo 1.55 ±0.47 0.86 ±0.13* 0.82 ±0.13 0.49 ±0.08*

Values are means ± SE; n = 8. *P < 0.05 vs. baseline.

AJP-Heart Cire Pkysiol • voL 284 • MAY 2003 • www.ajpheart.org

SINGLE-BEAT RIGHT VENTRICULAR ESPVR

H1629 is remarkably similar to the values reported for left

ventricular-aortic coupling (6, 15). According to Burk- hoff et al. (5), E^JE^ values of 2 are associated with a maximal ratio between mechanical work production and myocardial oxygen consumption. Our results thus confirm that tbe RV is optimally matched to its after- load in the normal state. They also confirm that intrin- sic mechanical properties of the right and left ventri- cles are similar, and that the apparent différences resuit ffom the much lower RV afterload (5, 8). Dobut- amine increased E^s and E^JE^, whereas propranolol decreased E^JE^- TÏie absence of effect of propranolol on Ees indicates a low S5nnpathetic tone, probably re- sulting ffom the anesthésia, normal blood volume and normal aortic pressure (in view of the decrease in EeJEs,, the absence of changes in Ses and E^ could also resuit ffom a type 2 error due to a large individuel variability). We conclude that our method adequately detects dobutamine-induced inotropic changes, and thus can be used to assess RV contractility.

Preload and afterload changes. Venous retum réduc­

tion increased E^, due to the increase in pulmonary vascular résistance and impédance (4). E^s remained unaffected, due to variable individuel effects of adren- ergic stimulation. Accordingly, adrenergic blockade in- hibited ail effects of venous retum on E^s and E^JE^.

Active (hypoxie) vasoconstriction and passive (mechan­

ical) arterial constriction increased E^. They also in­

creased Eee, possibly due to adrenergic stimulation.

However, both of them still increased E^

after adren­

ergic blockade. Such an adrenergic-unrelated Ees re- sponse to increased afterload is quite consistent with homeometric autoregulation or Anrep effect (22). Re­

cent studies (10, 19) reported RV homeometric auto­

regulation in animais with increased afterload due to respiratory distress syndrome or to pulmonary arterial occlusion. The Anrep effect is mediated by changes in intracellular calcium sensitivity and concentration and is unaffected by propranolol but inhibited by verapamil (29, 32). We therefore tried to prevent the Ees response by verapamil, but additional verapamil depressed con­

tractility so much that pulmonary arterial constriction resulted in rapid death. Contractility-unrelated effects of afterload on E^

therefore cannot be completely ex- cluded, but our results are entirely consistent with the assumption that single-beat-derived E

is a load-inde- pendent index of RV contractility in clinically relevant ranges of preload and afterload.

Perspectives. To our knowledge, the présent method is the first permitting assessment of RV contractility and RV arterial coupling without measuring RV vol­

ume or modifying preload or afterload. We used actual RV end-diastolic volume in our calculations, but any arbitrary value can be used without affecting Ees or E^

(see Fig. 3). Pulmonary arterial velocity and flow can be obtained by noninvasive Doppler and magnetic rés­

onance techniques. The présent method is thus already

the left ventricle, the présent method will be applicable to patients in a completely noninvasive way.

S. Brimioulle was supported by the Foundation for Cardiac Sur- gery (Belgium). P. Wauthy, B. Rondelet, and F. Vermeulen were supported by the Erasme Foundation (Belgium). The study was supported by Fund for Medical Scientific Research (Belgium) Grants 9.4513.94 and 3.4567.00. Phentolamine was kindly supplied by No­

vartis (Brussels, Belgium) and propranolol by Astra Zeneca (Brus- sels, Belgium).

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Wauthy et al

f

Inhaled nitric oxide versus prostacyclin in chronic shunt- induced pulmonary hypertension

Pierre Wauthy, MD®

Sophia Abdel Kafi, MD®

Wolter J. Mooi, MD, RnD**

Robert Naeije, MD, PhD®

Serge Brimioulle, MD, PhD®

Objective: Cardiac surgery for congénital heart defects is commonly complicated by shunt-induced chronic pulmonary hypertension and associated acute hypertensive crises. To investigate the effects of vasodilators in chronic and acute pulmonary hypertension, we used the innominate artery to create a growing aortopulmonary shunt in young piglets.

Methods: Pulmonary hemodynamics and right ventricular function and their re- sponses to hypoxia, intravenous prostacyclin, and inhaled nitric oxide were inves- tigated after closure of the shunt by using pulmonary flow-pressure relationships, pulmonary vascular résistance partitioning, pulmonary vascular impédance, and ventriculoarterial coupling expressed as the ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance.

From the Laboratory of Physiology," Free University of Brussels, Bnissels, Belgium;

the Department of Pathology,'’ Erasmus University Hospital, Rotterdam, The Neth- erlands; and the Department of Intensive Care," Erasme University Hospital, Brus- sels, Belgium.

P. Wauthy was supported by the Erasme Foundation (CPM grant), The study was supported by the Belgian Foundation for Cardiac Surgery and by the Belgian Fund for Medical Scientihc Research (grant no.

3.4567.00).

Received for publication Nov 27, 2002; ré­

visions requested Feb 20, 2003; révisions received April 26, 2003; accepted for pub­

lication July 17, 2003.

Address for reprints: Pierre Wauthy, MD, Département de Chirurgie Cardiaque, CHU Btugmann, 4, Place Van Gehuchten, B-1020 Brussels, Belgium (E-mail:

pierre.wauthy@wanadoo.be).

J Thotac Cardiovasc Surg 2003; 126:

1434-41

Copyright © 2003 by The American Asso­

Results: Shunt-induced pulmonary hypertension was associated with médial hyper- trophy of pulmonary arteries, increased résistance, increased elastance, increased wave reflection, and preserved ventriculoarterial coupling. Hypoxie pulmonary vasoconstriction was blunted in the shunt group. Compared with prostacyclin, inhaled nitric oxide was a more effective vasodilator in the shunt group and in hypoxia. Effective pulmonary arterial elastance and right ventricular end-systolic elastance increased in chronic (shunt) and acute (hypoxie) hypertension and de- creased with vasodilators, preserving a normal coupling.

Conclusions: A growing aortopulmonary shunt in the young pig is a reliable model of chronic pulmonary hypertension, with médial hypertrophy, increased résistance, and increased elastance. In this model inhaled nitric oxide is a better pulmonary vasodilator than intravenous prostacyclin, with neither drug having a spécifie inotropic effect, and normal coupling is preserved in chronic and acute pulmonary hypertension.

I

n congénital heart defects associated with left-to-right shunting, pulmonary hypertension is an important déterminant of morbidity and mortality after surgical shunt correction.' In earlier stages of the disease, pulmonary hypertension progressively résolves after the surgical correction. Vascular reactivity, however, remains increased for some days after the operation and can resuit in life-threatening postoperative hypertensive crises with

hypoxemia and right ventricular (RV) failure.' Later in the évolution of the disease,

irréversible strucmral changes are présent, and pulmonary hypertension might

persist despite surgical correction of the shunt.

Wauthy et al Surgery for Congénital Heart Disease

created an 8-mm aortopulmonary shunt in young pigs re- ported médial hypertrophy and moderate pulmonary hyper­

tension after 3 months.^'"* Attempts to generate more hyper­

tension with a 10-mm shunt failed because of acute pulmonary edema and death in ail animais.'' We therefore tried to obtain more pulmonary hypertension by using a shunt that would grow with the animais.

Pulmonary hypertensive crises might be triggered by hypoxemia, hypercapnia, metabolic acidosis, restlessness, and endotrachéal suctioning.' The treatment consists of oxygénation, hyperventilation, sédation, and muscle paral- ysis. If pulmonary hypertension persists, administration of a vasodilator is recommended. Prostacyclin and inhaled nitric oxide (iNO) are potent drugs selected for vasodilator testing in patients with pulmonary hypertension.^'^ Prostacyclin and its analogues hâve been associated with an increase in cardiac output and a positive inotropic effect,*’® but they cause systemic hypotension and inhibit platelet aggregation.

iNO might be a better pulmonary vasodilator after opera­

tions for congénital heart defects,'®"'^ but it has been asso­

ciated with an increase in left atrial pressure and a négative inotropic effect.'^ ’''

The aims of the présent study were to investigate more completely the changes in pulmonary vessels and the right ventricle that occur in chronic high-pressure high-flow pul­

monary hypertension caused by an aortopulmonary shunt and to compare the vasodilating effects of prostacyclin and iNO in acute and chronic shunt-induced pulmonary hyper­

tension.

Methods

Ail experiments were conducted in accordance with the “Guide for the Gare and Use of Laboratory Animais” and after approval by the Committee on the Gare and Use of Animais in Research of the Brussels Free University School of Medicine. Growing pigs were enrolled immediately after weaning from maternai feeding (âge 3-4 weeks).

Surgical Procedure

Animais were premedicated with 20 mg/kg intramuscular ket- amine and 0.1 mg/kg intramuscular midazolam. After 0.25 mg of intramuscular atropine, anesthésia was induced with 1 mg/kg in- travenous midazolam and 10 p.g/kg intravenous fentanyl and maintained with 0.1 mg • kg“' • h"' midazolam and 2 to 3 /ng • kg”' • h”'fentanyl. Paralysis was obtained with 0.2 mg • kg"' • h“‘ intravenous pancuronium bromide. The pigs were ventilated with an inspired oxygen fraction (FiOj) of 0.4, a tidal volume of 15 mL/kg, and a respiratory rate of 12 breaths/min. One gram of intravenous cefazolin was given before and 2 hours after the surgical procedure. A thoracotomy was performed through the third intercostal space, and the left innominate artery (diameter, 5-6 mm) was dissected and anastomosed to the pulmonary artery (Figure 1). At the end of the procedure, the shunt was either maintained (shunt group, n = 9) or closed (sham group, n = 8).

The lungs were re-expanded, and pleural air was evacuated before

Figure 1. Illustration of the surgical procedure. The left innomi- nate artery is connected to the main pulmonary artery to generate a shunt that will increase over time to induce high-flow, high- pressure pulmonary hypertension.

closure of the chest. The piglets were awakened and weaned from mechanical ventilation. They received 5 mg of subcutaneous mor­

phine twice daily for 2 days and 20 mg of intramuscular furo- semide to prevent pulmonary edema.

Préparation

Measurements were done 10 to 12 weeks later (77 ± 3 days; range, 69-83 days), with the same anesthetic regimen as for the first procedure. Anesthésia and mechanical ventilation were maintained until the end of measurement. Fémoral and pulmonary arteriai cathéters were inserted to monitor pressures, to measure cardiac output by means of thermodilution, and to draw arteriai and mixed venons blood. Thoracotomy was performed through the fourth left intercostal space. A micromanometer-tipped cathéter (SPC 350;

Millar Instrument, Houston, Tex) was introduced in the right ventricle, and a pressure and velocity sensor cathéter (SVPC- 664A, Millar) was introduced in the proximal main pulmonary artery. Micromanometer-derived pressures were processed by us­

ing TCB-500 units (Millar), and velocity was processed by using a FM501 flowmeter (Carolina Medical, King, NC). A tourniquet was placed around the inferior vena cava to control cardiac output by reducing venons retum. The lungs were fülly expanded, pleural air was evacuated, and the chest was tightly closed.

Measurements

In each set of measurements, cardiac output was measured and velocity and pressure signais were recorded in stable conditions for calculation of pulmonary vascular impédance (PVZ) and RV func- tion after inflation of the pulmonary arteriai balloon for calculation of capillary pressure and longitudinal pulmonary vascular résis­

tance partitioning and during vena caval compression for généra­

tion of flow-pressure curves. A complété set of measurements was done at baseline in hyperoxia (Fi

of 0.40) and repeated after 10 minutes of ventilation in hypoxia (FiOj of 0.12). After retum to hyperoxia and 30 minutes of hémodynamie stabilization, prosta-

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Surgery for Congénital Heart Disease Wauthy et al

TABLE 1. Baseline hentodynamics and blood gases in pig*

lets in the sham and shunt groups

Sham Shunt

Baseline

Before

closUre Baseline

Q, L-min“' 3.6 ± 0.2 3.3 ± 0.3 2.4 ± 0.2*

HR, beats/min 115±8 109 ± 9 126 ± 14

Psa, mm Hg 118 ± 10 127 ±6 121 ± 6

Pra, mm Hg 6± 1 6 ± 1 7 ± 1

Ppa, mm Hg 26 ± 1 40 ± r 27 ± 1*

Ppc, mm Hg 13 ± 1 - 16 ± 1

Pla, mm Hg 7±1 8 ± 1 8 ± 1

PVRa, % 65 ±3 - 68 ± 3

PHa 7.49 ± 0.01 7.45 ± 0.02 7.42 ± 0.03

PacOj, mm Hg 39 ±2 35 ± 1 37 ± 2

PvOj, mm Hg 201 ± 23 173 ± 15 176 ± 15

PaOj, mm Hg 46 ± 1 42 ± 4 43 ± 4

Values are means ± SE. û, Flow; HR, heart rate; Psa, systemic arterial pressure; Pra, right atrial pressure; Ppa, pulmonarv arterial pressure; Ppc, pulmonary capillarv pressure; Pla, left atrial pressure; PVRa, arterial corn- ponent of pulmonary vascular résistance; Pvo^ partial pressure of oxygen, mixed venous.

*P < .05 versus previous column.

cyclin (epoprostenol, Flolan; Glaxo-Smith-Kline, Genval, Bel- gium) was started and incremented as 2 ng • kg“' • min“' every 10 minutes until side effects appeared (decrease in arterial pressure of >30%, increase in heart rate of >30%, or prématuré beats).

Prostacyclin was decreased to the previous dose, and measure- ments were made again in hyperoxia and in hypoxia. After dis­

continuation of prostacyclin, retum to hyperoxia, and 30 minutes of hémodynamie stabilization, iNO was administered at 40 ppm, and measurements were done again in hyperoxia and in hypoxia (iNO was not titrated because the 40-ppm dose yields a maximal vasodilating response without causing side effects).

Data Analysis

Ail pressures and the velocity signais were digitized at 200 Hz and stored on a PC for offline analysis. Velocity was converted to flow by using the thermodilution value and was zeroed at the diastolic zero-flow value. Flow-pressure plots were obtained from 5 beats satnpled throughout the flow-reduction maneuver.'^ Pressures and flow values were submitted to linear corrélation analysis {r > 0.95) to generate individual régression lines and interpolate pulmonary arterial pressure minus left atrial pressure (Ppa - Pla) values at flows of 1.5 and 3.5 L • min“' ■ m“^.'* Capillary pressure (Ppc) was computed by means of biexponential fitting of the Ppa decay curve after inflation of the balloon of the pulmonary artery cath­

éter.'® The arterial component of résistance was calculated as (Ppa - Ppc)/(Ppa - Pla) and expressed as a percentage. PVZ was calculated from the Fourier sériés expressions of pressure and flow waves.'’' From PVZ spectra were derived the 0-Hz impédance

of the refiected wave (Rampl).'* Right ventriculoarterial coupling was computed from RV pressure-volume curves by using a single- beat method.'® The RV contractility was estimated as the slope of the end-systolic pressure-volume relationship (Ees), and the pul­

monary effective arterial elastance (Ea) was estimated as the slope of the end-diastolic to end-systolic relationship.^ Ventriculoarte­

rial coupling efficiency was defined as the Ees/Ea ratio.^ ' Pathology

Histologie examination was done by using standard methods.^" For each animal, at least 10 blocks of formalin-fixed lung tissue, randomly taken from the central and jreripheral areas of the lungs, were paraffin embedded by using standard protocols. Light microscopy was per- formed without knowledge of the group allocation or hémodynamie data. A hematoxylin-eosin stain and a resorcin-fiichsin stain for elastin were performed on 5-pm thick sections from each block. In each piece 10 small muscular pulmonary arteries of variable diameter (80-200 p.m) were studied. The médial thickness was measured with an eyepiece micrometer as the distance between the internai and exteraal elastic laminae. Thickness was expressed as a percentage of the extemal vessel diameter.

Statistical Analysis

Results are expressed as means ± SE. Effects of shunt, hypoxia, and vasodilators were assessed by means of repeated-measures analysis of variance and Fisher protected i tests.

Results

After the operation, ail piglets in the shunt group maintained a loud continuous murmur in the left chest that increased during the first week. Two piglets in the shunt group had pulmonary edema after the operation and received addi- tional furosemide; one died, and the other survived. One piglet in the sham group had mediastinitis and died. At the time of measurement, animais in the sham and shunt groups had similar body weights (mean, 21 vs 20 kg). AU pigs in the shunt group had a patent shunt that had grown to the size of 9 to 10 mm. The pulmonary/systemic flow ratio deter- mined by means of oximetry was 1.75 ± 0.07 (range, 1.36-2.00). After initial measurements, the shunt was closed to correctly evaluate pulmonary vascular résistance and PVZ.

Effects of Shunts

Before closure of the shunt and after the initial fluid admin­

istration reached a left atrial pressure of about 8 mm Hg, animais in the shunt group had a similar flow but higher Ppa than animais in the sham group (40 ± 1 vs 26 ± 1 mm Hg).

Other hémodynamie variables were comparable in the 2

groups (Table 1). Closure of the shunt reduced pulmonary

blood flow (3.3-2.4 L • min“’ • m“^) and Ppa in the shunt

Wauthy et al Surgery for Congénital Heart Disease

12 3 4

Cl, l.min-1 .tn-2

• Sham Baseline - O- Sham Hypoxia ék Shunt Baeeline

* Shunt Hypoxia

Figure 2. Composite pulmonary vascular flow pressure curves in the sham and shunt groups (means ± SE). Effects of hypoxia: *P < .01 versus baseline, £P < .05 versus sham. Pigs in the shunt group showed an upward shift of flow-pressure curves. Hypoxia shifted these curves upward in the sham group but not in the shunt group.

2.5 L ■ min“ ' • by decreasing venous retum to allow for meaningful comparisons (Tables 2-4). Compared with that in the sham group, the pulmonary circulation in animais in the shunt group was characterized by increases in Zo, Zc, and Rampl. The right ventricle showed a marked increase in afterload and in contractility (Ea and Ees). Pathologie ex­

amination showed a médial thickness of 11% ± 1% in the shunt group versus 7% ± 1% in the sham group (P < .05).

Some animais in the shunt group showed nonspecific indi­

ces of congestion (interstitial and alveolar edema, widened lymphatic vessels, and venous wall thickening). No différ­

ence was found between smaller and larger arteries in the investigated range (80-200 p,m).

Effects of Hypoxia

In the sham group hypoxia markedly shifted the pressure- flow plots upward (Figure 2). Ppa and Ppc increased pro- portionally, indicating changes in both arterial and venous résistances. PVZ data showed a hypoxia-induced increase in Zo, Zc, and Rampl (Table 2). Ventricular data showed a hypoxia-induced increase in Ea and a proportional increase in Ees, resulting in a préservation of Ees/Ea. In the shunt group flow-pressure plots, PVZ data, and RV data remained unaffected by hypoxia.

Effect of Prostacyclin and iNO

Two piglets in the shunt group died from ventricular tachy- cardia and fibrillation when prostacyclin was increased from 2 to 4 ng • kg” ' • min” ‘. Other side effects in the shunt and sham groups were prématuré beats in 10 pigs, hypotension in 2 pigs, and low cardiac output in 1 pig at 18 ng • kg” ' • min” '. At the time of measurement, the prostacyclin infu­

sion rate was 11 ± 2 ng • kg”' • min”' (range, 4-20 ng ■ kg”' • min”') in the sham group and 11 ± 2 ng • kg”' • min”' (range, 4-18 ng • kg”' ■ min”') in the shunt group;

for comparison, our patients with pulmonary hypertension tested for reversibility received 4 to 16 ng • kg” ' • min” '. At baseline, prostacyclin had no effect on flow-pressure plots (Figure 3), on PVZ, or on ventriculoarterial coupling (Table 3). iNO shifted flow-pressure plots downward in both the sham and shunt groups (Figure 3). iNO reduced Zo, Zc, and Ees in the shunt group but not in the sham group (Table 3).

Compared with prostacyclin, iNO reduced Zo, Zc, and Ees in the shunt group (Table 3). During hypoxia, prostacyclin somewhat shifted flow-pressure plots downward in the sham and shunt groups, whereas iNO had a more marked effect (Figure 4). At reference flow, iNO decreased Zo and Zc more than prostacyclin (Table 4). iNO decreased Ees compared with prostacyclin, but Ees/Ea was unaffected by both drugs.

Discussion

Experimental Model

Previous attempts to generate pulmonary hypertension with an aortopulmonary shunt had variable success. In utero aortopulmonary fistulas are associated with technical prob- lems and high mortality.^^'^"* In young piglets Rendas and associâtes^ reported more pulmonary hypertension in 4-week-old animais than in older animais. Pulmonary hy­

pertension, however, remained moderate with 8-mm fistu­

las, whereas severe pulmonary edema occurred with 10-mm fistulas.'* The présent study shows that serions chronic pul­

monary hypertension can be reliably caused by an aortopul-

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Surgery for Congénital Heart Disease Wauthy et al

TABLE 2. PVZ and right ventriculoarterial coupling in piglets in the sham and shunt groups

Sham Shunt

Baseline Hypoxie Baseline Hypoxia

Q, L ■ min"' • m"^ 2.2 ± 0.1 2.3 ± 0.2 2.4 ± 0.1 2.4 ± 0.1

Ppa, mm Hg 16 ±2 31 ±2* 27 ± 1t 29 ± 1

Zo, dynes ■ s"' • cm"® 600 ± 68 1087 ± 106* 918 ± 76 966 ± 96

Zc, dynes • s"' ■ cm"® 64 ± 7 126 ± 18* 130 ± 16t 160 ± 12

RampI, mm Hg 3.5 ± 0.5 5.3 ± 0.6* 4.8 ± 0.7 6.9 ± 1.4*

Ea, mm Hg/mL 1.3 ± 0.2 3.2 ± 0.7* 2.2 ± 0.2t 2.0 ± 0.2

Ees, mm Hg/mL 1.8 ± 0.4 4.7 ± 0.8 4.9 ± 0.8t 3.6 ± 0.8

Ees/Ea 1.4 ± 0.3 1.5 ± 0.2 2.2 ± 0.3 1.8 ±0.3

Values are means ± SE. fa. Effective pulmonary arterial elastance; Ees, RV end-systolic elastance; Ppa, pulmonary arterial pressure; û, flow; RampI, reflected wave amplitude: Zc, characteristic impédance; Zo, total pulmonary vascular résistance.

*P < .05 versus baseline;

tP < .05 versus sham.

TABLE 3. PVZ and right ventriculoarterial coupling; Eifect of prostacyclin and iNO

Sham Shunt

Baseline Prostacyclin iNO Baseline Prostacyclin iNO

û, L • min"' • m"^ 2.2 ± 0.1 2.4 ± 0.2 2.2 ± 0.1 2.4 ± 0.1 2.4 ± 0.1 2.5 ± 0.1

Ppa, mm Hg 16 ± 2 20 ± 2 14± 2Î 27 ± 1 26 ± 1 18 ± 1*î

Zo, dynes • s"' cm"® 600 ± 68 688 ± 38 479 ± 56t 918 ± 76 851 ± 77 577 ± 43*î

Zc, dynes • s"' cm"® 64 ± 7 76 ± 11 77 ± 6 130 ± 16 165 ± 54 91 ± 9*t

RampI, mm Hg 3.5 ± 0.5 3.3 ± 0.6 3.7 ± 0.8 4.8 ± 0.7 5.1 ± 0.8 3.4 ± 0.7*t

Ea, mm Hg/mL 1.3 ± 0.2 1.7 ± 0.3 1.4 ± 0.3 2.2 ± 0.2 1.7 ± 0.2 1.8 ±0.4

Ees, mm Hg/mL 1.8 ± 0.4 2.8 ± 0.7 2.4 ± 0.3 4.9 ± 0.8 3.9 ± 0.5 2.8 ± 0.4*

Ees/Ea 1.4 ± 0.3 1.7 ± 0.4 1.8 ± 0.3 2.2 ± 0.3 2.3 ± 0.4 1.6 ±0.4

Values are means ± SE. fa. Effective pulmonary arterial elastance; Ees, RV end-systolic elastance; Ppa, pulmonary arterial pressure; 0, flow; RampI, reflected wave amplitude; Zc, characteristic impédance; Zo, total pulmonary vascular résistance.

*P < .05 versus baseline, tP < .05 versus prostacyclin.

monary shunt created with the left innominate artery in growing piglets. The surgical procedure is simple, and se­

rions complications are uncommon because of the limited initial size of the fistula. The size of the fistula almost doubled over the 10 to 12 weeks, reaching a 9- to 10-mm diameter that would be léthal at the time of the operation. In comparison with an 8-mm fistula, the final 20% increase in diameter represented a 44% increase in section area and a theoretic 77% decrease in résistance. This larger final shunt explains why pulmonary hypertension was more severe in our study than in previous studies. In tum, the pulmonary hypertension explains why the pulmonary/systemic flow ratio was limited to about 1.75 at the time of measurement.

Pathology

Histologie examination essentially showed médial hypertro- phy of the 80- to 200-ju.m muscular pulmonary arteries in

arterial retraction. Moreover, this finding is consistent with grade 1 changes reported in patients with pulmonary arterial hypertension related to congénital left-to-right shunts.^’^^’^®

Further stages of this type of pulmonary hypertensive vas­

cular disease include concentric laminar intimai fibrosis, fibrinoid necrosis, dilatations, and plexiform lésions, espe- cially in the proximal parts of the supemumerary arteries.^^

Such features of advanced pulmonary hypertension were not found in our animais.

Pulmonary Hemodynamics

Most previous investigations on aortopulmonary shunts re­

ported data collected when the shunt was patent or used

pressures obtained at variable flow, so that the extent of

pulmonary hypertension remained unclear.^’^"'^’ In studies

in which data were taken after closure of the shunt and at

controlled flow, pulmonary arterial pressure and résistance

Wauthy et al Surgery for Congénital Heart Disease

Sham Shunt

Cl, l.min-1.m-2 Cl, l.mln-1.m-2

Figure 3. Effect of intravenous prostacyclin (PGI2) ani iNO on pulmonary vascular flow-pressure curves in pigs in the sham and shunt groups (means ± SE). *P < .05 versus baseline (BL), iP < .05 iNO versus prostacyclin. iNO shifted the curves downward in sham-treated pigs.

TABLE 4. PVZ and right ventriculoarterial coupling: Effect of prostacyclin and iNO during hypoxia

Sham-hypoxie Shunt-hypoxia

Baseline Prostacyclin iNO Baseline Prostacyclin iNO

Q, L-min“' -m"' 2.3 ± 0.2 2.3 ± 0.1 2.3 ± 0.1 2.4 ± 1 2.4 ± 1 2.6 ± 2*t

Ppa, mm Hg 31 ± 2 25 ± 3* 21 ± 3*t 29 ± 1 30 ± 3 21 ± 1*î

Zo, dynes • s~* • cm“® 1087 ± 106 867 ± 94* 671 ± 77*î 966 ± 96 1053 ± 92 645 ± 52*t

Zc, dynes • s“* • cm“^ 126 ± 18 99 ± 11* 71 ± 9*t 160 ± 12 138 ± 17 93 ± 9*î

RampI, mm Hg 5.3 ± 0.6 4.5 ± 0.9 4.2 ± 0.6 6.9 ± 1.4 5.0 ± 1.0 3.0 ± 0.6*t

Ea, mm Hg/mL 3.2 ± 0.7 2.9 ± 0.7 1.9 ± 0.3*t 2.0 ± 0.1 2.8 ± 0.3* 1.7 ± 0.2*T

Ees, mm Hg/mL 4.7 ± 1.0 4.9 ± 1.4 3.7 ± 0.8 3.6 ± 0.8 5.0 ± 1.4* 3.8 ± 0.6

Ees/Ea 1.5 ±0.2 1.7 ± 0.5 1.9 ± 0.4 1.8 ± 0.3 1.8 ± 0.4 2.2 ± 0.5

Values are means ± SE. fa. Effective pulmonary arterial elastance; Ees, RV end-systolic elastance; Ppa, pulmonary arterial pressure: Q, flow; HampI, reflected wave amplitude; Zc, characteristic impédance; Zo, total pulmonary vascular résistance.

*P < .05 versus baseline, tP < .05 versus prostacyclin.

method reported that a 14-month subclavian-pulmonary shunt increased arterial but not venous résistance in the shunted left lower lobe vasculature.^’ We used a single occlusion method with a 3-compartment model and biex- ponential fitting that has been shown to yield values closest to those of the double-occlusion method.'® In the présent study involving the complété pulmonary vasculature, our results show proportional increases in arterial and venous résistances, suggesting that pulmonary veins also contrib- uted to the increased résistance. Impédance data showed normal values in the sham groupé® and significant changes in the shunt group. Zo and Zc increased markedly, which is in keeping with previous observations in shunted animais'*

and in children with grade I pulmonary vascular disease caused by a congénital lefit-to-right shunt.^® The increase in Zo reflects the upward shift of flow-pressure curves. The increase in Zc might be related to a decreased cross-sec- tional area or an increased elastance (increased stiffness and decreased compliance) of the proximal arteries. Because the proximal arteries are passively dilated in pulmonary hyper­

tension, increased Zc thus indicates increased arterial elas­

tance. Our results also show increased reflected wave am­

plitude, an usual conséquence of increased elastance and wave velocity. Shunt-induced pulmonary hypertension was thus associated with a consistent hémodynamie picture of increased résistance of small distal vessels, increased elas-

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Surgery for Congénital Heart Disease Wauthy et al

Sham Shunt

Figure 4. Effect oi intravenous prostacyclin IPGI2) and iNO during tiypoxia on pulmonary vascular flow-pressure curves in pigs in the sham and shunt groups (means ± SE). *P < .05 versus baseline (BL), iP < .05 versus prostacyclin. iNO shifted the curves downward more than prostacyclin.

tance of large proximal vessels, and increased amplitude of wave reflection, ail of which contribute to the increase in RV afterload.

RV Function

Ees and Ea, commonly used to assess ventriculoarterial coupling for the left ventricle, can also be used for the normal right ventricle'^ and for the right ventricle facing pulmonary hypertension (Wauthy and colleagues, unpub- lished observations). Ea intégrâtes the major components of ventricular afterload (distal résistance, proximal elastance, and wave reflection), Ees reflects ventricular contractility, and the Ees/Ea ratio directly quantifies the ventriculoarterial coupling efficiency. Pigs in the sham group had a higher Ea than normal dogs, reflecting the natural increase in résis­

tance and elastance of the pulmonary circulation of this species.^^ Ees increased in such a way that the Ees/Ea ratio remained close to 2, the value also found in dogs and taken as optimal because it is associated with a maximal ratio between mechanical work production and oxygen consump- tion.^' Piglets in the shunt group had a further increase in Ea, confirming that the shunt-induced increases in résis­

tance and elastance resulted in an increased RV afterload.

Ees again increased in such a way that Ees/Ea remained

Hypoxia

In the sham group acute hypoxia was associated with an increase in pulmonary vascular résistance and elastance.

Such effects hâve been reported previously and might be attributed to hypoxia itself and to the resulting adrenergic stimulation.'^’^® In the shunt group the hypoxie response was significantly blunted. Previous studies reported aorto­

pulmonary shunts both to enhance^"* and to blunt'*’^® hy­

poxie responses.

Vasodilators

Prostacyclin and NO are natural vasodilators produced by endothélial cells and acting on smooth muscle cells to maintain a low basal pulmonary vascular tone.'° Both sub­

stances hâve been used as potent vasodilating drugs in varions States associated with pulmonary hypertension.*'"

Here, at baseline, prostacyclin had no significant effect, and iNO had only a mild vasodilating effect. These results indicate that basal pulmonary vascular tone was low be­

cause of the anesthésia, the normal blood flow and blood pressure, or both. In chronic (shunt-induced) pulmonary hypertension, prostacyclin had no effect, whereas iNO de- creased résistance and elastance. In acute (hypoxie) pulmo­

nary hypertension, whether isolated or superimposed on

chronic hypertension, prostacyclin partially reversed and