INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

UNIVENTRICULAR FONTAN circulation (7) has gained a wide acceptance as a functional corrective procedure for complex congenital heart defects with single ventricle physiology (3, 4). Basically, the concept is to place the pulmonary circulation in series with the systemic circulation rather than the parallel circulatory arrangement that is present before repair (8, 30). After this operation, the single ventricle is responsible for perfusion of both the systemic and pulmonary circulations, resulting in: 1) an unusual pathophysiology of a passive pulmonary pressure-flow relationship regulated by the pressure difference between the pulmonary arterial pressure (P_pa) and left atrial pressure (P_la) (8), and 2) additional resistance to venous return (RVR) due to the location of the pulmonary circulation at the end of the circulatory system (3). Of primary importance, the absence of right ventricular function means that the cardiac and vascular factors that determine venous return (Q_vr) (14) may become of critical hemodynamic importance in maintaining systemic blood flow (SBF) (3), because Q_vr is eight times more influenced by an increase in RVR than by a similar increase in systemic vascular resistances (SVR) (15). Moreover, it has been demonstrated that the essential function of the right ventricle is to maintain a low pressure in the highly compliant systemic venous system, and perfusion of both pulmonary and systemic circulations may be amply provided by the normal left ventricle (8). Although the consequences of Fontan circulations on cardiac function have long been researched (3, 8, 10, 30), the potential changes in the vascular factors determining Q_vr have not yet been studied in such circumstances.

In light of Guyton's theory on the circulatory system (13-17), factors that determine Q_vr have been extensively studied (18, 23, 34-35) and discussed (1, 23, 38) in biventricular circulations. First, just as the cardiac output curve (Frank-Starling mechanism) reflects the ability of the heart to pump blood, the Q_vr curve described by Guyton provides fundamental insight into the vascular factors that affect the tendency for blood to return to the heart. The relationship between Q_vr and mean central venous filling pressure (P_cv) defines a Q_vr curve characterized by a straight line with a negative slope and a positive x-intercept named as the estimated mean circulatory filling pressure (P_mcf) (13, 16, 17). Thereby, Q_vr = a  b · P_cv, where b is the conductance for Q_vr (G_vr) and 1/b represents the RVR between the point in the circulatory system where P_mcf exists and the right atrium where P_cv is measured (5, 38). Located in small veins and venules (34), P_mcf is the pressure throughout the cardiovascular system at zero flow. Its value is estimated by extrapolating on the Q_vr curve to Q_vr = 0, where P_cv = P_mcf = a/b, or observed during a transient circulatory arrest. Any changes in Q_vr parameters (i.e., P_mcf and G_vr), which are independent of the characteristics of the heart (14, 23, 35), will markedly induce change in Q_vr. Second, under steady-state conditions, Q_vr must be equal to cardiac output because the heart can only pump what it receives. Therefore the Q_vr curve coupled with the cardiac response curve defines the steady-state SBF and P_cv of the cardiovascular system at the intersection of the venous and cardiac function curves (13). At this obligatory equilibrium point, Guyton predicts that Q_vr depends on the driving force or pressure gradient between P_mcf and P_cv, and G_vr. Therefore SBF = Q_vr = (P_mcf  P_cv) · G_vr (1, 13, 14, 17, 18, 38). All factors on the right-hand side of the equation are relatively independent of each other (14). Q_vr parameters are mainly affected by blood volume, venous tone, and peripheral resistances. Conversely, P_cv is a common factor that affects both the ability of the heart to sustain cardiac output and the ability of blood to return to the heart when it is failing (14).

The purpose of the present study was to determine whether the location of pulmonary vascular resistance (PVR) at the end of the circulatory system may change the vascular factors determining Q_vr and whether Guyton's principles could accurately provide new insights into the cardiac and vascular factors that determine Q_vr in univentricular Fontan circulations. First, we reasoned that P_la, and not right atrial pressure (P_ra), is the downstream pressure for Q_vr in univentricular Fontan circulations. Second, we hypothesized that maintenance of an adequate Q_vr may be obtained owing to changes in Q_vr parameters occurring in response to the additional RVR produced by the location of PVR at the end of the systemic venous system. Therefore, G_vr and estimated and observed P_mcf were determined in two groups of pentobarbital sodium-anesthetized open-chest pigs, either in biventricular or univentricular Fontan circulations, while preserving SBF in each case with volume-loading adjustments.

Q_vr curves were obtained using a novel experimental model with an adjustable atrioventricular valve annuloplasty that allowed us to induce transient inverse relationships between P_ra and Q_vr in biventricular circulations and between P_la and Q_vr in univentricular Fontan circulations.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Animal preparation. Sixteen large white pigs weighing 31.4 ± 4 kg were medicated before the experiment with an intramuscular injection of ketamine hydrochloride (10 mg/kg) and atropine sulfate (0.2 mg/kg) and were anesthetized with pentobarbital sodium (30 mg/kg iv). Orotracheal intubation was aided by pancuronium bromide (0.2 mg/kg). Animals were ventilated using a Servo 900D volume-cycle respirator (Siemens, Solna, Sweden) with oxygen-enriched air and 0.5% halothane (20 breaths/min, tidal vol 10 ml/kg). Anesthesia was maintained using supplemental doses of pentobarbital sodium (3 mg · kg¹ · h¹). Thereafter, blood gas tensions, arterial oxygen saturation, pH and hematocrit values were measured using a Dow-Corning blood gas system (Ciba Corning, Medfield, MA) and were kept within physiological values. Body temperature was maintained at 39°C using a thermocontrolled operating table. Baseline hemodynamic values were recorded before further manipulations. The animals used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals by the National Research Council (1996).

Study design. Experiments were randomly divided into two groups, and biventricular (n = 8) or univentricular Fontan (n = 8) experimental circulations were surgically constructed. In each case the postoperative SBF was approximately set to the baseline level, to determine P_cv, the downstream pressure for Q_vr, which is P_ra in biventricular circulations and P_la in univentricular circulations. To elaborate Guyton's Q_vr curves implies that we induce a transient increase in P_cv (the independent variable, contrary to the usual convention) and record the resulting changes in Q_vr (the dependent variable) (13, 17). Thus Guyton's Q_vr curves were obtained using a novel experimental method with an adjustable tricuspid (biventricular) or mitral (Fontan) valve annuloplasty. Transient tightening of the annuloplasty results in an increase in P_cv and a decrease in ventricular end-diastolic pressure, and thus in ventricular output, paralleling changes in Q_vr. The studied relationship was between P_ra and pulmonary blood flow (biventricular) and between P_la and aortic blood flow (univentricular). Pulmonary or aortic blood flows in steady-state conditions were assumed to be equal to SBF. Observed P_mcf was determined using electrically induced ventricular fibrillation. Q_vr curves were considered to be adequately determined if: 1) a linear relationship was demonstrated in each experiment between P_cv and Q_vr using regression analysis, and 2) a correlation was established in biventricular and Fontan circulations between estimated (zero-flow intercept of the Q_vr curve) and observed (fibrillation) P_mcf.

Surgical preparations. A midline sternotomy was performed, and the anterior pericardium was opened and suspended. Preparations were realized under cardiopulmonary bypass established between the ascending aorta and both venae cavae, using a console with three roller pumps (Sarns Travenol, Ann Arbor, MI) and a Capiox SX-10 membrane oxygenator (Terumo, Leuven, Belgium) primed with fresh heparinized homologous blood. After establishment of full cardiopulmonary bypass, snares were tightened around the caval cannulas and ventricular fibrillation was electrically induced.

View larger version (31K): [in this window] [in a new window]   Fig. 1.   Surgical preparation: experimental biventricular circulation (A) and Fontan circulation (B).

Experimental protocol. Experiments were performed after a 20-min stabilization period to further bypass interruption. Systemic blood flow was set to its initial baseline level using only volume-loading adjustments with fresh heparinized homologous blood. Volume loading was 1.6 ± 1.2 versus 50.1 ± 6.1 ml/kg in biventricular versus Fontan circulations, respectively (P < 0.001). At that time, steady-state control hemodynamics were recorded in open-chest animals.

1

1

1

5

Data acquisition and recording. A standard lead II electrocardiogram was monitored for heart rate. A fluid-filled catheter was placed via the left subclavian artery into the aorta for aortic blood pressure (P_ao). Baseline values of P_ra, P_la, and P_pa were measured using direct puncture. At the end of the surgical preparation, indwelling fluid-filled catheters were placed in the right and left atria (biventricular) or in the pulmonary artery and left atrium (univentricular). Pressures were continuously monitored (Marquette Medical Systems, Milwaukee, WI) using disposable transducers (Baxter, Uden, Holland) that were simultaneously calibrated and zeroed to the level of the mid-right atrium. Weight-indexed pulmonary or aortic blood flow was continuously determined using ultrasound transit-time flow probes (Transonic Systems, Ithaca, NY) positioned around the pulmonary artery or ascending aorta and a precalibrated research flowmeter (Transonic). Electrocardiogram, pressures, and phasic flow signals were displayed on-line and continuously recorded on a multichannel direct-writing ink recorder (Gould, Cleveland, OH).

5

Statistical analysis. Group data are expressed as means ± SE. All data from individual pigs were stored and analyzed with a software package (Statview 5, Abacus Concepts, Berkeley, CA). Hemodynamic comparisons were performed using a Wilcoxon signed-rank test or a Mann-Whitney U test for non-normally distributed data, as appropriate. In each experiment, dependence of Q_vr on P_cv was analyzed by performing linear regression analysis. The eight slopes in each group were averaged to yield a single conductance for that curve. Q_vr parameters were skewed and thus summarized using the median, 25th, 75th, and 90th percentiles. The probability for a correlation between continuous variables was assessed using Spearman rank statistics. A value of P < 0.05 was considered statistically significant.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Surgery and steady-state hemodynamics. Biventricular and univentricular circulations were not statistically different for 1) animal weight, 32.7 ± 1.5 versus 30.2 ± 1.4 kg (P = 0.27); 2) extracorporeal circulation time, 33.8 ± 4.2 versus 38.3 ± 2.9 min (P = 0.46); and 3) ventricular fibrillation time, 11.4 ± 1.1 versus 13.5 ± 0.7 min (P = 0.12). There was no significant difference in baseline hemodynamics between biventricular and univentricular groups (Table 1). Postoperative hemodynamics were not significantly different from baseline values in biventricular circulations (Table 1). Conversely, postoperative hemodynamics in Fontan circulations, for a SBF not different from the baseline value (P = 0.49), showed marked increases in P_la, from 2.1 ± 0.5 to 7 ± 0.9 mmHg (P = 0.01), and in P_pa, from 9 ± 0.5 to 20.6 ± 1.2 mmHg (P = 0.01). PVR increased by 138 ± 37% (P = 0.02), without significant changes in SVR (Table 1). TVR after construction of Fontan circulations were higher than SVR in biventricular circulation without reaching statistical significance (P = 0.09).

Characteristics of Q_vr curves. The relationships between Q_vr and P_ra or P_la described straight lines with significant correlation coefficients (r) in each experiment and in either group (biventricular, r = 0.94 ± 0.01; univentricular, r = 0.98 ± 0.01). Figure 2 shows a representative experiment in Fontan circulations. The number of transient-induced changes in P_cv was 8.8 ± 0.4 (range 7-10) in biventricular and 7.4 ± 0.3 (range 7-9) in univentricular circulations. Figure 3 shows that estimated P_mcf was highly correlated and similar to observed P_mcf in biventricular (r = 0.94, slope = 1.09, P = 0.01) and Fontan circulations (r = 0.96, slope = 1.06, P = 0.02).

View larger version (45K): [in this window] [in a new window]   Fig. 2.   Representative experiment in Fontan circulations. A: hemodynamics effects of tightening the mitral annuloplasty. An increase in left atrial pressure (Pla) and a decrease in aortic pressure (Pao) were observed without significant change in pulmonary arterial pressure (Ppa), demonstrating the pivoting pressure of the Fontan circulatory system. B: observed mean circulatory filling pressure (Pmcf), measured 7-10 s after induction of electrical fibrillation, showing the onset of baroreflex action at a latter stage. C: linear regression analysis of transient changes in aortic blood flow/venous return. a.u., Arbitrary units.

View larger version (16K): [in this window] [in a new window]   Fig. 3.   Correlation between observed and estimated mean circulatory filling pressure (Pmcf) in biventricular () and Fontan () circulations.

Q_vr parameters in Fontan circulations. There was a downward rotation and rightward shift of the Q_vr curve in Fontan circulations (Fig. 4). Mean values and distribution of Q_vr parameters are presented in Table 2. Compared with biventricular circulations, G_vr in Fontan circulations was significantly smaller (4.51 ± 0.36 vs. 7.83 ± 0.69 ml · min¹ · kg¹ · mmHg¹, P = 0.002) and inversely correlated with PVR (r = 0.94, P = 0.01). RVR (18.55 ± 1.47 10³ dyn · s · cm⁵ · kg) was similar and strongly correlated with PVR (r = 0.98, P = 0.01; Fig. 5A).

View larger version (20K): [in this window] [in a new window]   Fig. 4.   Average venous return curves in biventricular versus Fontan circulations. Equilibrium point, steady-state systemic blood flow (SBF) where venous return = cardiac output.

View larger version (16K): [in this window] [in a new window]   Fig. 5.   Determinants of venous return in Fontan circulations: a good correlation between pulmonary vascular resistance (PVR) and resistance to venous return (RVR) (A); and a good correlation between the transpulmonary gradient and gradient for venous return expressed as estimated Pmcf  Pla (B).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The essential function of the right ventricle has been clearly demonstrated using a hydraulic model of the circulatory system (8). However, potential differences in regulatory mechanisms of Q_vr between two closed-loop circulatory systems with SVR and PVR located in series, one with a subpulmonary ventricle and the other without, remain unknown. The new findings of this study demonstrate that the pathophysiology of Fontan circulations can be analyzed according to Guyton's principles and also show marked changes in the vascular factors (i.e., G_vr and P_mcf) that determine Q_vr. Thus this study found evidence that placing SVR and PVR in series decreases G_vr. Moreover, the increase in pulmonary vascular input impedance induced a proportionally greater decrease in G_vr. The greater the decrease in G_vr, the more an increase in the pressure gradient for Q_vr is necessary to keep SBF at a biventricular level, because forces of flow resistances must be counteracted by a potential energy of pressure between P_mcf (similar to P_pa) and P_la. Taken together, these data suggest that Q_vr may be an independent variable of the SBF in Fontan circulations.

Components of the model. To compare hemodynamics between biventricular and Fontan circulations, important conditions have been fulfilled: 1) protocols were similar in both groups; 2) postoperative SBF was set to its baseline value to avoid simultaneous changes in preload, afterload, and SBF (24); 3) anesthesia caused a desirable decrease in baroreflex sensitivity (12, 18, 35); 4) use of extracorporeal circulation and transient ventricular fibrillation time did not affect hemodynamics in the biventricular group, indicating that univentricular Fontan hemodynamics were per se related to the circulatory arrangement; and 5) steady-state hemodynamic changes in P_la and PVR between baseline and experimental Fontan circulations were similar to those reported previously for either a decreased (20, 27, 36) or preserved resulting SBF (24).

G_vr in Fontan circulations. The present study demonstrates that in Fontan circulations, PVR were similar to RVR and induced the characteristic downward rotation of the Q_vr curve due to the proportional decrease in G_vr (13). Moreover, PVR values are increased in Fontan circulations (3, 20, 24, 27, 36), reducing G_vr as much. This can be related to: 1) a lack of dilatation and recruitment of the pulmonary vessels, 2) an asymmetric pulmonary perfusion, and 3) the loss of pulsatility of the pulmonary blood flow (3). The apparent resistance of pulmonary circulation to perfusion using steady flow is greater than that observed when pulsatile flow is present, accounting at worst for a fourfold increase in PVR in the neonatal period (19) precluding the use of this therapeutic approach in infancy. Mandelbaum and Burns (25) showed a 127% increase in PVR during nonpulsatile pulmonary perfusion, which is comparable to the data of the present study. Milnor et al. (26) demonstrated that estimation of the hydraulic flow obeying the Ohm's law (steady-state pressures and flows) underestimates the real energy required by SBF to go through the pulmonary vascular bed and that pulmonary impedance increases from 6 × 10³ dyn · s · cm⁵ · kg at a heart rate of 2 cycle/s to 12 × 10³ dyn · s · cm⁵ · kg at a heart rate of 0 cycle/s. Thus in the absence of pulsatility, the total (mean + pulsatile) hydraulic power is converted into a pure pressure gradient, increasing the necessary energy for the pulmonary blood flow to go through the pulmonary vascular bed.

Driving force for Q_vr in Fontan circulations. The pressure gradient for Q_vr, similar to the transpulmonary gradient, is higher than in biventricular circulations to counteract the increase in RVR. Thus Guyton's concept could be applied to Fontan circulations in which Q_vr depends on the difference between upstream pressure or vis a tergo, P_mcf, and downstream pressure or vis a fronte, P_la, for Q_vr (1, 17, 35). Therefore, slight changes in P_mcf or P_la may induce marked changes in Q_vr, as previously emphasized by Furey et al. (8).

Limitations. Use of an extracorporeal circulation could be associated with a change in venous tone. This limitation is somewhat offset because biventricular and univentricular Fontan circulations were subjected to identical study protocols, and no significant volume loading was necessary in biventricular circulations. Furthermore, experiments were performed in a sufficiently short period to avoid the occurrence of a significant stress relaxation, and volume loading, in univentricular circulations, was performed with blood, allowing a more durable vascular expansion (33). However, our preparation did not allow us to examine other factors that could influence Q_vr in univentricular circulations, such as gravity, ventilation, passive elastic recoil of the veins, venous tone, reflex, and humoral mechanisms (34, 35).

Modeling the Fontan operation. The findings of this study provide a link between changes in Q_vr-determining factors and several clinical observations, suggesting a graphical analysis of Fontan circulations (18) and consequently offering a physiological approach instead of pragmatic decision making.

View larger version (21K): [in this window] [in a new window]   Fig. 6.   Theoretical graphical analysis of Fontan circulations. A: differences in venous return curves between biventricular and univentricular Fontan circulations. Change in cardiac function curves are related to right (biventricular) vs. left (univentricular) ventricular function curves (10). B: high-risk Fontan patients with either diastolic or systolic dysfunction of the single ventricle leading to a decrease in venous return. C: effect of increased PVR in Fontan circulations (arrow 1) and volume loading counteracting this effect (arrow 2). Equilibrium point is the steady-state SBF where venous return = cardiac output.