Vincent Tchana-Sato

Effects of endotoxic shock on right ventricular systolic function and mechanical efficiency

OBJECTIVE To investigate the effects of endotoxin infusion on right ventricular (RV) systolic function and mechanical efficiency. METHODS Six anesthetized pigs (Endo group) received a 0.5 mg/kg endotoxin infusion over 30 min and were compared with six other anesthetized pigs (Control group) receiving placebo for 5 h. RV pressure-volume (PV) loops were obtained by the conductance catheter technique and pulmonary artery flow and pressure were measured with high-fidelity transducers. RESULTS RV adaptation to increased afterload during the early phase of endotoxin-induced pulmonary hypertension (T30) was obtained by both homeometric and hetereometric regulations: the slope of the end-systolic PV relationship of the right ventricle increased from 1.4+/-0.2 mmHg/ml to 2.9+/-0.4 mmHg/ml (P<0.05) and RV end-diastolic volume increased from 56+/-6 ml to 64+/-11 ml (P<0.05). Consequently, right ventricular-vascular coupling was maintained at a maximum efficiency. Ninety minutes later (T120), facing the same increased afterload, the right ventricle failed to maintain its contractility to such an elevated level and, as a consequence, right ventricular-vascular uncoupling occurred. PV loop area, which is known to be highly correlated with oxygen myocardial consumption, increased from 1154+/-127 mmHg/ml (T0) to 1798+/-122 mmHg/ml (T180) (P<0.05) while RV mechanical efficiency decreased from 63+/-2% (T0) to 45+/-5% (T270) (P<0.05). CONCLUSIONS In the very early phase of endotoxinic shock, right ventricular-vascular coupling is preserved by an increase in RV contractility. Later, myocardial oxygen consumption and energetic cost of RV contractility are increased, as evidenced by the decrease in RV efficiency, and right ventricular-vascular uncoupling occurs. Therefore, therapies aiming at restoring right ventricular-vascular coupling in endotoxic shock should attempt to increase RV contractility and to decrease RV afterload but also to preserve RV mechanical efficiency.

Effective arterial elastance as an index of pulmonary vascular load.

The aim of this study was to test whether the simple ratio of right ventricular (RV) end-systolic pressure (Pes) to stroke volume (SV), known as the effective arterial elastance (Ea), provides a valid assessment of pulmonary arterial load in case of pulmonary embolism- or endotoxin-induced pulmonary hypertension. Ventricular pressure-volume (PV) data (obtained with conductance catheters) and invasive pulmonary arterial pressure and flow waveforms were simultaneously recorded in two groups of six pure Pietran pigs, submitted either to pulmonary embolism (group A) or endotoxic shock (group B). Measurements were obtained at baseline and each 30 min after injection of autologous blood clots (0.3 g/kg) in the superior vena cava in group A and after endotoxin infusion in group B. Two methods of calculation of pulmonary arterial load were compared. On one hand, Ea provided by using three-element windkessel model (WK) of the pulmonary arterial system [Ea(WK)] was referred to as standard computation. On the other hand, similar to the systemic circulation, Ea was assessed as the ratio of RV Pes to SV [Ea(PV) = Pes/SV]. In both groups, although the correlation between Ea(PV) and Ea(WK) was excellent over a broad range of altered conditions, Ea(PV) systematically overestimated Ea(WK). This offset disappeared when left atrial pressure (Pla) was incorporated into Ea [Ea * (PV) = (Pes - Pla)/SV]. Thus Ea * (PV), defined as the ratio of RV Pes minus Pla to SV, provides a convenient, useful, and simple method to assess the pulmonary arterial load and its impact on the RV function.

Alteration of Right Ventricular-Pulmonary Vascular Coupling in a Porcine Model of Progressive Pressure Overloading

In acute pulmonary embolism, right ventricular (RV) failure may result from exceeding myocardial contractile resources with respect to the state of vascular afterload. We investigated the adaptation of RV performance in a porcine model of progressive pulmonary embolism. Twelve anesthetized pigs were randomly divided into two groups: gradual pulmonary arterial pressure increases by three injections of autologous blood clot (n = 6) or sham-operated controls (n = 6). Right ventricular pressure-volume (PV) loops were recorded using a conductance catheter. Right ventricular contractility was estimated by the slope of the end-systolic PV relationship (Ees). After load was referred to as pulmonary arterial elastance (Ea) and assessed using a four-element Windkessel model. Right ventricular-arterial coupling (Ees/Ea) and efficiency of energy transfer (from PV area to external mechanical work [stroke work]) were assessed at baseline and every 30 min for 4 h. Eaincreased progressively after embolization, from 0.26 ± 0.04 to 2.2 ± 0.7 mmHg mL−1 (P < 0.05). Ees increased from 1.01 ±0.07 to 2.35 ± 0.27 mmHg mL−1 (P < 0.05) after the first two injections but failed to increase any further. As a result, Ees/Ea initially decreased to values associated with optimal SW, but the last injection was responsible for Ees/Ea values less than 1, decreased stroke volume, and RV dilation. Stroke work/PV area consistently decreased with each injection from 79% ± 3% to 39% ± 11% (P < 0.05). In response to gradual increases in afterload, RV contractility reserve was recruited to a point of optimal coupling but submaximal efficiency. Further afterload increases led to RV-vascular uncoupling and failure.

Effect of a novel thromboxane A2 inhibitor on right ventricular-arterial coupling in endotoxic shock.

We investigated the effects of a dual thromboxane (TX)A2 synthase inhibitor and TXA2 receptor antagonist (BM-573) on right ventricular-arterial coupling in a porcine model of endotoxic shock. Thirty minutes before the onset of 0.5 mg/kg endotoxin infusion, six pigs (Endo group) received an infusion with a placebo solution, and six other pigs (Anta group) with BM-573. Right ventricular pressure–volume loops were obtained by the conductance catheter technique. The slope (Ees) of the end-systolic pressure–volume relationship and its volume intercept at 25 mmHg were calculated as measures of right ventricular systolic function. RV afterload was quantified by pulmonary arterial elastance (Ea), and Ees/Ea ratio represented right ventricular-arterial coupling. Mechanical efficiency was defined as the ratio of stroke work and pressure-volume area. In this model of endotoxic shock, BM-573 blunted the early phase of pulmonary hypertension, improved arterial oxygenation, and prevented a decrease in right ventricular myocardial efficiency and right ventricular dilatation. However, the drug could not prevent the loss of homeometric regulation and alterations in right ventricular-arterial coupling. In conclusion, dual TXA2 synthase inhibitor and receptor antagonists such as BM-573 have potential therapeutic applications, improving right ventricular efficiency and arterial oxygenation in endotoxic shock.

Comparison between single-beat and multiple-beat methods for estimation of right ventricular contractility

Objective:It was investigated whether pharmacologically induced changes in right ventricular contractility can be detected by a so-called “single-beat” method that does not require preload reduction. Design:Prospective animal research. Setting:Laboratory at a large university medical center. Subjects:Eight anesthetized pigs. Interventions:End-systolic elastance values obtained by a recently proposed single-beat method (Eessb) were compared with those obtained using the reference multiple-beat method (Eesmb). Measurements and Main Results:Administration of dobutamine increased Eesmb from 1.6 ± 0.3 to 3.8 ± 0.5 mm Hg/mL (p = .001), whereas there was only a trend toward an increase in Eessb from 1.5 ± 0.2 to 1.7 ± 0.4 mm Hg/mL. Esmolol decreased Eesmb from 1.7 ± 0.3 to 1.1 ± 0.2 mm Hg/mL (p = .006), whereas there was only a trend for a decrease in Eessb from 1.5 ± 0.2 to 1.3 ± 0.1. Conclusions:The present method using single-beat estimation to assess right ventricular contractility does not work as expected, since it failed to detect either increases or decreases in right ventricular contractility induced by pharmacologic interventions.

Veno‐venous extracorporeal CO2 removal improves pulmonary hemodynamics in a porcine ARDS model

Protective lung ventilation is recommended in patients with acute respiratory distress syndrome (ARDS) to minimize additional injuries to the lung. However, hypercapnic acidosis resulting from ventilation at lower tidal volume enhances pulmonary hypertension and might induce right ventricular (RV) failure. We investigated if extracorporeal veno‐venous CO2 removal therapy could have beneficial effects on pulmonary circulation and RV function.

Effects of U-46619 on Pulmonary Hemodynamics Before and After Administration of BM-573, a Novel Thromboxane A2 Inhibitor

We studied the effects on pulmonary hemodynamics of U-46619, a thromboxane A2 (TXA 2) agonist, before and after administration of a novel TXA 2 receptor antagonist and synthase inhibitor (BM-573). Six anesthetized pigs (Ago group) received 6 consecutive injections of U-46619 at 30-min interval and were compared with six anesthetized pigs (Anta group) which received an increasing dosage regimen of BM-573 10min before each U-46619 injection. Consecutive changes in pulmonary hemodynamics, including characteristic resistance, vascular compliance, and peripheral vascular resistance, were continuously assessed during the experimental protocol using a four-element Windkessel model. At 2 mg/kg, BM-573 completely blocked pulmonary hypertensive effects of U-46619 but pulmonary vascular compliance still decreased. This residual effect can probably be explained by a persistent increase in the tonus of the pulmonary vascular wall smooth muscles sufficient to decrease vascular compliance but not vessel lumen diameter. Such molecule could be a promising therapeutic approach in TXA 2 mediated pulmonary hypertension as it is the case in pulmonary embolism, hyperacute lung rejection and endotoxinic shock.

Comparison of the effects of propofol and pentobarbital on left ventricular adaptation to an increased afterload

The purpose of this study was to compare the hemodynamic effects of pentobarbital and propofol and their effects on cardiovascular adaptation to an abrupt increase in left ventricular afterload. Experiments were performed in 12 open-chest pigs instrumented for measurement of aortic pressure and flow, and left ventricular pressure and volume. In one group (n = 6), anesthesia was obtained with sodium pentobarbital (3 mg · kg−1 · h−1), and, in the second group B (n = 6), with propofol (10 mg · kg−1 · h−1). Both groups received sufentanil (0.5 μg · kg−1 · h−1) and pancuronium bromide (0.1 mg · kg−1). Left ventricular function was assessed by the slope of end-systolic pressure-volume relationship and stroke work. After baseline recordings, left ventricular afterload was increased by aortic banding. The cardiovascular adaptations triggered by the aortic banding, such as tachycardia, vasoconstriction, and augmentation of myocardial contractility were prevented with propofol, suggesting interference with the baroreflex. Increase in left ventricular afterload decreased mechanical efficiency, regardless of anesthetic agent. These results showed that pentobarbital at 3 mg · kg−1 · h−1 has less deleterious hemodynamic effects than propofol at 10 mg · kg−1 · h−1.

Effects of increased afterload on left ventricular performance and mechanical efficiency are not baroreflex-mediated

OBJECTIVE To assess baroreflex intervention during increase in left ventricular afterload, we compared the effects of aortic banding on the intact cardiovascular system and under hexamethonium infusion. METHODS Six open-chest pigs, instrumented for measurement of aortic pressure and flow, left ventricular pressure and volume, were studied under pentobarbital-sufentanil anesthesia. Vascular arterial properties were estimated with a four-element windkessel model. Left ventricular contractility was assessed by the slope of end-systolic pressure-volume relationship. RESULTS The effects of aortic banding on mechanical aortic properties were unaffected by autonomic nervous system inhibition. However, increase in peripheral arterial vascular resistance and in heart rate were prevented by hexamethonium. Aortic banding increased left ventricular contractility and stroke work. Left ventricular-arterial coupling remained unchanged, but mechanical efficiency was impaired. These ventricular changes were independent of baroreflex integrity. CONCLUSIONS Our results demonstrate that an augmentation in afterload has a composite effect on left ventricular function. Left ventricular performance is increased, as demonstrated by increase in contractility and stroke work, but mechanical efficiency is decreased. These changes are observed independently of baroreflex integrity. Such mechanisms of autoregulation, independent of the autonomic nervous system, are of paramount importance in heart transplant patients.

Cardiovascular haemodynamics and ventriculo-arterial coupling in an acute pig model of coronary ischaemia-reperfusion

Although reperfusion after coronary occlusion is mandatory for myocardial salvage, reperfusion may trigger a cascade of harmful events (reperfusion injury) adding to myocardial injury. We investigated effects of reperfusion on left ventricular (LV) haemodynamics and ventriculo‐arterial (VA) coupling in pigs following acute myocardial ischaemia induced by coronary artery occlusion. Experiments were performed in six animals, with measurements of cardiac and arterial function at baseline, after 60 min of ischaemia (T60) and after 2 (T180) and 4 h of reperfusion (T300). Ventriculo‐arterial coupling was assessed using the ventriculo‐arterial elastance ratio of paper, as well as using a ‘stiffness coupling’ and ‘temporal coupling’ index. Reperfusion following ischaemia (T180 versus T60) induced a progressive decline in cardiovascular function, evidenced by a decrease in mean arterial blood pressure, cardiac output and ejection fraction which was not restored at T300. Although reperfusion also induced an increase in slope of the end‐systolic pressure–volume relationship (ESPVR), the ESPVR curve shifted to the right, associated with a depression of contractile function. Histology demonstrated irreversible myocardial damage at T300. The ventriculo‐arterial elastance ratio and the ‘stiffness coupling’ index were unaffected throughout the protocol, but the ‘temporal coupling’ parameter indicated a relative shift between heart period and the time constant of the arterial system. It is unlikely that these alterations are attributable to ischaemic injury alone. The combination of both the stiffness and temporal coupling index may provide more information when studying ventriculo‐arterial coupling than the more commonly used ventricular end‐systolic stiffness/effection arterial elastance (Ees/Ea) ratio.