Alexandre Ghuysen

Computed tomographic pulmonary angiography and prognostic significance in patients with acute pulmonary embolism

Background: Patients with acute pulmonary embolism (APE) present with a broad spectrum of prognoses. Computed tomographic pulmonary angiography (CTPA) has progressively been established as a first line test in the APE diagnostic algorithm, but estimation of short term prognosis by this method remains to be explored. Methods: Eighty two patients admitted with APE were divided into three groups according to their clinical presentation: pulmonary infarction (n = 21), prominent dyspnoea (n = 29), and circulatory failure (n = 32). CTPA studies included assessment of both pulmonary obstruction index and right heart overload. Haemodynamic evaluation was based on systolic aortic blood pressure, heart rate, and systolic pulmonary arterial pressure obtained non-invasively by echocardiography at the time of diagnosis of pulmonary embolism. Results: The mortality rate was 0%, 13.8% and 25% in the three groups, respectively. Neither the pulmonary obstruction index nor the pulmonary artery pressure could predict patient outcome. In contrast, a significant correlation with mortality was found using the systolic blood pressure (p<0.001) and heart rate (p<0.05), as well as from imaging parameters including right to left ventricle minor axis ratio (p<0.005), proximal superior vena cava diameter (p<0.001), azygos vein diameter (p<0.001), and presence of contrast regurgitation into the inferior vena cava (p = 0.001). Analysis from logistic regression aimed at testing for mortality prediction revealed true reclassification of 89% using radiological variables. Conclusion: These results suggest that CTPA quantification of right ventricular strain is an accurate predictor of in-hospital death related to pulmonary embolism.

New Developments on Thromboxane and Prostacyclin Modulators Part I: Thromboxane Modulators

The pathogenesis of numerous cardiovascular, pulmonary, inflammatory, and thromboembolic diseases can be related to arachidonic acid (AA) metabolites. One of these bioactive metabolites of particular importance is thromboxane A(2) (TXA(2)). It is produced by the action of thromboxane synthase on the prostaglandin endoperoxide H(2)(PGH(2)), which results from the enzymatic degradation of AA by the cyclooxygenases. TXA(2) is a potent inducer of platelet aggregation, vasoconstriction and bronchoconstriction. It is involved in a series of major pathophysiological states such as asthma, myocardial ischemia, pulmonary hypertension, and thromboembolic disorders. Therefore, TXA(2) receptor antagonists, thromboxane synthase inhibitors and drugs combining both properties have been developed by several pharmaceutical companies since the early 1980s. Several compounds have been launched on the market and others are under clinical evaluation. Moreover, the recent literature reported the interest of thromboxane modulators, which combine another pharmacological activity such as, platelet activating factor antagonism, angiotensin II antagonism, or 5-lipoxygenase inhibition. In this review, we will propose a description of the recently described thromboxane modulators of major interest from both a pharmacological and a chemical point of view.

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.

Model-based cardiac diagnosis of pulmonary embolism

A minimal cardiac model has been shown to accurately capture a wide range of cardiovascular system dynamics commonly seen in the intensive care unit (ICU). However, standard parameter identification methods for this model are highly non-linear and non-convex, hindering real-time clinical application. An integral-based identification method that transforms the problem into a linear, convex problem, has been previously developed, but was only applied on continuous simulated data with random noise. This paper extends the method to handle discrete sets of clinical data, unmodelled dynamics, a significantly reduced data set theta requires only the minimum and maximum values of the pressure in the aorta, pulmonary artery and the volumes in the ventricles. The importance of integrals in the formulation for noise reduction is illustrated by demonstrating instability in the identification using simple derivative-based approaches. The cardiovascular system (CVS) model and parameter identification method are then clinically validated on porcine data for pulmonary embolism. Errors for the identified model are within 10% when re-simulated and compared to clinical data. All identified parameter trends match clinically expected changes. This work represents the first clinical validation of these models, methods and approach to cardiovascular diagnosis in critical care.

Model-based identification and diagnosis of a porcine model of induced endotoxic shock with hemofiltration

A previously validated cardiovascular system (CVS) model and parameter identification method for cardiac and circulatory disease states are extended and further validated in a porcine model (N=6) of induced endotoxic shock with hemofiltration. Errors for the identified model are within 10% when the model is re-simulated and compared to the clinical data. All identified parameter trends over time in the experiments match clinically expected changes both individually and over the cohort. This work represents a further clinical validation of these model-based cardiovascular diagnosis and therapy guidance methods for use with monitoring endotoxic disease states.

Comparison of functional residual capacity and static compliance of the respiratory system during a positive end-expiratory pressure (PEEP) ramp procedure in an experimental model of acute respiratory distress syndrome

IntroductionFunctional residual capacity (FRC) measurement is now available on new ventilators as an automated procedure. We compared FRC, static thoracopulmonary compliance (Crs) and PaO2 evolution in an experimental model of acute respiratory distress syndrome (ARDS) during a reversed, sequential ramp procedure of positive end-expiratory pressure (PEEP) changes to investigate the potential interest of combined FRC and Crs measurement in such a pathologic state.MethodsARDS was induced by oleic acid injection in six anesthetised pigs. FRC and Crs were measured, and arterial blood samples were taken after induction of ARDS during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O.ResultsARDS was responsible for significant decreases in FRC, Crs and PaO2 values. During ARDS, 20 cm H2O of PEEP was associated with FRC values that increased from 6.2 ± 1.3 to 19.7 ± 2.9 ml/kg and a significant improvement in PaO2. The maximal value of Crs was reached at a PEEP of 15 cm H2O, and the maximal value of FRC at a PEEP of 20 cm H2O. From a PEEP value of 15 to 0 cm H2O, FRC and Crs decreased progressively.ConclusionOur results indicate that combined FRC and Crs measurements may help to identify the optimal level of PEEP. Indeed, by taking into account the value of both parameters during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O, the end of overdistension may be identified by an increase in Crs and the start of derecruitment by an abrupt decrease in FRC.

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.

Validation of subject-specific cardiovascular system models from porcine measurements

A previously validated mathematical model of the cardiovascular system (CVS) is made subject-specific using an iterative, proportional gain-based identification method. Prior works utilised a complete set of experimentally measured data that is not clinically typical or applicable. In this paper, parameters are identified using proportional gain-based control and a minimal, clinically available set of measurements. The new method makes use of several intermediary steps through identification of smaller compartmental models of CVS to reduce the number of parameters identified simultaneously and increase the convergence stability of the method. This new, clinically relevant, minimal measurement approach is validated using a porcine model of acute pulmonary embolism (APE). Trials were performed on five pigs, each inserted with three autologous blood clots of decreasing size over a period of four to five hours. All experiments were reviewed and approved by the Ethics Committee of the Medical Faculty at the University of Liege, Belgium. Continuous aortic and pulmonary artery pressures (P(ao), P(pa)) were measured along with left and right ventricle pressure and volume waveforms. Subject-specific CVS models were identified from global end diastolic volume (GEDV), stroke volume (SV), P(ao), and P(pa) measurements, with the mean volumes and maximum pressures of the left and right ventricles used to verify the accuracy of the fitted models. The inputs (GEDV, SV, P(ao), P(pa)) used in the identification process were matched by the CVS model to errors <0.5%. Prediction of the mean ventricular volumes and maximum ventricular pressures not used to fit the model compared experimental measurements to median absolute errors of 4.3% and 4.4%, which are equivalent to the measurement errors of currently used monitoring devices in the ICU (∼5-10%). These results validate the potential for implementing this approach in the intensive care unit.

Unique parameter identification for cardiac diagnosis in critical care using minimal data sets

Lumped parameter approaches for modelling the cardiovascular system typically have many parameters of which a significant percentage are often not identifiable from limited data sets. Hence, significant parts of the model are required to be simulated with little overall effect on the accuracy of data fitting, as well as dramatically increasing the complexity of parameter identification. This separates sub-structures of more complex cardiovascular system models to create uniquely identifiable simplified models that are one to one with the measurements. In addition, a new concept of parameter identification is presented where the changes in the parameters are treated as an actuation force into a feed back control system, and the reference output is taken to be steady state values of measured volume and pressure. The major advantage of the method is that when it converges, it must be at the global minimum so that the solution that best fits the data is always found. By utilizing continuous information from the arterial/pulmonary pressure waveforms and the end-diastolic time, it is shown that potentially, the ventricle volume is not required in the data set, which was a requirement in earlier published work. The simplified models can also act as a bridge to identifying more sophisticated cardiac models, by providing an initial set of patient specific parameters that can reveal trends and interactions in the data over time. The goal is to apply the simplified models to retrospective data on groups of patients to help characterize population trends or un-modelled dynamics within known bounds. These trends can assist in improved prediction of patient responses to cardiac disturbance and therapy intervention with potentially smaller and less invasive data sets. In this way a more complex model that takes into account individual patient variation can be developed, and applied to the improvement of cardiovascular management in critical care.