Reflex sympatho-vagal coactivation and concealed QTc prolongation: Lessons from hERG-blockers and long QT syndromes type 1 and type 2

Background and Purposes: Several hERG blocking molecules known for their propensity in triggering Torsades de Pointes (TdP) were reported as increasing High Frequency QT oscillations (HFQT). This effect was found as reflecting a sympatho-vagal coactivation. The present work aims to characterise the mechanism(s) leading to this particular state of the autonomic nervous system. Experimental approach: Effects of 20 hERG blockers including 15 torsadogenic molecules were assessed by telemetry in beagle dogs. Electrocardiogram and stroke volume modelled from the pulse contour method were analysed at the first dose level causing either QTc prolongation and/or HFQT increase. Cardiac autonomic control was analysed using the High Frequency Autonomic Modulation (HFAM) model in dogs and in untreated genotyped LQT1 and LQT2 individuals, for comparison. Key results: The sympatho-vagal coactivation induced by torsadogenic molecules is elicited by reflex compensatory mechanisms in response to changes in stroke volume or cardiac output related to hemodynamic off-targets and/or QT prolongation. QTc prolongation was concealed or markedly blunted by the sympathetic component activation in a large proportion of tested torsadogenic drugs. Sympathetic reflex mechanisms in LQT patients similar to that found for dofetilide was also revealed in both patients exhibiting QTc prolongation and concealed QTc prolongation, irrespective to LQT type. Conclusions and implications: QTc prolongation and/or drug-induced hemodynamic side effects enhance beat to beat ventricular repolarisation variability via sympatho-vagal reflex compensatory mechanisms. Considering the sympathetic reflex component via analysis of HFQT oscillations dramatically improves prediction, sensitivity and specificity of drug induced Torsades de pointes risk assessment.

Comparison of estimation of cardiac output using an uncalibrated pulse contour method and echocardiography during veno-venous extracorporeal membrane oxygenation

Introduction: During veno-venous extracorporeal membrane oxygenation, cardiac output monitoring is essential to assess tissue oxygen delivery. Adequate arterial oxygenation depends on the ratio between the extracorporeal pump blood flow and the cardiac output. The aim of this study was to compare estimates of cardiac output and blood flow/cardiac output ratios made using an uncalibrated pulse contour method with those made using echocardiography in patients treated with veno-venous extracorporeal membrane oxygenation. Methods: Cardiac output was estimated simultaneously using a pulse contour method (MostCareUp; Vygon, Encouen, France) and echocardiography in 17 hemodynamically stable patients treated with veno-venous extracorporeal membrane oxygenation. Comparisons were made using Bland–Altman and linear regression analysis. Results: There were significant correlations between cardiac output estimated using pulse contour method and echocardiography and between blood flow/cardiac output estimated using pulse contour method and blood flow/cardiac output estimated using echocardiography (r = 0.84, p < 0.001 and r = 0.87, p < 0.001, respectively). Bland–Altman analysis showed a good agreement (bias −0.20 ± 0.50 L/min) and a low percentage of error (25%) for the cardiac output values estimated by the two methods. The bias between the blood flow/cardiac output ratios obtained with the two methods was 5.19% ± 12.3% (percentage of error = 28.1%). Conclusions: The pulse contour method is a valuable alternative to echocardiography for the assessment of cardiac output and the blood flow/cardiac output ratio in patients treated with veno-venous extracorporeal membrane oxygenation.

Using the Pulse Contour Method to Measure the Changes in Stroke Volume during a Passive Leg Raising Test

The pulse contour method is often used with the Windkessel model to measure stroke volume. We used a digital pressure and flow sensors to detect the parameters of the Windkessel model from the pulse waveform. The objective of this study was to assess the stability and accuracy of this method by making use of the passive leg raising test. We studied 24 healthy subjects (40 ± 9.3 years), and used the Medis® CS 1000, an impedance cardiography, as the comparing reference. The pulse contour method measured the waveform of the brachial artery by using a cuff. The compliance and resistance of the peripheral artery was detected from the cuff characteristics and the blood pressure waveform. Then, according to the method proposed by Romano et al., the stroke volume could be measured. This method was implemented in our designed blood pressure monitor. A passive leg raising test, which could immediately change the preloading of the heart, was done to certify the performance of our method. The pulse contour method and impedance cardiography simultaneously measured the stroke volume. The measurement of the changes in stroke volume using the pulse contour method had a very high correlation with the Medis® CS 1000 measurement, the correlation coefficient of the changed ratio and changed differences in stroke volume were r2 = 0.712 and r2 = 0.709, respectively. It was shown that the stroke volume measured by using the pulse contour method was not accurate enough. But, the changes in the stroke volume could be accurately measured with this pulse contour method. Changes in stroke volume are often used to understand the conditions of cardiac preloading in the clinical field. Moreover, the operation of the pulse contour method is easier than using impedance cardiography and echocardiography. Thus, this method is suitable to use in different healthcare fields.