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Background Echocardiographic quantification of mitral regurgitation (MR) remains challenging, requiring dedicated image acquisition, and is limited by potential error from geometric assumptions of annular dimensions. Volume is a product of area and flow and assuming proportional mitral/aortic areas, an increased mitral-inflow volume compared to LV/RV-outflow semi-quantitatively represents greater MR regurgitant volume. Therefore, we investigated the feasibility and diagnostic performance of the mitral-aortic velocity-time integral (VTI) ratio in isolated MR. We also investigated the use of the mitral-pulmonary VTI ratio as an alternative in clinical situations where the LV outflow tract (LVOT) VTI could not be used. Methods We reviewed 166 consecutive patients (54 (33% severe MR by multi-parameter integrated expert opinion)). Pulsed-Doppler VTI at the mitral leaflet tips and the left ventricular outflow and continuous-wave Doppler of the right ventricular outflow tract were measured individually and independently by blinded readers (expert and trainee status) to derive the ratio. Receiver operator characteristic area under the curve (AUC) comparison was calculated and compared with effective regurgitant orifice area (EROA >40 mm), regurgitant volume (RVol >6 0mL), vena contracta (VC >0.7 cm), E-velocity >1.2 cm, systolic flow reversal (SFR), left atrial and ventricular dilatation. Results Increasing ratio was associated with severe MR (AUC 0.94) with optimal threshold defined at 1.3. This provided significant discrimination for severe MR (AUC 0.81) compared to EROA (0.68), VC (0.52), LV dilatation (0.69), LA dilatation (0.70), SFR (0.73), E-velocity (0.68) all p<0.05, with sensitivity 82% and specificity 94%. The mitral-pulmonary VTI ratio demonstrated similar discrimination (AUC 0.92) with optimal threshold defined at 1.14. Excellent inter-observer reproducibility (intra-class correlation 0.97) was seen between trainee and expert readers. There was no difference in AUC comparison by MR mechanism or patient rhythm. Conclusions The mitral-aortic or mitral-pulmonary VTI ratio is a simple, geometric-free parameter feasibly reproducible from routine echocardiographic datasets and is an excellent discriminative tool for severe MR. Readers should consider integration of this parameter in routine reporting. Funding Acknowledgement Type of funding sources: None.

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Background Beta-lactam antibiotics are the mainstay of therapy for most bacterial causes of infective endocarditis (IE). Traditionally considered as agents with a broad therapeutic index, there is increasing recognition that standard doses may be subtherapeutic or toxic in critically ill patients. Optimizing therapy for efficacy requires a defined pharmacokinetic (PK)/pharmacodynamic (PD) target associated with clinical and microbiological cure. Objectives To elucidate the factors that influence beta-lactam PK and PD variability in IE and to examine optimal PK/PD target parameters for therapy. Methods The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Clinical and laboratory in vivo animal or human studies examining PK and/or PD of beta-lactam antibiotics in IE were eligible. Ovid MEDLINE, Embase and Cochrane Central Registry were searched using defined terms. The Office of Health Assessment and Translation (OHAT) tool was used for assessing risk of bias. Results From 2677 abstracts, 62 articles were selected for review and synthesis, comprising: 45 animal studies investigating the broad categories of beta-lactam diffusion into vegetations, PK/PD determinants of outcome, mode of antibiotic delivery and synergistic impact of agents; and 17 human studies totalling 347 participants. Findings supported the importance of time-dependent killing for beta-lactams but heterogeneous data limited the determination of an optimal PK/PD target for IE treatment. Conclusion Beta-lactam PK and PD in endocarditis are variable and specific to the particular antibiotic-organism combination. Time-dependent killing is important, consistent with non-endocarditis studies, but there is little agreement on optimal drug exposure. Clinical studies examining PK/PD targets in endocarditis are required to further inform drug selection and dosing.

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