Patients
Before starting the study, we obtained the agreement of our institutional review board (Comité pour la protection des personnes Ile-de-France VI, ref # 2016-A00959-42). All patients or their relatives accepted to participate in the study. It took place at a 25-bed medical intensive care unit of a university hospital between June and November 2016.
Patients were included in the study if they met the following criteria:
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Age ≥ 18 years.
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A PiCCO2 device (Pulsion Medical Systems, Feldkirchen, Germany) already in place for clinical purposes.
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Decision to perform a PLR test made by the attending physicians.
Patients were excluded if the PLR maneuver was contraindicated (intracranial hypertension), if PLR was supposed to be unreliable (venous compression stocking and intraabdominal hypertension) or if it was impossible to perform vascular Doppler measurements.
Hemodynamic measurements
All patients were equipped with a jugular or subclavian venous catheter and a thermistor-tipped femoral arterial catheter (PV2024, Pulsion Medical Systems). Hemodynamic variables were recorded continuously by using a data acquisition software (HEM 4.2, Notocord, Croissy-sur-Seine, France). Cardiac Index was recorded by the PiCCO Win 4.0 software (Pulsion Medical Systems). For all thermodilution measurements, the results obtained from three consecutive saline boluses were averaged [15, 16].
Doppler measurements
One investigator (VG) performed all ultrasound measurements. Images were analyzed and measurements were performed offline by two investigators (VG and TG). Ultrasound examination was performed with a CX50 (Philips Healthcare, Eindhoven, The Netherlands) by using a 12–5 MHz flat linear probe.
At each step of the protocol, we obtained images of the common carotid artery. First, a long-axis view of the carotid artery was obtained approximately 1–2 cm before its bifurcation. We assessed pulsed wave Doppler, the sampling volume being positioned in the middle of the lumen with caliper parallel to blood flow (Fig. 1). Time average mean velocity (TAMEAN) and peak systolic velocity (PSV) were automatically estimated by the echograph software. Velocity-time integral (VTI) was measured by manually tracing the flow envelope for each image (Fig. 1). We kept an insonation angle of 60° between Doppler beam and sample. In longitudinal view, the maximal diameter was measured from intima to intima with an angle of 90° to the vessel.
To determine carotid blood flow, we used two different methods, one based on VTI (cm) and the other on TAMEAN (cm/s):
where “r” (in cm) represents the radius of the vessel that was assumed to be circular.
In addition, we measured TAMEAN with both narrow and large sampling windows within the arterial lumen, in order to compare two different ways of calculating carotid blood flow.
Measurements were also performed at the level of the common femoral artery before the bifurcation into superficial femoral artery and deep femoral artery. Blood flow, peak systolic velocity and diameter were measured with the same method and formulas as described before. Nevertheless, at this level, the only method that was used to measure femoral blood flow was the one based on VTI. Indeed, the contour of the femoral velocity that was automatically traced by the device for measuring time average mean velocity included both positive and negative values of femoral velocities, eventually providing very low values of TAMEAN. We decided to trace the contour manually, including only the positive values in the measurement of VTI.
Study design
At baseline, a first set of transpulmonary thermodilution and Doppler measurements were recorded (Additional file 1: Figure S1). Two PLR tests (“PLR1” and “PLR2”) were then consecutively performed because it was not feasible to simultaneously record carotid and femoral Doppler indices during the same PLR test. The PLR position was maintained until the maximal value of pulse contour analysis-derived cardiac index was reached, what always occurs within 1 min [5]. Between the two PLR tests, we waited for approximately 5 min to obtain stable hemodynamic baseline values. Each PLR test was performed as previously described [6]. At its maximum effect, a second set of hemodynamic and Doppler measurements was performed (Additional file 1: Figure S1). The effects of PLR on cardiac output were measured by pulse contour analysis and not by transpulmonary thermodilution because these effects must be assessed by a real-time monitoring technique [6]. In practice, we observed the continuously changing value of pulse contour analysis-derived cardiac index while performing the Doppler measurements. As soon as the cardiac index value started to decrease, we considered that it had reached its maximum. At this precise time, we froze the image of the echograph and performed the Doppler measurements on the values displayed during the previous seconds. If pulse contour analysis-derived cardiac index increased ≥ 10% during the PLR tests, compared to the baseline value, the patient was regarded as responder to the tests [8]. In total, the two PLR tests were performed within 15 min.
After the second PLR, another transpulmonary thermodilution was performed. Then, according to the decision of the clinicians in charge, only responders to the first PLR test were given 500 mL of normal saline over 10 min. All echographic and hemodynamic variables were then recorded at the end of fluid infusion, including transpulmonary thermodilution (Additional file 1: Figure S1). Catecholamines dosages and ventilation settings were kept constant during the study period.
Data analysis
All data were normally distributed (Kolmogorov–Smirnov test for normality). Date are expressed as mean ± standard deviation (SD) or number and frequency (n, %). Comparison between time points of the study was performed using paired Student’s t tests. Comparison between PLR responders and non-responders was performed using two-tailed Student’s t tests. Pearson correlation coefficient was calculated to compare carotid/femoral blood flow and cardiac index as well as their relative changes following PLR and fluid infusion. A receiving operating characteristics (ROC) curve was constructed to evaluate the ability of the PLR-induced changes in carotid and femoral blood flows and velocities to detect responsiveness to PLR. The inter- and intraindividual variability of carotid Doppler measurements were also calculated. Considering a α-risk of 20% and a β-risk of 10%, to evidence an increase in 20% of carotid and femoral blood flows during PLR [9, 10], we planned to include 50 cases in the study. Statistical significance was defined by a p value < 0.05. The statistical analysis was performed using MedCalc 11.6.0 software (MedCalc, Mariakerke, Belgium).