The study’s objectives and procedures were approved by the local independent ethics committee (Comité de Protection des Personnes Nord-Ouest II, Amiens, France; RNI2014–39 on November 26th, 2014). According to French law, all patients received written information about the study and provided their verbal consent to participate. The present manuscript was drafted in compliance with the STROBE checklist for cohort studies .
This prospective, observational study was performed in the Amiens University Hospital cardiothoracic ICU (Amiens, France) during 1 year between 2015 and 2016. The main inclusion criteria were as follows: age 18 or over, controlled positive ventilation, and a clinical decision to perform FC for volume expansion within the first hours of admission to ICU. Exclusion criteria were permanent arrhythmia, cardiac conduction block, pacemaker (or need for temporary pacemaker using epicardial wires), norepinephrine, epinephrine or dobutamine, poor echogenicity, aortic regurgitation, and right heart dysfunction. The indications for FC were arterial hypotension (systolic arterial pressure (SAP) less than 90 mmHg, or mean arterial pressure (MAP) less than 65 mmHg), or SV change greater than 10% during a passive leg raising manoeuvre, or clinical signs of hypoperfusion (skin mottling, and capillary refill time greater than 3 s).
Transthoracic echocardiography (with the CX50 ultrasound system and an S5–1 Sector Array Transducer, Philips Medical System, Suresnes, France) was performed by a physician blinded to the study outcomes. Left ventricular ejection fraction (LVEF), end-systolic volume (ESV), and end-diastolic volume (EDV) were measured using Simpson’s method on a four-chamber view. The aortic velocity-time integral (VTIAo), pre-ejection time and systolic time were measured by pulsed Doppler at the left ventricular outflow tract on a five-chamber view. Stroke volume (SV; mL) was calculated as VTIAo×SAo, and was expressed as indexed SV (SVi) = SV/body surface area (ml.m− 2). Cardiac output (CO) was calculated as SV × heart rate (HR), and was expressed as indexed CO (CI) = CO/ body surface area (ml min− 1 m− 2). Mean echocardiographic parameters were calculated from five measurements (regardless of the respiratory cycle) and analysed retrospectively.
Left ventricular end-systolic elastance, arterial elastance, ventricular-arterial coupling
ELV, an index of ventricular contractility, was evaluated by using the non-invasive, single-beat method described by Chen et al. . This method is based on the assumption that time-variation of left ventricular elastance is not influenced by loading conditions or heart rate. ELV was calculated by the formula: ELV = (Pd – (ENd(test) * Pes * 0.9)) / (SV * ENd(test)). ENd(test) was obtained from a group-averaged normalized elastance curve value at this same time td (ENd(avg)), baseline LVEF and the ratio of diastolic to systolic arterial pressure (Pd / Pes) . ENd(avg) was determined by a seven-term polynomial function that includes the ratio of pre-ejection period to total systolic period . We calculated the coefficient of variation (CV), precision and least significant change (LSC) for ELV in the first ten patients. CV was 7.7% ± 0.6 and LSC was 10.9% ± 0.8.
Sunagawa et al. demonstrated that arterial load could be characterized in the time domain as arterial elastance (EA) . EA was calculated as end systolic pressure (ESP)/ SV (mmHg ml− 1) where ESP is 0.9 x systolic arterial pressure (SAP) .
Arterial pressure was measured by an invasive radial artery approach. In healthy men and women, mean EA/ELV, EA, and ELV values measured invasively at rest are 1.0 ± 0.36, 2.2 ± 0.8 mmHg.ml− 1, and 2.3 ± 1.0 mmHg.ml− 1, respectively [14, 15]. In the present study, patients with an EA/ELV ratio over 1.36 were classified as uncoupled .
The total energy generated by each cardiac contraction is called the “pressure-volume area” (PVA), corresponding to the sum of the external mechanical work exerted during systole (SW) and the potential energy (PE) stored at the end of systole: PVA = SW + PE . SW is calculated as end systolic pressure (ESP) x SV. PE is calculated as ESP x ((ESV-V0)/2), and assumes that V0 is negligible compared to ESV. The SW/PVA ratio corresponds to the mechanical efficiency of converting the total mechanical energy (PVA) available to the left ventricular SW . The SW/PVA ratio is associated to myocardial oxygen consumption.
Indexed systemic vascular resistance (SVRi) (mmHg.ml-1.m− 2) was calculated as MAP-central venous pressure (CVP)/ cardiac index (CI), and total arterial compliance (CA) (ml.mmHg− 1) was calculated as SV/arterial pulse pressure .
The following clinical parameters were recorded: demographic, ventilation parameters, and primary diagnosis. After an equilibration period, capillary refill time (measured at the distal phalanx of the index finger), heart rate (HR), systolic arterial pressure (SAP), MAP, diastolic arterial pressure (DAP), CVP, SVi, CI, EDV, ESV, pre-ejection time, systolic time interval, and blood gas levels were measured at baseline. In the present study, FC always consisted of a 10-min infusion of 500 ml of lactated Ringer’s solution [18, 19]. A second set of measurements was performed immediately after FC. All patients were mechanically ventilated in volume-controlled mode with a tidal volume set at 7–9 ml kg− 1 ideal body weight, and a positive end-expiratory pressure (PEEP) of 5–8 cmH2O. Ventilator settings were not modified during the study period.
The sample size was calculated on the reproducibility initially measured in the study reported by Chen et al. . With a reproducibility of 20%, we calculated that a sample of thirty patients would be sufficient to demonstrate an absolute change of more than 20% in the EA/ELV ratio in response to FC. The distribution of the variables was assessed by a Shapiro-Wilk test. Data are expressed as number, proportion (in per cent), mean ± standard deviation (SD) or median [interquartile range (IQR)], as appropriate. Fluid response was defined as a greater than 15% increase in SV after FC [19, 20]. This cutoff value was considered to be clinically relevant and in accordance with measurement variability. The non-parametric Wilcoxon rank sum test, Student’s paired t test, Student’s t test, and the Mann-Whitney test were used to assess statistical significance, as appropriate. A receiver-operating characteristic curve was established for the ability of EA, ELV, the EA/ELV ratio to predict a greater than 15% increase in SV. The limit for statistical significance was p < 0.05. SPSS® software (version 22, IBM, New York, NY, USA) was used for all statistical analyses.