Study design and oversight
An ambidirectional study of 480 semi-elective cardiac surgery patients at two community hospitals was undertaken. The study was approved by the Macquarie University Human Research Ethics Committee in Australia (Ethics Ref 5201200007), Hunter New England Human Research Ethics Committee (Ref 13/10/16/4.03), and by the Medical Advisory Committees of the two community hospitals. Patients with a logistic Euroscore [26] predicted mortality below 10% undergoing on-pump or off-pump cardiac surgery were included in the study. Data was prospectively collected with patient consent for the 67 patients managed using the pressure field between 2014 and 2017. For the conventional group, data was retrospectively extracted from a database of patients undergoing cardiac surgery between 2004 and 2012. Data on age, sex, surgery type, pre- and post-operative blood hemoglobin concentrations, and units of packed red blood cells given during bypass was collected for all patients. Intraoperative hemodynamic and intravenous fluid data was collected for the pressure field group; this data was not available for the conventional group.
Transfusion principles
For all patients, arterial blood gas measurement was performed prior to surgery, during surgery and cardiopulmonary bypass, and on completion of surgery. In all patients, allogeneic donor blood was transfused if hematocrit decreased below 20%, or if there was hemodynamic instability with a downward-trending blood hemoglobin.
Measurement and management of perfusion using fluid and vasoactive drugs
All patients were monitored with a radial intra-arterial pressure line, a central venous line, and a pulmonary artery catheter (Edwards Lifesciences, CA, US). In most of the conventional group and all the pressure field group, patients were also monitored using a FloTrac arterial transducer, a TruWave central venous pressure transducer and the EV1000 hemodynamic monitoring platform (Edwards Lifesciences, CA, US).
In the pressure field group, following insertion of lines and zeroing of all transducers, a continuous stream of pressure and stroke volume (SV) data was transmitted from the EV1000 monitoring platform via a serial-to-USB cable to an investigational software tool which displayed a ‘pressure field’. The mean arterio-venous pressure gradient (that is, [MAP–CVP]) of a specific cardiac cycle can be defined in terms of the SV contributed by the heart and the systemic elastance (Es) contributed by the vasculature such that:
$$\left[ {MAP - CVP} \right] = SV \times Es$$
(1)
where MAP is mean arterial pressure, CVP is central venous pressure, SV is stroke volume and Es = systemic elastance.
The high-frequency plotting of values according to Eq. (1) defines a ‘pressure field’. Es was calculated at the frequency at which MAP, CVP, and SV were measured in the intact circulation by the EV1000 monitoring platform, that is every 20 s. The three parameters of [MAP–CVP], SV, and Es were displayed in a 2D visualization (see Fig. 1). This visualization provides a real-time graphical view, updated every 20 s, of how ventricular-vascular interaction produces a particular pressure.
The ‘pressure field’ defined over a short interval before induction of anaesthesia generated a patient-specific template to guide the administration of fluid, pressors and inotropes during the pre-bypass period and after weaning from bypass. Vertical movements in SV may signify changes in cardiac volume (preload) or contractility, with the relative importance of each differentiated by the response to interventions; Hartmann’s solution was administered in boluses of 1 mL/kg to address issues of preload with the roller clamp otherwise kept closed, and norepinephrine was administered to address issues of contractility. Horizontal movements in Es signify changes in vasomotor tone or intra-vascular volume, with norepinephrine (NE) and low-dose glyceryl trinitrate (GTN) commenced at induction and then titrated to minimise movement in Es. Norepinephrine at 4 mcg/min was commenced 10 min before induction to prime the central venous line and the dose was then varied according to changes in the pressure field (typically between zero and 10 mcg/min), and GTN was given in a concentration of 1 mg/mL at an infusion rate of 1 mL/h throughout surgery.
All patients had two large-bore peripheral venous cannulas. In the conventional group, patients had a freely running infusion of Hartmann’s solution, and in the pressure field group both lines were clamped. Management of perfusion was otherwise according to anesthesiologist preference with NE, GTN, and dobutamine or milrinone administered as required.
In both the conventional group and the pressure field group, pressure was deliberately lowered for harvesting of venous and arterial conduits where this was requested by the surgeon, and before going onto bypass. After weaning from bypass, perfusion pressure was maintained above 65 mmHg. The conduct and management of cardiopulmonary bypass in both groups was performed by a board certified perfusionist.
The principal difference of the pressure field from the conventional group was the titration of fluid and drugs based on continuous visualization of a ‘pressure field’ (see Additional file 1).
Additional PBM interventions
Additional PBM techniques were employed. In both the conventional and pressure field groups, subjects were administered antifibrinolytics (viz. tranexamic acid) at induction and during surgery, there was careful attention to hemostasis, and the cardiopulmonary bypass circuit was primed with Ringer’s solution. In the conventional group, pump blood was directly reinfused at the completion of bypass. In the pressure field group, pump blood was directly reinfused at the completion of bypass in 48 patients; in 17 patients a cell-saver was used to scavenge blood in the surgical field, and on completion of bypass the scavenged and pump blood was spun down and reinfused as a red cell concentrate. Acute normovolemic hemodilution was not used in either group.
Outcomes and statistical analysis
The primary outcomes of the study were the change from pre-operative to completion-of-surgery blood hemoglobin, and the quantity of packed red blood cells transfused during surgery. Intravenous fluid load for the pressure field group was also examined.
Numerical variables for the conventional group and the pressure field group were compared by Welch two sample t-test, or where non-normally distributed a Wilcoxon rank sum test. Categorical variables were compared by Chi-squared test. Stepwise multiple linear regression was performed to find the predictors of blood hemoglobin concentration change, with the inputs of the statistical model being age, sex, fluid management technique (conventional or pressure field), pre-surgical blood hemoglobin concentration, and surgery type. The relationship between administered fluid where known, including units of blood, was investigated in relation to changes in hemoglobin concentration by linear regression. Analysis was conducted in R (version 4.1.1).