Beat-to-beat Evaluation of Atrial Pacing to Test Fluid Responsiveness

INTRODUCTION AND RATIONALE Fluid administration is still the cornerstone in the treatment of hemodynamically unstable patients to enhance oxygen delivery and ensure adequate tissue perfusion. The intended effect is an increase in cardiac output by increasing preload.

However, the effectiveness of fluid therapy depends heavily on the patient's fluid responsiveness, defined as the ability of the heart to increase stroke volume in response to a fluid challenge [1]. Despite its central role in intensive care, fluid management remains a challenge, with both under- and over-resuscitation posing risks to patient outcomes [2,3].

Excessive fluid resuscitation, commonly referred to as "fluid overload," has been linked to adverse outcomes, including increased risk of organ dysfunction, prolonged mechanical ventilation, and higher mortality rates [4,5]. On the other hand, insufficient fluid administration can exacerbate hypoperfusion and organ failure [6]. The need for accurate and timely assessment of fluid responsiveness has therefore become a priority in optimizing care for critically ill patients [7].

Challenges in current methods for fluid responsiveness assessment Current methods for evaluating fluid status have limitations concerning their invasiveness, applicability, and sensitivity and specificity. For example, static preload indicators such as central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) have failed to reliably predict fluid responsiveness [8]. Dynamic variables such as pulse pressure variation (PPV) offer improved accuracy, but their predictive value is restricted to specific conditions [9], limiting their broader applicability [10]. Moreover, techniques like passive leg raising (PLR), though effective, are non-continuous, technically challenging, and require real-time stroke volume monitoring [11]. Premature ventricular complexes and preload variation From observational studies, preclinical data and modelling, the physiological concept of acutely varying preload and measuring the heart's contractile response has potential for assessing fluid status and predicting fluid responsiveness. A premature ventricular complex (PVC) causes such an acute preload change by causing a compensatory pause and increasing preload. Proof-of-concept studies in cardiac surgery patients [12] and critically ill populations [13] have demonstrated the potential of PVCs in predicting fluid responsiveness. However, since extrasystoles do not consistently occur in all patients, their usefulness for standardized fluid responsiveness evaluation is limited.

This limitation has led to interest in controlled methods for inducing acute preload variations. Advances in cardiac pacing technology have made it possible to manipulate heart rate and RR-intervals in a controlled manner, offering a potential solution.

Hypothesis We hypothesize that atrial pacing (AAI) with controlled variations in RR-intervals (time intervals between registered ECG beats indicated by RR-intervals) can be used to induce acute changes in both atrial and ventricular preload under wellregulated conditions in a standardized patient population. Recent computational modeling and simulation studies suggest that beat-to-beat changes in RR-intervals can lead to acute changes in left ventricular preload (e.g., end-diastolic volume and filling pressure), with the corresponding effects on systolic function (e.g., stroke volume and arterial pulse pressure) depending on the intrinsic contractility of the left ventricle [14]. Furthermore, a recent study showed that accelerated pacing reduced left-heart filling pressures in patients undergoing atrial fibrillation catheter ablation and in computer simulation models (CircAdapt) [15]. However, whether these pacing-induced changes in preload can reliably predict fluid responsiveness in critically ill patients remains unknown.

Current study This study addresses a critical gap in the assessment of fluid responsiveness by introducing a novel, minimally invasive approach that leverages atrial pacing technology. The novelty is the use of an existing pacemaker to induce different lengths of the cardiac filling cycle. If a patient has not enough filling and there is more time for filling the hearth, cardiac output will increase. This potentially marks whether a fluid bolus is indicated. If a patient does not need a fluid bolus, the pacemaker induced different lengths of the cardiac filling cycle most likely do not affect the filling of the heart in a way that it has effects on the cardiac output. This would mark a patient that does not require a fluid bolus. However, first we need to establish whether variation the cardiac filling cycle, in different patients, can change cardiac output. If successful, this method could provide a reliable tool for guiding fluid management in critically ill patients. The ability to predict fluid responsiveness with greater accuracy has the potential to optimize fluid therapy, improve patient outcomes, and reduce the risks associated with both fluid overload and inadequate resuscitation. Reducing fluid overload is a major issue in state-of-the-art intensive care medicine for decades, and further precision will favor patients. This study will improve our understanding of fluid management intensive care patients in general, and in (post-operative) patients with a pacemaker in situ this may lead to a more precise fluid balance, reducing complications of fluid overload.

By integrating physiological insights, computational modeling, and clinical investigation, this study contributes to refining critical care practices and advancing personalized medicine in the ICU setting.

Objectives of the study Primary Objective: To evaluate whether beat-to-beat ramped atrial pacing is related to fluid responsiveness in postcardiac surgery patients.

This will be assessed by analyzing changes in stroke volume induced by pacing-induced preload variations using:

• Velocity Time Integral (VTI) of the left ventricular outflow tract (LVOT) measured via non-invasive transthoracic echocardiography.
• Arterial wave form analysis derived from intra-arterial blood pressure monitoring acquired via an arterial line that is in place in routine ICU clinical practice.

Secondary Objective(s):

• To compare the degree of stroke volume change detected through VTI and pulse contour analysis with fluid responsiveness, defined as a ≥10% increase in stroke volume following the administration of a 500 mL bolus of balanced solution (Ringer's lactate).
• To validate and reproduce the clinical findings of stroke volume changes and fluid responsiveness using the CircAdapt computational model.
• To explore the relationship between changes in pacing-induced preload and other hemodynamic parameters, such as central venous pressure (CVP) and arterial pulse pressure.
• To compare the primary objectives before and after 500 mL fluid bolus.

Design This will be a prospective interventional cohort study conducted in post-cardiac surgery patients admitted to the intensive care unit (ICU) at Maastricht University Medical Center+ (MUMC+). The study is designed to investigate whether atrial pacing-induced preload variations can be detected using cardiac ultrasound and whether such detection is altered after a fluid bolus of 500ml, in order to assess whether pacemaker-induced fluid responsiveness is detectable. Duration: We will monitor the patients during the first two hours of planned ICU admission after surgery. This is in line with the routine clinical monitoring and administration of a fluid bolus. In addition, we will keep following the patient during the ICU admission and collect variables that are measured because of routine clinical care and obligatory national benchmarking for ICUs. The total study period, including data collection for all participants, is expected to be six months.

Setting: The study will be conducted in the department of Intensive Care, MUMC+

Intestigational product of intervention * No therapeutic intervention will take place. A pacemaker wire is routinely placed by the cardiac surgeon after the surgery, as part of the standard care that occurs with every surgery. As part of the study protocol, an atrial pacing protocol is performed, starting with pacing at 80 bpm, then increasing by 10 beats per minute until reaching 120 bpm, followed by a gradual decrease back to 80 bpm. This protocol is repeated after the administration of the 500 mL fluid bolus. Additionally: As part of routine care, the intensivist frequently adjusts the pacemaker in this manner to test its function.

Main study parameter/endpoint The main study parameter is the change in stroke volume measured before and after fluid administration in response to beat-to-beat atrial pacing. Stroke volume will be assessed using VTI of the LVOT via transthoracic echocardiography. This change will be compared between fluid responders (defined as a ≥10% increase in stroke volume following fluid administration) and non-responders to assess the predictive accuracy of the pacing protocol.

The secondary study parameters include:

• Arterial wave form analysis (via intra-arterial blood pressure monitoring) to compare the ability of wave form analysis to detect stroke volume changes.
• Complementation of the clinical findings with computer simulations (CircAdapt) in a comparable virtual cohort of patients
• CVP measurements during the pacing protocol to evaluate changes in preload.
• Clinical outcomes, including the incidence of any adverse events related to the pacing protocol (e.g., arrhythmias, hypotension, or complications during fluid administration).

Potential burden/risks for the study population There is no additional burden for the participant, and no extra procedures are performed other than the pacing protocol (which is also carried out in routine care for pacemaker threshold testing). The pacing protocol is performed using a routinely present pacemaker wire, and measurements are taken via a routinely placed arterial line. No additional punctures or blood samples are taken.

Specific SAEs anticipated in this study may include:

• Type 2 Wenchebach AV block
• Atrial fibrillation or other sustained arrhythmias during atrial pacing
• Hypotension requiring immediate medical intervention