WO2025193619A1 - An electrochemical catheter based on saline electrodilution for physiological flow measurement - Google Patents

Abstract

An electrochemical catheter for measurement of physiological flow comprises an elongated catheter shaft comprising an outer wall and plurality of lumens extending between a proximal end portion and a distal end portion, the distal end portion comprising a distal tip portion; an electrochemical cell sensor comprising a plurality of microwire electrode leads, each lead being partially exposed through the outer wall of the shaft at the distal end portion; an analyte injection port at the proximal end portion of the shaft; and an analyte release port at the distal end portion of the shaft, proximal to the electrochemical cell sensor. The electrochemical cell sensor is configured to generate a current signal proportional to a change in concentration of an analyte indicator between the analyte injection port and the analyte release port.

Description

An Electrochemical Catheter Based on Saline Electrodilution for Physiological Flow Measurement CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority to United States Provisional Application Number 63/563,675 that was filed on March 11, 2024. The entire content of the applications referenced above is hereby incorporated by reference herein. S^TATEMENT R^EGARDING F^EDERALLY S^PONSORED R^ESEARCH This invention was made with government support under Grant No. EB027299 awarded by the National Institutes of Health. The U.S. government has certain rights in the invention. B^ACKGROUND Oxygen is distributed to the body through blood that is continuously pumped by the heart. The amount of blood that the heart outputs to the body is referred to as cardiac output. Cardiac output is an aggregate marker of health and is often measured in critically ill patients and those undergoing certain surgical procedures. Currently, thermodilution is an indicator-dilution approach to estimating blood flow and is referred as the de facto clinical-standard of cardiac output measurement. For thermodilution cardiac output measurement, a physician advances a specialized catheter – equipped with a thermistor to sense changes in temperature – from a central vein through the right-heart and to the pulmonary trunk. The physician then makes controlled injections of cooler-than-blood saline in the right atrium of the heart. As the saline bolus mixes with the flowing blood, there is an induced drop in the local temperature of blood. The thermistor observes a small change in the local temperature of the blood (generally <1℃) followed by a more gradual recovery up to baseline temperature. With calibration, these temperature changes can be used to estimate cardiac output. However, correlating small changes in temperature to flow rate can lead to poor reliability due to numerous confounding factors. Indicator loss is the biggest challenge with thermodilution and is defined as the diminishing temperature difference between the injected saline solution and the flowing blood. As the procedure is performed, the saline solution will unavoidably and continuously conduct heat from the room or catheter wall in contact with warm blood. Consequently, cardiac output measurements made using thermodilution are considered to have a precision error of 20%. It is evident that small changes in temperature are a poor proxy to flow rate. Accordingly, new medical devices and methods are needed to measure cardiac output with improved accuracy, reproducibility, and repeatability. S^UMMARY Certain embodiments provide an electrochemical catheter for measurement of physiological flow comprising: an elongated catheter shaft comprising an outer wall and plurality of lumens extending between a proximal end portion and a distal end portion, the distal end portion comprising a distal tip portion; an electrochemical cell sensor comprising a plurality of microwire electrode leads, each lead being partially exposed through the outer wall of the shaft at the distal end portion; an analyte injection port at the proximal end portion of the shaft; and an analyte release port at the distal end portion of the shaft, proximal to the electrochemical cell sensor; wherein the electrochemical cell sensor is configured to generate a current signal proportional to a change in concentration of an analyte indicator between the analyte injection port and the analyte release port. In certain embodiments, the microwire electrode leads comprise platinum-iridium microwires. In certain embodiments, the distal tip portion is configured for placement in a subject’s pulmonary artery. In certain embodiments, the electrochemical catheter further comprises an inflatable distal tip balloon at the distal tip portion of the catheter. In certain embodiments, the analyte release port is configured for placement in a subject’s right atrium. In certain embodiments, the analyte indicator comprises hypertonic saline. In certain embodiments, the electrochemical cell sensor is configured to measure at least one of the following physiological flow rates: cardiac blood flow rate, circulatory system blood flow rate, extracorporeal blood flow rate, cerebrospinal fluid flow rate, pleural fluid flow rate, and urine flow rate. In certain embodiments, the change in concentration of the analyte indicator is inversely related to a measured flow rate of a physiological fluid. Certain embodiments provide a system for determining a measurement of physiological flow comprising: the electrochemical catheter; and a processor communicatively linked to the electrochemical catheter; wherein the processor is configured to determine a measurement of physiological flow based on a scoring algorithm. In certain embodiments, the scoring algorithm comprises: a) recording a current signal generated by the electrochemical cell sensor; b) extracting a current envelope from the current signal; c) isolating an injection wavelet from the current envelope; d) determining a baseline of the injection wavelet; e) calculating an electrodilution metric using the baseline of the injection wavelet; and f) optionally, repeating steps a-e. In certain embodiments, the algorithm further comprises generating an electrodilution curve. In certain embodiments, the electrodilution metric comprises a change in total charge defined by the area under the electrodilution curve. In certain embodiments, the processor is configured to determine a measurement of cardiac output. In certain embodiments, the system further comprises a display configured to display the measurement of physiological flow. In certain embodiments, the display is further configured to display the current signal generated by the electrochemical cell sensor. In certain embodiments, the display is configured to display a measurement of cardiac output. Other objects, features, and advantages of the present invention will be apparent to one of skill in the art from the following detailed description and figures. BRIEF DESCRIPTION OF DRAWINGS The present application can be understood by reference to the following drawings, wherein like reference numerals represent like elements. The drawings are merely exemplary to illustrate certain features that may be used singularly or in combination with other features and the present application should not be limited to the embodiments shown. Figure 1: Schematic illustration of an embodiment of a saline indicator-dilution based electrochemical pulmonary artery catheter in accordance with the present disclosure. Figure 2: Computer-aided design (CAD) model of the catheter of Figure 1. Figure 3: Block diagram of a system for determining a measurement of physiological flow in accordance with the present disclosure. Figure 4: Schematic of an embodiment of a display of the system of Figure 3. Figure 5: (A) Measured current signal over time for three hypertonic saline injections at each of six flow rates for SBF—from 5 to 0.1 L/min using Pt-Ir|Pt-Ir. (B) The measured current signal after a single injection; the densely sampled sinusoidal AC signal appears as a filled curve; (C) the positive envelope of the measured current signal is extracted to obtain the electrodilution curve. (D) The electrodilution metric Max Percent Change is determined from characteristic. Figure 6: (A) Effect of the flow rate of SBF under steady flow conditions on the electrodilution metric Max Percent Change for each electrode material configuration studied. The data represent average and one standard deviation for N = 12. (B) Cyclic voltammograms at the peak response and baseline for saline electrodilution in SBF for each electrode material configuration studied. The data visualized is for one hypertonic saline injection at 0.1 L/min. Figure 7: (A) The frequency spectrum of the transient current measured showing the first ten harmonics of the fundamental frequency (fo=10 Hz). (B) The corresponding percent change in current amplitude between baseline and peak response at each harmonic. Figure 8: 3D model of the novel electrochemical catheter prototype for cardiac output measurement using the electrodilution approach. The right atrium infusion port was used to mount platinum-iridium microwires to the catheter wall. All incisions were sealed to leave only the catalyst electrodes exposed to the flowing media. Figure 9: (A) Measured current signal over time for one hypertonic saline injection at each of seven flow rates of anticoagulated porcine blood—from 3.5 to 0.5 L/min using the novel electrochemical catheter. (B) The measured current signal after a single injection; the densely sampled sinusoidal AC signal appears as a filled curve; (C) the positive envelope of the measured current signal is extracted to obtain the electrodilution curve. (D) The electrodilution metric ∆ Total Charge is determined from characteristic landmarks of the electrodilution curve. All experiments were carried out at LASV parameters of 2 V_pk and 100 Hz sampled at 2.5 kHz. Figure 10: (A) Effect of the flow rate of anticoagulated porcine blood under pulsatile flow conditions on the electrodilution metric Δ Total Charge. (B) CO estimate determined using Eq.3 with K=0.394. The data was collected using the novel electrochemical catheter prototype. The data represent average and one standard deviation for N = 8. Figure 11: (A) Measured current signal over time for three hypertonic saline injection at each of three flow rates of anticoagulated porcine blood—from 1.75 to 8.3 L/min using the novel electrochemical catheter. (B) Effect of the flow rate of anticoagulated porcine blood under steady flow conditions on the electrodilution metric Δ Total Charge. (C) CO estimate determined using Eq.3 with K=0.394. Figure 12: Visualization of the measured current data from in vivo cardiac output measurement using the electrodilution approach in adult pigs. Data acquired from one hypertonic saline injection for (A) animal 1 under normal conditions, (B) animal 1 with increased cardiac output due to volume responsiveness, (C) animal 2 under normal conditions, and (D) animal 2 with diminished cardiac output due to lung injury. All measurements were carried out at LASV parameters of 2 V_pk and 100 Hz sampled at 2.5 kHz. Figure 13: Animal data summary showing estimated cardiac output measurements. Figure 14: Flow chart of the semi-automated MATLAB scoring algorithm used to calculate electrodilution metrics. Figure 15: Schematic illustrations and dimensions of the microelectrodes used for the sensing electrochemical cell configurations. (A) Platinum-Iridium (tip) and Stainless Steel (collar) microelectrode assembly used for (Pt-Ir|St.St.) and (Pt-Ir|Pt-Ir) configurations. (B) Glassy carbon microelectrode assembly used for (GC) configurations. (C) Y-junction used to mount our electrochemical cell in series in our flow loop apparatus. The (Pt-Ir|Pt-Ir) configuration is shown schematically. The electrode surface area for Platinum-Iridium, Stainless Steel, and Glassy Carbon is 0.078 mm², 0.26 mm², and 0.00091 mm², respectively. Figure 16: Schematic diagram of the experimental flow loop apparatus used for steady flow conditions. Figure 17: Schematic diagram of the electrochemical pulmonary artery catheter with Pt- Ir|Pt-Ir sensing cell configuration. The surface areas of the both the working and counter electrodes are 0.465 mm². Figure 18: Schematic diagram of the experimental flow loop apparatus for pulsatile flow conditions. DETAILED DESCRIPTION Referring now to the drawings wherein like reference numerals are used to identify like elements in the various views, Figure 1 is a schematic illustration of an embodiment of a saline indicator-dilution based electrochemical pulmonary artery (PA) catheter (also referred to as “electrochemical PA catheter” or “catheter”) 100 within the heart anatomy and the associated electrodilution operating principle. The electrochemical PA catheter 100 leverages well- developed principles from electrochemistry and fluid mechanics for in vivo physiological flow measurement, such as cardiac output (the blood flow rate of the heart). While the presently disclosed catheter 100 is described herein as a PA catheter for measuring cardiac output, it should be noted that the catheter 100 can be used for other physiological flow measurements, both within and outside the heart. For example, the catheter 100 can be used to measure blood flow rate in specific vessels in the circulatory system, such as the coronary arty and the cerebral artery. The catheter 100 can be used to measure blood flow rates during extracorporeal flow (e.g., ECMO) and blood flow rates during dialysis. The catheter 100 can also be used for cerebrospinal fluid (CSF) flow rate measurement, such as the flow rate of CSF in the spinal canal or in shunt devices (e.g., hydrocephalus shunt). Additionally, the catheter 100 can be used to measure the flow of other physiological fluids, such as pleural fluid from the chest or urine flow within the urinary system or extracorporeally. Clinically, cardiac output is most often measured by thermodilution, in which cold saline is injected into the flowing blood and the resulting changes in local blood temperature are used to estimate its flow rate. The electrochemical PA catheter 100 is a novel alternative to this method, as it circumvents the unavoidable confounding factors related to temperature that lead to limitations in accuracy and reliability. While the catheter 100 retains operational similarity for flow measurement compared to the clinical-standard, it is equipped with a microelectrode electrochemical cell sensor 102 at the distal tip, which is configured to be placed in the pulmonary artery (e.g., the pulmonary truck) of a mammalian subject (e.g., a patient). The electrochemical cell sensor 102 operates using the principle of electrodilution to generate signals that are proportional to instantaneous changes in saline concentration of the physiological fluid. This approach circumvents issues associated with using temperature and provides more robust data for signal analysis that leads to more accurate flow estimates. As shown in Figure 2, the electrochemical PA catheter 100 includes an elongated catheter shaft (e.g., 7.5 French diameter) having an outer wall 104 and a plurality of lumens 106a-f extending between a proximal end portion and a distal end portion (Figure 2 shows the distal end portion). The distal end portion includes a distal tip portion. In some embodiments, the distal tip portion includes an inflatable distal tip balloon 108 (shown in Figure 1). The electrochemical cell sensor 102 at the distal end portion of the catheter 100 includes at least two microwire electrode leads 110a, 110b. In an embodiment, the microwire electrode leads 110a, 110b are platinum-iridium microwires. In other embodiments, the microwire electrode leads 110a, 110b are made from alternative materials, such as stainless steel and glassy carbon. The microwire electrode leads 110a, 110b can be insulated by copper wire, for example. As shown in Figure 2, each microwire electrode lead 110a, 110b is partially exposed through the outer wall 104 of the catheter shaft at the distal end portion. This allows the microwire electrode leads 110a, 110b to make contact with flowing blood within the heart and/or pulmonary artery. The catheter 100 also includes an analyte injection port 112 at the proximal end portion of the shaft and an analyte release port 114 at the distal end portion of the shaft, proximal to the electrochemical cell sensor 102 (shown in Figure 1). The analyte release port 114 is configured to be placed the right atrium of a subject. The catheter 100 operates according to the principle of electrodilution. When voltage is applied to microwire electrode leads 110a, 110b in contact with blood (e.g., the partially exposed portions), the introduction and commixture dilution of an analyte indicator, such as hypertonic saline (e.g., 7 wt. % NaCl), results in a charge transfer (faradaic process) and/or charge redistribution (capacitive process) and release a measurable change in the current magnitude. These temporal changes in current—current dilution—are related to the blood flow rate because faster flow rates result in quicker dilution. For cardiac output measurements the catheter 100 can be advanced into the right-heart anatomy, so the tip of the catheter sits in the pulmonary trunk (see Figure 1). The microwire electrode leads 110a, 110b are polarized, and the resulting current signal is recorded. A manual injection of saline analyte bolus is made into the right atrium via analyte injection port 112. The bolus mixes with blood and flows towards the electrochemical sensor 102. As the bolus passes over the sensor 102, a measurable response and recovery in the current signal is recorded. The strength of the response and its recovery time will be affected by the flow rate of blood. The signal response is then processed and used to estimate cardiac output. The two microwire electrode leads 110a, 110b can be used as a sensor by applying the electrochemical technique of large-amplitude sinusoidal voltammetry (e.g., with AC parameters of 2V_pk, 100Hz). When the polarized microwire electrode leads 110a, 110b are in contact with flowing blood, a baseline current signal is measured. This electrochemical signal is sensitive to perturbations in local concentrations of analyte of the flowing blood at the vicinity of the electrodes. Therefore, controlled injections of hypertonic saline (7wt% NaCl) analyte bolus into the flowing blood can be used to induce a measurable change in the current signal that is proportional to cardiac output. Referring again to Figure 1, the analyte bolus is released in the right atrium and mixes with the flowing blood. The distal electrochemical cell sensor 102 detects changes in local concentration of the analyte-blood mixture over time. A model current envelope illustrates the response to analyte injection at the different stages of electrodilution. At stage (a), the analyte indicator is injected. At stage (b), the current response is initiated as the mixture reaches the electrochemical cell 102. At stage (c), peak current response to the injectate mixture is recorded. At stage (d), dilution by the continued flow of blood, and the resulting decrease in current, is observed. At stage (e), the current returns to baseline. The area under the curve represents the total change in charge, which is inversely proportional to cardiac output. This is because a smaller change in total charge corresponds to a faster flow rate (larger cardiac output). In other words, the faster flow rate means there is greater dilution of the analyte indicator (and therefore less current response; i.e., less change in total current from baseline) and a quicker return to baseline (and therefore a shorter time period of that response), both of which will result in a smaller area under the curve. Similarly, a larger change in total charge corresponds to a slower flow rate (smaller cardiac output) because a slower flow rate means there is lesser dilution of the analyte indicator (and therefore greater current response; i.e., more change in total current from baseline) and a slower return to baseline (and therefore a greater time period of that response), both of which will result in a larger area under the curve. Figure 3 is a block diagram illustrating an embodiment of a system 300 for determining a measurement of physiological flow, such as cardiac output, including the catheter 100. The system also includes a processor 116 and a display 118, communicatively linked (e.g., via a wireless or wired connection) to each other and to the catheter 100. The processor 116 is configured to determine a measurement of physiological flow based on a scoring algorithm (see Figure 14). The scoring algorithm can be semi-automated (e.g., a semi-automated MATLAB scoring algorithm), with some steps requiring user interaction and some steps being automated. In an embodiment, the scoring algorithm includes the following steps: a) recording a current signal generated by the electrochemical cell sensor; b) extracting a current envelope from the current signal; c) isolating an injection wavelet from the current envelope; d) determining a baseline of the injection wavelet; e) calculating an electrodilution metric using the baseline of the injection wavelet; and f) optionally, repeating steps a)-e). In an embodiment, the algorithm further includes generating an electrodilution curve, and the electrodilution metric is the change in total charge defined by the electrodilution curve. Figure 4 is an example of a display 118a showing output from the scoring algorithm. The output can include the full current signal acquired from the catheter 100, an isolated response signal to the injection of the analyte indicator, the estimated cardiac output determined from the scoring algorithm, and the estimated heart rate (which can be calculated from cardiac output according to the Fick principle, as known to those of ordinary skill in the art). The invention will now be illustrated by the following non-limiting Examples. E^XAMPLES Example 1. Electrochemical Catheter for Cardiac Output Monitoring Introduction In vivo measurement of cardiac output—the blood flow rate of the heart—is often necessary for monitoring critically ill patients and those undergoing certain surgical procedures. Cardiac output is a key aggregate marker of cardiac performance and is considered an integral part of therapeutic approaches to sustain adequate tissue oxygenation. Unlike flow measurement of synthetic fluids in man-made structures, physiological fluid flow measurement is significantly more challenging because flow occurs in arbitrarily shaped structures, presents limited access to these conduits, and poses risks of complications from the measurement itself (Reuter et al., 2010; Argueta and Paniagua, 2019). Many invasive and non-invasive approaches to blood flow measurement have been developed (Alkhodair et al., 2018; Grensemann, 2018; Saugel et al., 2019; Demir et al., 2022; Murata et al., 2022). In general, non-invasive methods have poor reproducibility and reliability, as it is difficult to calibrate for intra- and inter-patient variability and other confounding factors (Caruso et al., 2002; Altamirano-Diaz et al., 2018; Sanders et al., 2020). As a result, invasive approaches are more often used in the intensive care and operating room settings (Beurton et al., 2019; Kusaka et al., 2019; Vetrugno et al., 2019; Murata et al., 2022). Furthermore, clinicians can acquire additional information using invasive techniques – otherwise not accessible via non-invasive approaches – that may be used in decision making while treating critically ill patients or monitoring perioperative patients (Swan et al., 1970; Eisenberg et al., 1984; Reuter et al., 2010). Most invasive techniques used in the clinic are based on indicator-dilution methods (Argueta and Paniagua, 2019) with thermodilution (TD) being the de facto clinical-standard of cardiac output measurement (Reuter et al., 2010). For TD cardiac output measurement, a physician will advance a specialized pulmonary artery catheter – equipped with a distal-tip thermistor to sense changes in temperature and ports for infusion – from a peripheral vein through the right-heart anatomy until the tip of the catheter is within the pulmonary artery trunk. The physician would then make controlled injections of cooler-than-blood saline in the right atrium of the heart. As the saline bolus mixes with the flowing blood, there is an induced drop in the local temperature. The thermistor distal to the injection observes a small change in the local temperature of the blood (generally <1℃) followed by a more gradual recovery up to baseline temperature. With calibration, this temperature response curve can be used to estimate cardiac output (Hosie et al., 1964; Ganz et al., 1971). However, correlating small changes in temperature to flow rate can lead to inaccuracies due to numerous confounding factors (Runciman et al., 1981; Nishikawa and Dohi, 1993). Indicator loss is the diminishing temperature difference between the injected saline solution and the flowing blood. As the procedure is performed the saline solution will unavoidably and continuously conduct heat from the room or catheter wall in contact with warm blood. Consequently, the signal-to-noise ratio of the change in temperature response signal is negatively affected and may lead to up to signal loss (Kim and Lin, 1980; Runciman et al., 1981). This is a significant source of error for TD and results in overestimation and irreproducibility. In fact, studies suggest that each degree of warming of the saline solution will result in overestimation of cardiac output (Wong et al., 1978; Nelson and Anderson, 1985; Reuter et al., 2010). Another factor that plays a role in TD inaccuracies is patient breathing. It is well established that baseline temperatures oscillate due to patient breathing, and as a result clinicians should aim to make saline injections at the same point in the patient’s respiratory cycle. If the clinician does not regard the patient’s breathing cycle while making injections, a measurement error of up to may occur (Woods et al., 1976; Kirkeby-Garstad et al., 2015). Both indicator loss and baseline temperature variability – in addition to other exogenous physical factors not mentioned – limit TD’s repeatability and reproducibility of cardiac output measurement. Studies show that TD has average reproducibility of about , but measurement errors may be as low as and in adult and pediatric patients, respectively (Stetz et al., 1982; Giraud et al., 2017). Overall, small changes in temperature induced by an injected indicator can lead to poor accuracy and reproducibility in cardiac output measurement. The field of cardiac output measurement is primed for a more dependable approach – one that does not use a volatile proxy to flow rate such as temperature. Giraud et al. emphasizes the clinical importance for more reliable cardiac output monitoring, “…especially important for techniques measuring CO [cardiac output] because we are more interested in variations of CO values over time than in a given CO value. In this regard, reproducibility of a technique capable of measuring CO is important…” (Giraud et al., 2017). Electrodilution principle Sarathy et al. proposed the electrodilution method as an alternative indicator-dilution technique to measure fluid flow rates in the body. Electrodilution is operationally similar to TD but leverages a different subset of physics to side-step the challenges associated with measuring changes in temperature (Sarathy et al., 2021). In electrodilution, when a voltage is applied to electrodes in contact with the flowing media, the introduction and commixture dilution of a tracer will result in a charge transfer (faradaic process) and/or charge redistribution (capacitive process) and release a measurable change in the current magnitude. These temporal changes in current—current dilution—will be related to the blood flow rate because the greater the flow, the quicker the dilution. The working principle is schematically illustrated in Figure 1, described above. (a) The analyte tracer is injected which mixes with the flowing medium, following which (b) the mixture reaches the electrochemical cell and causes a measurable change in the current. (c) The temporary change in the electrical current reaches its peak. (d) The flowing medium will dilute this response, and (e) the measured current eventually returns to the baseline. The strength of the response and its dilution time – the temporal current response curve – will be affected by the volumetric flow rate of the fluid medium. Thus, with calibration, the above dilution curve may be used to recover the medium’s flow rate (Stewart, 1893). Sarathy et al. showed that electrodilution metrics are reproducible and correlated to flow rate. However, that proof-of- concept study did have some limitations. The design of flow loop apparatus inhibited flow rates above to be tested, which falls in the cardiac output range for infants while normal adult cardiac outputs are more than . Electrodilution has yet to be shown effective in characterizing higher flow rates that are representative of what is observed in the clinical setting (Sarathy et al., 2021). There were also other limitations such as the use of steady flow (blood flow in the heart is pulsatile) that affected the fidelity of the investigation. In this study, the electrodilution approach was further developed and a novel electrochemical catheter prototype to measure cardiac output in vivo was designed. The final design of the catheter manifested from a series of iterative experiments to understand the factors that influence sensitivity and overall performance. Flow loop apparatuses were designed to test a _{broad range of flow rates ( under both steady and pulsatile flow conditions, and} the sensing electrochemical cell was miniaturized to resemble a form factor that can be used in the clinical setting. Electrode material comparison studies were conducted to select the material used for the catheter prototype. The catheter prototype was studied in high-fidelity in vitro experiments using anticoagulated animal blood to identify an electrodilution metric that best correlates with cardiac output. These high-fidelity in vitro studies were used to develop and calibrate an automated algorithm to report the estimated cardiac output of a given measurement. The prototype catheter was demonstrated in vivo using an adult porcine model to corroborate findings from the high-fidelity in vitro studies. Results Electrode material sensitivity studies Electrodilution experiments using simulated body fluid (SBF) as the flowing media and _{hypertonic saline ( ) as the injectate were performed to assess the sensitivity of three} electrode material combinations. Each material combination was used in a flow loop apparatus and tested under steady flow conditions. This study was performed using six different flow rates, and three injections of hypertonic saline bolus were made for each flow rate. As the electrodes were polarized using large-amplitude sinusoidal voltammetry (LASV) techniques (AC parameters of data acquisition rate of ), the release of injectate into the flowing media resulted in a detectable current response consistent with the electrodilution principle. The current response to the injectate bolus follows a typical dilution curve – a steep rise and a more gradual fall back to the baseline. To characterize the sensor current response for comparison, data was post-processed using a semi-automated algorithm to calculate a metric that correlates to flow rate of the media. Figure 5 shows the progression of processing of the measured data to acquire the representative electrodilution curve for a given injection. Figure 5C shows the electrodilution curve for one bolus injection made in SBF flowing To quantitatively assess the flow sensitivity of each electrode material combination, an electrodilution metric was calculated for each curve: is defined as the change in signal amplitude normalized to the detection threshold value (see Eq.1). where, : average of baseline currents before and after dilution curve : of baseline currents before and after dilution curve : maximum current reached in the dilution curve : peak current = : start-time of dilution curve when current breaches : end-time of dilution curve when current falls below Note: is calculated by truncating the dilution curve to minimize effect from any current spike artifact. Figure 6A visualizes the current response profile behavior of the electrodilution metric as a function of flow rate for each material combination tested. To investigate the relative contributions of faradaic (e.g. electron transfer) versus capacitive (e.g. charge redistribution) processes in the current response to injection for each electrode material further analysis was performed. To qualitatively assess the measured signal, current-potential data were visualized. Cyclic voltammograms are shown in Figure 6B for each of the three electrode material combinations tested. For a quantitative assessment of relative change in the faradaic and capacitive current compositions of the response, the current signal was examined in the frequency domain. The information acquired from the frequency spectrum was then compared to determine the percent increase in faradaic current response at each harmonic of the fundamental frequency for each electrode material tested. Frequency spectrum and percent change in current amplitude for each material configuration tested are shown in Figure 7. Electrochemical catheter prototype design The novel electrochemical catheter prototype was designed to maintain complete functionality of a pulmonary artery catheter (PAC) that is used in a clinical setting for making cardiac output measurements. A commercially available multi-lumen PAC intended for thermodilution (Swan-Ganz 831F75, Edwards Lifesciences Corp., Irvine, CA United States) was used to construct the electrodilution catheter prototype. Figure 8 shows a 3D model of the catheter prototype fitted with an electrochemical sensor for cardiac output measurements using the electrodilution approach. Using the right-atrium infusion port of the PAC, platinum-iridium microwires were mounted and sealed onto the catheter wall. The electrodes were fixed along the length of the catheter body to avoid damage to the electrodes as it passes through an introducer sheath upon use. High-fidelity studies using the novel electrochemical catheter prototype The novel electrochemical catheter was tested under pulsatile flow conditions to assess the performance in characterizing flow rate in realistic physiological flow conditions. A flow loop apparatus was designed to test the novel catheter using anticoagulated porcine blood as the flowing media. The test flow loop was designed to produce physiologically representative pressure and velocity waveforms that mimic what the catheter would experience in a clinical setting. Seven different flow rates were studied – ranging from to . Using LASV, the electrodes were polarized (AC parameters of data acquisition rate of injection of hypertonic saline bolus was made each flow rate. The current response profile to injection was consistent with the electrodilution principle. To characterize the temporal current response, data was post-processed using a semi-automated algorithm to calculate a metric that correlates to flow rate of the media. Figure 9 shows the progression of post-processing the measured data to acquire the representative electrodilution curve. Figure 9C shows the electrodilution curve for one bolus injection made in anticoagulated porcine blood flowing at . To quantitatively characterize the relationship between flow rate and the electrodilution curve response in the time domain, a more-robust electrodilution metric was calculated for each curve: is defined as the charge observed during the duration of the rise from the baseline and fall back to baseline of current (area under the dilution curve (see Eq.2)). This metric is consistent with metrics in other indicator-dilution techniques and lends itself to model flow rate using a theoretically-based relationship. The Stewart-Hamilton relationship can be modified – analogous to thermodilution – for application of electrochemical signals as a proxy for cardiac output. In short, the Stewart- Hamilton equation models temporal impulse response of local fluid concentration that is induced by rapidly injecting a tracer into the flowing medium. The change in concentration signal measured by the sensor is expected to have an inverse relationship with flow rate. That is, the greater the flow rate the lesser the change in signal from baseline. From principles of electrochemistry, it is known that the measured current is proportional to the concentration of electrolyte in contact with the electrochemical cell. Therefore, the measured current signal response to injection is a reliable proxy for change in local fluid concentration. Furthermore, the electrodilution metric can be used to reasonably estimate cardiac output using the following modified version of the Stewart-Hamilton relationship: where, calibration constant in the Stewart-Hamiltion relationship mass of indicator injected into the flowing media (hypertonic saline for electrodilution) change in local fluid concentration caused by releasing indicator empirical calibration constant used to recover flow rate in electrodilution using Figure 10 shows effect of blood flow rate on the electrodilution metric and the estimated flow rate measurement determined using Eq.3. The empirical calibration constant was determined using regression. For the novel electrochemical prototype, it was calculated that . Novel electrochemical catheter prototype validation in steady flow The novel electrochemical catheter for cardiac output measurement was tested in a flow loop apparatus for validation of the empirical calibration constant derived from the high-fidelity pulsatile flow study. Using anticoagulated porcine blood flowing under steady conditions, three hypertonic saline bolus injections were made at three different flow rates. The flow rates tested constitute the range of adult cardiac output that would be observed in a clinical setting _{( to ). Using LASV, the electrodes were polarized (AC parameters of and} with data acquisition rate of ) and a measurable change in the current signal consistent with the electrodilution principle was observed as a response to injections of hypertonic saline. Figure 11 shows effect of blood flow rate on the electrodilution metric and the estimated flow rate measurement determined using Eq.3 with . Animal studies using the novel electrochemical catheter prototype Live animal studies were conducted using the novel electrochemical catheter prototype to corroborate the findings from the benchtop studies and assess the performance of the catheter design during use. Using a porcine model, the novel catheter was tested for the ability to make cardiac output measurements using the electrodilution approach in vivo. Two adult pigs were used to test the novel catheter flow sensitivity and ability to characterize changes in cardiac output. One animal was used to measure cardiac output under normal conditions and increased cardiac output resulting from volume responsiveness via rapid crystalloid infusion. The second was used to measure cardiac output under normal conditions and diminished cardiac output resulting from increased pulmonary resistance (afterload) due to induced lung-injury. For cardiac output measurements, the catheter was inserted to a central vein using standard catheterization techniques. The inflatable distal tip balloon was then deployed to advance the catheter through the right-heart anatomy until the distal tip of the catheter reached the pulmonary trunk (see Figure 1). Using LASV, the electrodes were polarized (AC parameters of and with data acquisition rate of ) and a measurable change in the current signal consistent with the electrodilution principle was observed as a response to injections of hypertonic saline. Figure 12 shows the electrodilution data acquired using the novel electrochemical catheter prototype. Discussion Sarathy et al. proposed the electrodilution method as an alternative approach to thermodilution for physiological fluid flow measurement. Electrodilution side-steps the challenges associated with measuring changes in temperature – using a more reliable proxy to flow rate – while remaining operationally like thermodilution. Their study showed electrodilution to be a feasible technique for characterizing fluid flow in water and anticoagulated bovine blood, alike. However, limitations in their sensing cell and flow loop designs inhibited flow rates greater than to be tested. In this study, electrodilution experiments were performed to assess the performance of the approach under more physiologically representative conditions. A novel electrochemical catheter prototype was designed and developed to make cardiac output measurements using the electrodilution method. The catheter was tested in high-fidelity in vitro studies and a semi- automated algorithm was developed to calculate a metric that correlates to flow rate and estimate cardiac output. Three microelectrode material combinations were tested using an electrochemical blood analog and compared to identify the combination to be used in the novel catheter prototype. Experiments with SBF as the flowing medium were conducted to identify the sensing cell material combination that has the greatest flow sensitivity. SBF was selected as the flowing media as experiments with animal blood are cumbersome and time-sensitive due to the shelf-life of blood. All sensing electrochemical cell combinations investigated were found to lend themselves to the electrodilution method for characterizing flow rate. The electrodilution metric was used as a proxy to characterize flow rate and compared relative sensitivity between material combinations. As expected from the electrodilution principle, has an inverse relationship with fluid flow rate for each material combination tested. was found to outperform the other material combinations tested. The current response due to analyte injection is more flow rate sensitive to hypertonic saline injection as observed by comparing (see Figure 6A). shows the greatest signal to noise ratio between baseline and peak response current. This leads to better characterization of the current response signal and more accurate estimates of cardiac output. To look beyond the electrodilution performance based on a metric acquired in the time- domain, data in the frequency-domain was analyzed. Cyclic voltammograms and the frequency- spectrum were analyzed to assess the relative contributions of faradaic and capacitive current responses. Increased faradaic currents may give a more relevant insight to specific electrochemical interactions occurring at the working electrode surface (Brazill et al., 2002). In Figure 6B the cyclic voltammograms for the three configurations tested are shown. The current response to analyte injection for is primarily capacitive; indicated by a primarily elliptical profile that is preserved but pitches up during peak injection response. There is no prevalent faradaic response. In show increased faradaic current response due to analyte injection – greater shape change in profile from baseline to peak injection response. For this can be seen when the potential is decreasing towards ; an exponential increase in current is observed. The cyclic voltammogram for shows this material combination has the greatest increase faradaic current contribution due to injection of analyte. This is revealed by the exponential current response at higher potentials and current shoulders from The current response to injection of analyte for each material combination tested was further investigated in the frequency-domain. Figure 7 shows a frequency spectrum comparing baseline currents and peak response currents measured during was found to have the greatest percent change in current contributions at higher-order harmonics. The information acquired from the cyclic voltammograms and frequency spectrums further advocate the use for the electrodilution approach to cardiac output measurement. The increased faradaic currents at higher-order harmonics that are promoted by analyte injection may be leveraged to increase the sensitivity and specificity of the electrodilution approach. Using information from the frequency domain, an electrochemical fingerprint may be determined for the analyte – allowing for differentiation of the current response due to analyte injection and interferants in blood (Brazill et al., 2002; Bell et al., 2011). The findings in material comparison studies with SBF as the flowing media strongly advocate for using in the novel electrochemical catheter design. There were some limitations in this study to consider with respect to the flow media used to develop and test the novel catheter prototype. SBF was selected as an electrochemical blood analog to test electrochemical cell material combinations as experiments with blood can be cumbersome, limited due to supply, and time-sensitive due to blood’s shelf-life. SBF was prepared to mimic ion concentrations of human blood plasma, but it lacks the formed elements in whole blood that may play a role in the electrochemical properties (Toh et al., 2014). Similarly, the porcine blood used in this study was anticoagulated. The solution was porcine blood to sodium-citrate; the citrate buffer may have altered the baseline physiological electrochemical properties of the blood (Berkh et al., 2011). In addition, frequent injections of hypertonic saline can lead to adverse effects on the patient. Sodium concentration in the blood can quickly accumulate and lead to hypernatremia (Roquilly et al., 2021). Further development of the prototype needs to involve limiting the mass of saline delivered to the patient. Conclusion It was found that the electrodilution method is an alternative and operationally-similar approach to measuring cardiac output. This electrochemical approach circumvents the major challenge that exists with clinical-standard thermodilution methods. The novel catheter prototype that was developed was tested in vivo for measuring cardiac output. Materials and Methods Large-amplitude sinusoidal voltammetry Flow injection analysis experiments were conducted at various flow rates to characterize how the electrodilution curves are influenced by the flow rate of the medium. For electrodilution measurements, the sensing electrochemical cell was connected (2-electrode configuration; counter electrode serving as the reference electrode as well) to a potentiostat control unit (VSP- 300, BioLogic Science Instruments, Seyssinet-Pariset, France). Using large-amplitude sinusoidal voltammetry (LASV), a potential waveform with predetermined AC parameters of was applied to the working electrode and the resulting current signal was continuously recorded. The pump was set to a predetermined flow rate, and the medium was allowed to flow until the measured current of the cell reached equilibrium. Next, multiple manual injections of injectate was delivered over into the flowing medium proximal to the sensing cell. The resulting current response and recovery were recorded. The process was repeated for various flow rates ranging _{from to which constitute the ranges of blood flow for pediatric and adult patients.} Each experiment was repeated at least 2 times to test for reliability and reproducibility. The intended application of this method is to recover cardiac output through hypertonic saline injections. However, experiments with blood ex vivo are complex and cumbersome due to the tendency of blood thrombus formation. As a result, experiments were first conducted using SBF, an electrochemical blood analog, to assess the feasibility of electrodilution with microelectrodes and hypertonic saline. Subsequently, controlled experiments using anticoagulated porcine blood as the flowing media were performed to corroborate these findings with more physiologically representative flowing media. Post-processing: semi-automated scoring algorithm Figure 14 schematically illustrates steps of the semi-automated MATLAB scoring algorithm used to calculate the electrodilution metrics. The user must manually isolate each current response signal and select a portion before and after the electrodilution curve to establish the nominal signal baseline value and standard deviation. The algorithm then proceeds to calculate electrodilution metrics and prompts the user to continue scoring or save the data to a text file. Flowing media: simulated body fluid and animal blood Anticoagulated porcine blood solution was prepared to have a ratio of porcine blood to sodium citrate (Mann et al., 2007). Porcine blood samples were acquired from a local abattoir as needed. Simulated body fluid (SBF) is a solution that has similar ion concentration to human blood plasma and serves as an electrochemical blood analog for this study (Kokubo et al., 1990). SBF was prepared following the protocol proposed by Leonor et al. (Leonor et al., 2007). Table 1 shows the comparison of ionic concentrations of SBF and human blood plasma. Chemicals were purchased from Research Products International (Mount _{Prospect, IL, United States): potassium phosphate ( , ), potassium chloride ( , ), sodium citrate ( , ).; Fisher Chemical (Fair Lawn, NJ, United States): sodium chloride ( , ), sodium bicarbonate ( , ), magnesium chloride hexahydrate ( ), calcium chloride dihydrate ( , ), sodium sulfate ( , ); EM Science (Gibbstown, NJ, United States): hydrochloric acid ( ,} ). Deionized water was used as the solvent. Table 1. Comparison of ionic concentrations in human blood plasma and the SBF prepared in this study. All concentrations are reported in [mM]. Injectate H_{ypertonic saline solution was prepared as the injectate solution.} Chemicals were purchased from Fisher Chemical (Fair Lawn, NJ, United States): sodium c_{hloride ( , . Deionized water was used as the solvent.} Sensing electrochemical cell: materials testing Commercially available microelectrodes were selected to assess electrodilution performance with different biocompatible electrode materials. Platinum-Iridium (Pt-Ir) (Microprobes for Lifescience, Gaithersburg, MD, United States) and Glassy Carbon (Kation Scientific, Minneapolis, MN, United States) microelectrodes allowed for three different electrochemical cell configurations. For Pt-Ir as the working electrode and stainless steel (St.St.) a_{s the counter electrode ( ), the assembly in Figure 15A was positioned in the y-} junction shown in Figure 15C. Similarly, for glassy carbon as both the working and counter e_{lectrodes ( ), the assembly in Figure 15B was positioned in the y-junction. In order to test Pt- Ir as both the working and counter electrodes ( ) two assemblies shown in Figure} 15A were fitted into the Y-junction as depicted in Figure 15C. Flow loop apparatus: steady flow experiments An experimental apparatus with a predetermined flow of a medium past an electrochemical cell, with the ability to inject an analyte is shown in Figure 16. A continuous flow pump (75211–62 variable speed pump drive, Cole-Parmer Instrument Company LLC., Burlington, IL United States) along with two inline flow meters (Masterflex direct reading variable area flow meter, Cole-Parmer Instrument Company LLC., Vernon Hills, IL United States) in parallel were used to sustain the predetermined flow rate. Microelectrodes were used to make up the sensing electrochemical cell and were positioned approximately downstream from the analyte injection port. The reservoir was filled with at least of flowing media to limit dilution and significant changes in electrochemical properties as repeated hypertonic saline injections are made. Novel electrochemical catheter prototype A multi-lumen pulmonary artery catheter (PAC) intended for TD (Swan-Ganz 831F75, Edwards Lifesciences Corp., Irvine, CA United States) was used to construct the electrodilution catheter prototype for cardiac output characterization. Figure 17 shows a schematic diagram of the PAC outfitted with the sensing electrochemical cell configuration. This was achieved by threading copper wire in two of the individually insulted catheter lumen. Pt-Ir wire (Microprobes for Lifescience, Gaithersburg, MD, United States) was soldered to each copper lead and the catheter tip was sealed using silicone. Only of the Pt-Ir wire was exposed at the catheter tip and the electrode spacing was . The PAC is equipped to have analyte injectate released from the catheter itself – operationally similar to TD. The analyte release port is located proximal to the sensing cell at the catheter tip. Flow loop apparatus: steady flow experiments To test electrodilution using the novel electrochemical catheter prototype under conditions that more closely mimic a clinical setting, high-fidelity flow injection analysis experiments were conducted using physiologically representative pulsatile flow conditions. Saline electrodilution experiments as described were conducted using an adapted flow loop apparatus. Figure 18 shows a schematic diagram of the flow loop constructed for pulsatile flow conditions. A programmable piston pump (SuperPump pulsatile pump, ViVitro Labs Inc., Victoria, BC Canada) was used to drive flow using a physiologically representative velocity waveform of large-artery blood flow. A tunable compliance chamber and pinch valve were used to target physiologically representative pressure waveforms. The hacked PAC was introduced into the flow loop via a catheter access port and the catheter was advanced so that of the catheter was exposed to the flowing media. 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Nelson, L., and Anderson, H. (1985). Patient selection for iced versus room temperature injectate for thermodilution cardiac output determinations. Crit. Care Med.13, 182–184. Nishikawa, T., and Dohi, S. (1993). Errors in the measurement of cardiac output by thermodilution. Can. J. Anaesth.40, 142–153. doi:10.4103/0971-9784.91464. Reuter, D. A., Huang, C., Edrich, T., Shernan, S. K., and Eltzschig, H. K. (2010). Cardiac output monitoring using indicator-dilution techniques: Basics, limits, and perspectives. Anesth. Analg.110, 799–811. doi:10.1213/ANE.0b013e3181cc885a. Roquilly, A., Moyer, J. D., Huet, O., Lasocki, S., Cohen, B., Dahyot-Fizelier, C., et al. (2021). Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients with Traumatic Brain Injury: The COBI Randomized Clinical Trial. JAMA - J. Am. Med. Assoc.325, 2056–2066. doi:10.1001/jama.2021.5561. Runciman, W. B., Ilsley, A. H., and Roberts, J. G. (1981). An evaluation of thermodilution cardiac output measurement using the Swan-Ganz catheter. Anaesth. Intensive Care 9, 208–220. doi:10.1177/0310057x8100900302. Sanders, M., Servaas, S., and Slagt, C. (2020). Accuracy and precision of non-invasive cardiac output monitoring by electrical cardiometry: a systematic review and meta-analysis. J. Clin. Monit. Comput.34, 433–460. doi:10.1007/s10877-019-00330-y. Sarathy, S., Nino, M. A., Ghanim, A. H., Rajagopal, S., Mubeen, S., and Raghavan, M. L. (2021). Electrochemical Approach to Measure Physiological Fluid Flow Rates. Front. Chem.9, 1–7. doi:10.3389/fchem.2021.680099. Saugel, B., Cecconi, M., and Hajjar, L. A. (2019). Noninvasive Cardiac Output Monitoring in Cardiothoracic Surgery Patients: Available Methods and Future Directions. J. Cardiothorac. Vasc. Anesth.33, 1742–1752. doi:10.1053/j.jvca.2018.06.012. Stetz, C. W., Miller, R., Kelly, G., and Raffin, T. A. (1982). Reliability of the Thermodilution Method in the Determination of Cardiac Output in Clinical Practice. Am. Rev. Respir. Dis.126, 1001–1004. Stewart, G. N. (1893). Researches on the Circulation Time in Organs and on the Influences which affect it. J. Physiol.15, 1–89. Swan, H., Ganz, W., Forrester, J., Harold, M., and Chanotte, D. (1970). Catheterization of the Heart in Man with Use of a Flow-Directed Balloon-Tipped Catheter. N Engl J Med 283, 447–451. Toh, R. J., Peng, W. K., Han, J., and Pumera, M. (2014). Direct in vivo electrochemical detection of haemoglobin in red blood cells. Sci. Rep.4, 1–6. doi:10.1038/srep06209. Vetrugno, L., Bignami, E., Barbariol, F., Langiano, N., De Lorenzo, F., Matellon, C., et al. (2019). Cardiac output measurement in liver transplantation patients using pulmonary and transpulmonary thermodilution: a comparative study. J. Clin. Monit. Comput.33, 223–231. doi:10.1007/s10877-018-0149-9. Wong, M., Skulsky, A., and Moon, E. (1978). Loss of indicator in the thermodilution technique. Cathet. Cardiovasc. Diagn.4, 103–109. doi:10.1002/ccd.1810040115. Woods, M., Scott, R., and HArken, A. (1976). Practical considerations for the use of a pulmonary artery thermistor catheter. Surgery 91, 469–475. Although at least one embodiment of an electrochemical catheter and system have been described above with a certain degree of particularity, those skilled in the art could make numerous alterations to the disclosed embodiments without departing from the spirit or scope of this disclosure. All directional references (e.g., upper, lower, upward, downward, left, right, leftward, rightward, top, bottom, above, below, vertical, horizontal, clockwise, and counterclockwise) are only used for identification purposes to aid the reader's understanding of the present disclosure, and do not create limitations, particularly as to the position, orientation, or use of the disclosure. Joinder references (e.g., attached, coupled, connected, and the like) are to be construed broadly and can include intermediate members between a connection of elements and relative movement between elements. As such, joinder references do not necessarily infer that two elements are directly connected and in fixed relation to each other. It is intended that all matter contained in the above description or shown in the accompanying drawings shall be interpreted as illustrative only and not limiting. Changes in detail or structure can be made without departing from the spirit of the disclosure as defined in the appended claims. Various embodiments are described herein to various apparatuses, systems, and/or methods. Numerous specific details are set forth to provide a thorough understanding of the overall structure, function, manufacture, and use of the embodiments as described in the specification and illustrated in the accompanying drawings. It will be understood by those skilled in the art, however, that the embodiments may be practiced without such specific details. In other instances, well-known operations, components, and elements have not been described in detail so as not to obscure the embodiments described in the specification. Those of ordinary skill in the art will understand that the embodiments described and illustrated herein are non- limiting examples, and thus it can be appreciated that the specific structural and functional details disclosed herein may be representative and do not necessarily limit the scope of the embodiments, the scope of which is defined solely by the appended claims. Reference throughout the specification to “various embodiments,” “some embodiments,” “one embodiment,” or “an embodiment,” or the like, means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrases “in various embodiments,” “in some embodiments,” “in one embodiment,” or “in an embodiment,” or the like, in places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Thus, the particular features, structures, or characteristics illustrated or described in connection with one embodiment may be combined, in whole or in part, with the features structures, or characteristics of one or more other embodiments without limitation given that such combination is not illogical or non-functional. It will be appreciated that the terms “proximal” and “distal” may be used throughout the specification with reference to a clinician manipulating one end of an instrument used to treat a patient. The term “proximal” refers to the portion of the instrument closest to the clinician and the term “distal” refers to the portion located furthest from the clinician. It will be further appreciated that for conciseness and clarity, spatial terms such as “vertical,” “horizontal,” “up,” and “down” may be used herein with respect to the illustrated embodiments. However, surgical instruments may be used in many orientations and positions, and these terms are not intended to be limiting and absolute. The terms “about” and “approximately” may be used throughout the specification when referring to a measurable value, such as an amount, a distance, a temporal duration, and the like. The terms “about” and “approximately” are meant to encompass variations of ±20% or ±10%, in certain embodiments ±5%, in certain embodiments ±1%, in certain embodiments ±0.1% from the specified value, as such variations are appropriate in accordance with the present disclosure. Any patent, publication, or other disclosure material, in whole or in part, that is said to be incorporated by reference herein is incorporated herein only to the extent that the incorporated materials does not conflict with existing definitions, statements, or other disclosure material set forth in this disclosure. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material set forth herein will only be incorporated to the extent that no conflict arises between that incorporated material and the existing disclosure material.

Claims

WHAT IS CLAIMED IS: 1. An electrochemical catheter for measurement of physiological flow comprising: an elongated catheter shaft comprising an outer wall and plurality of lumens extending between a proximal end portion and a distal end portion, the distal end portion comprising a distal tip portion; an electrochemical cell sensor comprising a plurality of microwire electrode leads, each lead being partially exposed through the outer wall of the shaft at the distal end portion; an analyte injection port at the proximal end portion of the shaft; and an analyte release port at the distal end portion of the shaft, proximal to the electrochemical cell sensor; wherein the electrochemical cell sensor is configured to generate a current signal proportional to a change in concentration of an analyte indicator between the analyte injection port and the analyte release port.

2. The electrochemical catheter of claim 1, wherein the microwire electrode leads comprise platinum-iridium microwires.

3. The electrochemical catheter of claim 1, wherein the distal tip portion is configured for placement in a subject’s pulmonary artery.

4. The electrochemical catheter of claim 1, further comprising an inflatable distal tip balloon at the distal tip portion of the catheter.

5. The electrochemical catheter of claim 1, wherein the analyte release port is configured for placement in a subject’s right atrium.

6. The electrochemical catheter of claim 1, wherein the analyte indicator comprises hypertonic saline.

7. The electrochemical catheter of claim 1, wherein the electrochemical cell sensor is configured to measure at least one of the following physiological flow rates: cardiac blood flow rate, circulatory system blood flow rate, extracorporeal blood flow rate, cerebrospinal fluid flow rate, pleural fluid flow rate, and urine flow rate.

8. The electrochemical catheter of claim 1, wherein the change in concentration of the analyte indicator is inversely related to a measured flow rate of a physiological fluid.

9. A system for determining a measurement of physiological flow comprising: the electrochemical catheter of claim 1; and a processor communicatively linked to the electrochemical catheter; wherein the processor is configured to determine a measurement of physiological flow based on a scoring algorithm.

10. The system of claim 9, wherein the scoring algorithm comprises: a) recording a current signal generated by the electrochemical cell sensor; b) extracting a current envelope from the current signal; c) isolating an injection wavelet from the current envelope; d) determining a baseline of the injection wavelet; e) calculating an electrodilution metric using the baseline of the injection wavelet; and f) optionally, repeating steps a-e.

11. The system of claim 9, wherein the algorithm further comprises generating an electrodilution curve.

12. The system of claim 11, wherein the electrodilution metric comprises a change in total charge defined by the area under the electrodilution curve.

13. The system of claim 9, wherein the processor is configured to determine a measurement of cardiac output.

14. The system of claim 9, further comprising a display configured to display the measurement of physiological flow.

15. The system of claim 14, wherein the display is further configured to display the current signal generated by the electrochemical cell sensor.

16. The system of claim 14, wherein the display is configured to display a measurement of cardiac output.