When performing a preload challenge using the wireless, wearable Doppler ultrasound system, there are a number of critical steps that the user should consider. Written and informed consent was obtained for this protocol; the study was reviewed and approved by the Research Ethics Board of Health Sciences North. The procedures followed were in accordance with the local ethical standards of the committee on human experimentation and with the Helsinki Declaration of 1975.
1. Identifying an appropriate patient
<ol>
	<li>Identify a patient on whom the wearable Doppler ultrasound device will be placed. Ensure that the patient is calm and relatively motionless to minimize phonation and deglutition for the duration of the assessment (1-5 min).</li>
	<li>Position the patient in the semi-recumbent or semi-Fowler position in the hospital bed or gurney. Specifically, adjust the bed such that the torso is at an angle of 30-45&#176; above horizontal.</li>
</ol>
2. Obtaining the carotid artery and internal jugular Doppler signals
<ol>
	<li>Turn on the wearable Doppler ultrasound by pressing the round button in the center of the ultrasound device. Blue lights around the periphery of the button will flash, signaling that the device is on and ready to pair with a smart device.</li>
	<li>Turn on the dedicated application on the smart device. Press the start button on the smart device application. Observe the list displayed on the application showing the discoverable, wearable, ultrasound devices within physical proximity of the smart device. Match the number affixed to the face of the desired ultrasound device to the indicated device on the application list. Press connect to pair the desired ultrasound device to the application.</li>
	<li>Confirm the desired ultrasound device is paired by observing white flashing lights around the button in the center of the device. Press correct on the smart device application to complete the pairing.</li>
	<li>Apply a small amount of ultrasound gel to the large face of the transducer wedge on the back of the ultrasound device. 
	NOTE: The gel application produces a characteristic Doppler signal artifact, which can be seen on the smart device application.</li>
	<li>Tap the large face of the transducer wedge to ensure the device is live and paired to the smart device application. Ensure that the volume on the smart device application is turned on by pressing the volume icon button in the top-right corner of the application display.</li>
	<li>With the patient&#39;s neck slightly extended, note the laryngeal prominence, and hold the ultrasound device so that the large face of the transducer wedge faces downward toward the patient&#39;s heart. Place the wedge of the device on the lateral aspect of the patient&#39;s laryngeal prominence. Look for an audio and visual response on the smart device application: the top portion of the application will display a waveform spectrum for the carotid artery and jugular vein. The bottom portion of the application quantifies the corrected flow time (ccFT) for each cardiac cycle, displayed as green bars.</li>
	<li>Slide the transducer face on the patient&#39;s neck laterally from a perpendicular plane defined by the trachea until the carotid Doppler spectrum is detected both visually and audibly on the smart device application. 
	&#8203;NOTE: In most patients, the audio and visual Doppler spectra of the carotid artery and jugular vein are detected within a few centimeters of the lateral laryngeal border.</li>
</ol>
3. Optimizing the carotid artery and internal jugular Doppler signals
<ol>
	<li>While holding the device in place, observe the carotid Doppler spectrum and its features on the top of the application display. A good carotid artery Doppler signal is identified by its characteristic sharp velocity upstroke with a good signal-to-noise ratio and a clear dicrotic notch, which demarcates the end of mechanical systole. The application will automatically begin tracing the Doppler spectrum once a strong enough signal is obtained, indicated by a white line around the maximum of the waveform.</li>
	<li>While holding the device in place, observe the velocity measurements using the scale on the top left-hand side of the smart device display. Using the auto-trace over the carotid artery maximum, ensure that the trace is in a typical range. The peak systolic velocity of the carotid artery is typically between 50 cm/s and 120 cm/s, and the end diastolic velocity is typically less than 20 cm/s.</li>
	<li>Slowly slide the ultrasound device laterally slightly by a few millimeters while looking at the dicrotic notch on the artery spectrum to ensure that a clear velocity nadir is observed reliably. If the dicrotic notch velocity becomes difficult to see, repeat this step, but slide the ultrasound device medially.</li>
	<li>Repeat steps 3.1-3.3 over the contralateral carotid artery to assess for the presence of a clearer dicrotic notch velocity.</li>
	<li>After observing for the presence of a clear dicrotic notch velocity on both carotid arteries, select the side of the neck to which the device will be adhered. Choose the side with the most obvious dicrotic notch velocity. If both sides of the neck have equally acceptable dicrotic notch velocities, choose the side of the neck with the most robust internal jugular Doppler spectrum.</li>
</ol>
4. Adhering the ultrasound device to the neck
<ol>
	<li>Prepare to adhere the device to the chosen carotid artery by visually noting where on the neck the best signal was obtained. If needed, use a skin-marking pen to identify the optimal placement position. Lift the device from the neck, and remove the protective backing from the adhesive attached to the ultrasound device.</li>
	<li>Observe the transducer face on the ultrasound device, and determine if there is a sufficient amount of ultrasound gel remaining. If needed, reapply a small amount of ultrasound gel to the transducer face. Remove excess ultrasound gel from the neck that may have remained during signal discovery as this may interfere with the adhesion of the device.</li>
	<li>Return the device to the neck to the location identified in step 4.1, with the large face of the transducer wedge pointing downward toward the heart. Smooth the wings of the adhesive across the neck. Remove the protective backing from the tips of the adhesive after pulling tight; place the filming against the skin to fully secure the device to the neck. Monitor the carotid and jugular spectra throughout adhesion to ensure that the signal is not lost.</li>
</ol>
5. Performing a preload challenge&#160;&#160;via a passive leg raise (PLR)
<ol>
	<li>Ensure that the patient is in the semi-recumbent position on the hospital bed or gurney, as identified in step 1.2.</li>
	<li>Clear the smart device application data by pressing restart on the smart device application. Press begin assessment on the smart device application to obtain the baseline measures for the passive leg raise (PLR). Begin with 30-60 s of resting baseline with the patient in the semi-recumbent position on the hospital bed or gurney. Look for a marker displayed on the bottom portion of the application display to signify the beginning of the assessment.</li>
	<li>Prepare the necessary measures to perform a PLR (e.g., obtain extra nursing help as needed).</li>
	<li>Once ready to perform a PLR, press mark intervention on the smart device application to signify the beginning of the preload challenge (in this case, a PLR). Look for a marker displayed on the bottom portion of the application display to signify the beginning of the intervention. Perform a PLR; without touching the patient, reposition the hospital bed or gurney so that the torso is moved downward to the horizontal and the legs are lifted to 30-45&#176; above the horizontal. 
	NOTE: The user must take great care to keep the patient fully passive during this maneuver.</li>
	<li>Keep the patient in the PLR position for 90-120 s. 
	NOTE: Throughout the maneuver, it is imperative that the patient keep their neck completely still so as not to change the insonation angle between the transducer face and the vessels in the neck. If needed, manually stabilize the patient&#39;s neck.</li>
	<li>Observe the jugular Doppler spectrum on the smart device application during the intervention; assess for changes in the absolute jugular venous velocity and its pattern as a surrogate for the jugular venous pressure.</li>
	<li>Observe the evolution of the green bars on the smart device application during the intervention; assess for changes in the ccFT before and after the start of the preload challenge. The smart device application automatically quantifies the ccFT for each cardiac cycle and represents this as a green bar.</li>
	<li>Once the intervention is complete, press end assessment on the smart device application. Look for a marker that will be displayed on the bottom portion of the application display to signify the end of the assessment.</li>
	<li>Return the patient back to the baseline, semi-recumbent position.</li>
	<li>If desired, press save on the smart device application to save the assessment and export the data files (see additional data notes for more details).</li>
</ol>
6. Observing the changes in the carotid corrected flow time (ccFT) on the smart device application following the completed assessment
<ol>
	<li>Observe the assessed changes in the ccFT displayed in a yellow box on the lower-right side of the application. 
	NOTE: The smart device application automatically quantifies the changes in ccFT between the recorded baseline measurements and the preload challenge/intervention measurements.</li>
	<li>Press save on the application, and wait for the data to be split into the following files: two .txt format files containing IQ and Tick data from the Doppler device hardware; one PKL format file containing the spectrogram information (use this to visualize the real-time collected data online); and two .json format files containing the session information (such as the date and time, smart device hardware settings, user settings, and more) and real-time calculations per cardiac cycle.</li>
</ol>

J.E.S.K., S.O.G., D.J., L.M.H., E.R., G.C., J.K.E. work for Flosonics Medical, the start-up that builds the wearable Doppler ultrasound; R.A. and B.N. declare no competing interests.

The main purpose of this visual experiment is to describe a protocol for contemporaneously tracking the surrogates of cardiac preload and output during a well-validated PC using a wireless, wearable ultrasound. The goal is not to describe a specific study protocol in patients, per se. However, the description of continuous venous and arterial Doppler serves as a practical and physiological foundation for designing studies in patients both in need of resuscitation (e.g., perioperative period, sepsis) or de-resuscitation (e.g., congestive heart failure, dialysis, failure to liberate from mechanical ventilation)15,36.
The method described employs a wearable, continuous wave Doppler ultrasound that simultaneously insonates a major vein and artery to infer the cardiac function during a PC15. Critical to this method is the selection of an appropriate, cooperative patient and ensuring a minimal angle change between the vessels and the transducer throughout the assessment. Furthermore, assuring a clear and consistent dicrotic notch velocity is paramount to allow for the consistent measurement of the systolic time. Finally, the user must appreciate the venous Doppler morphology and its variation across a spectrum of jugular venous pressure (JVP), as discussed above in the representative results.
As a modification to the method described, instead of a PLR, the PC might consist of a rapid infusion of intravenous fluid9, moving a completely supine patient from horizontal to head down by 15-30&#176; (i.e., Trendelenburg positioning)10, or respiratory maneuvers such as end-expiratory occlusion34. These approaches are beneficial in that there is less patient movement and, ostensibly, a reduced risk of angle change during the assessment. In general, troubleshooting all PCs with the wearable ultrasound requires stable neck positioning, extra adhesive to secure the insonation angle, the prolongation of the assessment when phonation or deglutition artifacts occur, the repositioning of the device, or the addition of ultrasound gel to optimize the acoustic coupling to the patient31.
There are limitations to the method of cardiovascular inference described within this manuscript. With regard to the jugular venous signal, the Doppler morphology is a surrogate of the jugular venous pressure, which itself is a surrogate of the right atrial pressure37,38,39,40. Therefore, there is no certainty that the cardiac preload is increased based on the venous Doppler changes alone. Nevertheless, the venous Doppler waveform varies its morphology based upon the pressure deflections of the right atrium17,18,41; this has been observed in multiple great veins in addition to the jugular. For example, evaluations of the superior and inferior vena cava and the hepatic, portal, intrarenal, and femoral veins all qualitatively estimate the venous pressure42. More specifically, the prominent venous velocity wave during systole is formed by the x-descent of the right atrial pressure and the diastolic velocity wave by the y-descent of the right atrial pressure. The velocity nadir between systole and diastole is due to the right atrial pressure &#34;v wave&#34;16,17,18,42.
Additionally, while the duration of mechanical systole is directly proportional to the stroke volume, the systolic time, similar to SV, is mediated by the heart rate, preload, afterload, and contractility43. While the ccFT equation corrects for heart rate, a limitation of the ccFT as a surrogate for the stroke volume is that it is determined by other hemodynamic inputs. Nevertheless, increases in the ccFT by at least 7 ms24 or by +2%-4% have been shown to accurately detect a 10% rise in the SV in critically ill patients24, healthy volunteers performing a preload modifying maneuver44,45, and healthy volunteers undergoing simulated moderate-to-severe hemorrhage resuscitation27. Furthermore, ccFT has been used to accurately track changing SVs in the elective surgical population during respiratory maneuvers46. Thus, assuming that afterload and contractility are relatively constant during a focused PC, the ccFT varies primarily due to changes in the SV.
Furthermore, the absolute and relative contraindications for this approach have yet to be elaborated, especially in patients. As noted above, the most common contraindication is likely an inability to cooperate (e.g., delirious, speaking, movement, rigors). This is true for many modern vital sign monitors, though the wearable ultrasound is particularly sensitive to phonation and neck movement. Accordingly, the device works very well in intubated and paralyzed patients in the operating room; a study using the device on patients receiving elective coronary artery bypass grafting is currently enrolling. Physiological variation between the opposing carotid arteries in a particular patient is possible; however, this concern is mitigated because, in the PC paradigm, the patient acts as their own control (i.e., a pre-post intervention). Accordingly, we anticipate that while the different sides of the neck (Figure 5) may produce slightly different venous and arterial Doppler signals, the change should be consistent barring any significant unilateral abnormalities (e.g., stenosis). Physical limitations may also pose problems (e.g., central lines, cervical-spine collars, tracheotomy straps, trauma, short necks, or severe cervical kyphosis). Physiological contraindications such as moderate-to-severe carotid stenosis, aortic stenosis, arrhythmia, and abnormal respiratory patterns are also of potential concern. Generally, however, a PLR with real-time measures of cardiac output is resistant to many of these issues, including arrhythmia4,11. The device is currently being studied in both spontaneously breathing emergency department patients and in the operating room; the proportion with unusable signals will be gleaned from this data.
The significance of the method described above is that the adhered ultrasound can sample minutes of continuous data, while hand-held approaches are typically limited to a few cardiac cycles48,49. Additionally, the software for the wearable ultrasound measures the arterial Doppler coefficient of variation. From this, a &#34;smart window&#34; is implemented to sample a sufficient number of cardiac cycles at baseline and during the intervention; this statistical instrument tailors the measurement precision for each preload challenge47. Moreover, given that the wearable ultrasound remains affixed to the patient, the risk of human factors50,51 that increase the measurement variability is diminished; this holds for both arterial and venous insonation. Another significant aspect of this method is that contemporaneous venous and arterial Doppler assessment allows the clinician to indirectly assess the cardiac preload during a dynamic maneuver; this is recommended by experts in the field13 but rarely performed because measuring the right atrial pressure is cumbersome. Accordingly, continuous venous-arterial Doppler during a PC gives a deeper picture of the cardiac function at the bedside. While this method described above may be used to judge intravenous fluid resuscitation, it also holds promise for gauging &#34;de-resuscitation&#34;15,52 or predicting weaning from mechanical ventilation53 and should be explored in future clinical research. For example, the diuresis of patients with volume overload may be revealed by signs of falling right atrial pressure within the venous Doppler signal as the volume removal progresses. Further, should the patient receive a PLR before and after dialysis, the change in arterial Doppler measures should indicate increased cardiac function, as previously reported52.
A method of continuous venous-arterial Doppler during a PC is best accomplished by following the six general steps outlined above in the protocol section. A novel, wireless, wearable Doppler ultrasound system assists this paradigm by adhering to a patient and enabling a relatively fixed insonation angle during the preload change. Fundamentally, simultaneous, instantaneous, venous-arterial Doppler may elaborate the two axes of the Frank-Starling-Sarnoff relationship and, therefore, give new insights into cardiac function. This is especially important when managing acutely ill patients; both volume administration and removal could be refined by this new approach. While the above discussion is largely limited to inpatient applications, additional outpatient uses within the spheres of congestive heart failure, chronic renal failure, and pulmonary hypertension are also possibilities. Accordingly, continuous venous-arterial Doppler may unlock unforeseen channels of exploration within hemodynamics and related medical disciplines.

At its foundation, the Frank-Starling-Sarnoff curve describes the relationship between cardiac preload and output1,2,3,4. Historically, this curve is depicted by plotting the right atrial pressure on the abscissa and the cardiac output or stroke volume (SV)5 on the ordinate. Assessing the slope of this curve is clinically important because the relationship between cardiac filling and output is dynamic; thus, the slope of the curve informs the resuscitation strategy1,4. Specifically, if the slope of the Frank-Starling-Sarnoff (i.e., &#34;cardiac function&#34;) curve is steep, then increasing the preload (e.g., administering intravenous fluid) augments the output. By contrast, if the slope of the cardiac function curve is shallow, then providing intravenous (IV) fluid does not increase the SV2.
Knowing when IV fluid does or does not increase the SV is important so that the treating clinician can avoid physiologically ineffective fluid4,6, in other words, the scenario in which giving IV fluid to a patient does not increase the SV7,8. Identifying this relatively common clinical state is achieved via a preload challenge (PC), which is a clinical maneuver that &#34;tests&#34; the slope of the cardiac function curve3. A PC is achieved by rapidly increasing the cardiac filling and measuring the change in SV9. As above, IV fluid can act as a PC, as can gravitational maneuvers such as moving the head below the level of the heart (i.e., Trendelenburg positioning)10 or moving from a semi-recumbent position to supine with the legs elevated (i.e., a passive leg raise)11. In fact, the passive leg raise (PLR) is a well-accepted and well-validated PC that is employed in modern intensive care units and recommended by experts prior to IV fluid administration during sepsis resuscitation4,12. Importantly, it is suggested that during the PLR, the clinician should measure both the cardiac preload (e.g., the change in right atrial pressure) and the output (e.g., the change in SV) to adequately test the cardiac function curve13. However, the former is rarely performed as simultaneous measures are cumbersome and an invasive catheter placed into the right atrium is often required.
Ultrasonographic surrogates of cardiac filling and output have grown in popularity over the last few decades, especially in emergency departments and intensive care units2,14. Specifically, the simultaneous assessment of both a great vein and large artery acts as a surrogate for cardiac preload and output, respectively2,15. For example, morphological changes in great vein Doppler have been found to track right atrial pressure-this is true for the internal jugular16,17,18, hepatic, and portal veins19, superior vena cava20, inferior vena cava21, femoral veins22, and even intrarenal veins23. Thus, great vein Doppler velocimetry operates as a surrogate for cardiac filling2. However, the Doppler of a large artery can transiently track changes in cardiac output. For instance, measures of common carotid artery systolic time24,25, velocity26,27,28, and flow 29,30 have shown promise for detecting SV changes.
A novel, wireless, wearable, continuous wave Doppler ultrasound that simultaneously insonates both the internal jugular vein and common carotid artery has previously been described14,15,27,28,31,32,33,34,35,36. Herein, a method using this device during a commonly employed, clinical PC-the passive leg raise-is illustrated. Further, the internal jugular and common carotid arterial Doppler morphologies during the PC are described as possible surrogates of cardiac preload and output, respectively. This protocol is clinically important because it provides both a practical and physiological foundation for future patient study. For example, inpatients (e.g., perioperative setting, sepsis, critically ill) and outpatients (e.g., congestive heart failure, dialysis) could be monitored by the method, or modifications thereof, described below.

<table><tbody><tr><td>FloPatch</td><td>Flosonics</td><td></td><td></td></tr><tr><td>iPad</td><td>Apple</td><td></td><td></td></tr><tr><td>ultrasound gel</td><td></td><td></td><td></td></tr></tbody></table>

continuous venous-arterial doppler ultrasound during a preload challenge

A preload challenge (PC) is a clinical maneuver that, first, increases the cardiac filling (i.e., preload) and, second, calculates the change in cardiac output. Fundamentally, a PC is a bedside approach for testing the Frank-Starling-Sarnoff (i.e., "cardiac function") curve. Normally, this curve has a steep slope such that a small change in the cardiac preload generates a large change in the stroke volume (SV) or cardiac output. However, in various disease states, the slope of this relationship flattens such that increasing the volume into the heart leads to little rise in the SV. In this pathological scenario, additional cardiac preload (e.g., intravenous fluid) is unlikely to be physiologically effective and could lead to harm if organ congestion evolves. Therefore, inferring both the cardiac preload and output is clinically useful as it may guide intravenous (IV) fluid resuscitation. Accordingly, the goal of this protocol is to describe a method for contemporaneously tracking the surrogates of cardiac preload and output using a novel, wireless, wearable ultrasound during a well-validated preload challenge.

With respect to interpreting the continuous venous-arterial Doppler ultrasound during a preload challenge, general physiological responses are illustrated in Figure 1, Figure 2, Figure 3, and Figure 4.
First, in a patient with a normal, upright cardiac function curve, a small increase in the cardiac preload (e.g., as inferred by jugular venous Doppler) is accompanied by a relatively large rise in the stroke volume (e.g., as indicated by ccFT augmentation)2,14,36; this is exemplified by Figure 1. Inferring changes in the jugular venous pressure (JVP) from the jugular Doppler spectrum during the preload challenge deserves some elaboration. Again, this physiological variable is a surrogate for cardiac preload or filling. Normally, the jugular vein is collapsed in the upright position when the jugular venous pressure is less than the atmospheric pressure. In the Doppler spectrum, this translates to a relatively high velocity (i.e., usually more than 50 cm/s) with minimal pulsations and low amplitude (i.e., the intensity or &#34;brightness&#34; of the jugular signal). Then, if the jugular venous pressure rises during the maneuver, the vein rounds out in diameter, its velocity falls (i.e., usually to less than 50 cm/s), the intensity (i.e., &#34;brightness&#34;) increases, and the waveform becomes more pulsatile2,14,36. As shown in Figure 1, the change in the venous Doppler morphology indicates that the jugular vein has increased in diameter (i.e., falling velocity, rising amplitude) and is beginning to follow the right atrial pressure deflections. Though not pictured, with increased right atrial pressure, the &#34;v&#34; wave during late systole can cleave the monophasic wave seen in Figure 1 into a systolic &#34;s&#34; velocity wave and a diastolic &#34;d&#34; velocity wave2,14,36. In as-of-yet unpublished data in healthy volunteers, we observed that jugular venous Doppler morphology was the most accurate venous ultrasonographic measure for distinguishing low from high preload states.
In contrast, an abnormal response is depicted in Figure 2. A clinical example of this pathophysiology is a hypovolemic, veno-dilated, septic patient with evolving septic cardiac dysfunction2,15,36. Such a patient has diminished venous return (which reduces the cardiac preload, i.e., the right atrial or jugular venous pressure) and simultaneously depressed cardiac function2,15,35,36. Therefore, at baseline, this patient demonstrates a continuous, low-JVP venous Doppler morphology that increases (i.e., becomes more pulsatile) during the preload challenge without a significant rise in the ccFT. This effectively describes a flattened slope of the cardiac function curve.
The results from continuous venous-arterial Doppler could also alert the treating clinician to problems with the PLR itself. For example, in some situations, the PLR may not recruit enough venous blood from the lower extremities and splanchnic circulation to generate a physiologically effective preload challenge4. Without assessing the cardiac filling, this could result in a &#34;false negative&#34; PLR. However, if the clinician sees little ccFT response (i.e., as a stroke volume surrogate) coupled with no change in the venous Doppler (i.e., as a surrogate for preload), this could herald an ineffective PLR, as seen in Figure 3.
Lastly, it is critical that the PLR maneuver is true to its namesake, meaning that there is no exertion by the patient when the torso falls and the legs elevate13. This avoids adrenergic discharge, which may increase the cardiac function independently of the venous return; however, as described in Figure 4, this undesired scenario may be indicated by the parameters of a rising stroke volume in the arterial signal coupled with a venous Doppler morphology, suggesting diminished venous pressure.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/64410/64410fig01.jpg" /> 
Figure 1: Increased slope of the cardiac function curve. In an example of a &#34;normal&#34; or &#34;expected&#34; result, the venous waveform progresses from being high velocity, low amplitude, and non-pulsatile to being lower velocity, higher amplitude, and pulsatile in character. The pulsatile venous waveform can be marked by a monophasic signal, as seen here. Concomitantly, the arterial Doppler waveform shows an increase in the ccFT from baseline, suggesting that the increase in the cardiac preload is met by a rising cardiac output. These responses, taken together, indicate a &#34;cardiac function&#34; curve with a steep slope. The y-axis on the spectrum represents the velocity in centimeters per second. The positive velocity is toward the brain (e.g., the carotid artery), while the negative velocity is toward the heart (e.g., the jugular velocity). The x-axis on the spectrum is time. <a href="https://www.jove.com/files/ftp_upload/64410/64410fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/64410/64410fig02.jpg" /> 
Figure 2: Flattened slope of the cardiac function curve. An &#34;abnormal&#34; response during a preload challenge is marked by a venous Doppler waveform that evolves as above but with an arterial response that reveals no significant change or even a decrease in the ccFT as compared to baseline, as seen here. This constellation of venous and arterial findings implies a flat or, potentially, impaired cardiac function curve with increased preload. <a href="https://www.jove.com/files/ftp_upload/64410/64410fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/64410/64410fig03.jpg" /> 
Figure 3: No change in the venous Doppler. A preload challenge that shows no significant change in the venous Doppler waveform could represent an inadequate change in cardiac filling, meaning no change in the arterial spectrum is expected. <a href="https://www.jove.com/files/ftp_upload/64410/64410fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/64410/64410fig04.jpg" /> 
Figure 4: Falling preload during a preload challenge. A preload challenge that shows rising venous velocity and a significant increase in arterial Doppler measures may mean augmented adrenergic tone (i.e., sympathetic stimulation) such that the cardiac function increases independently of the venous return. This circumstance could be the result of a &#34;non-passive&#34; leg raise, for example, if the patient strains to change their body position. <a href="https://www.jove.com/files/ftp_upload/64410/64410fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/64410/64410fig05.jpg" /> 
Figure 5: The device on a volunteer. <a href="https://www.jove.com/files/ftp_upload/64410/64410fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Continuous Venous-Arterial Doppler Ultrasound During a Preload Challenge at JoVE.com

Continuous Venous-Arterial Doppler Ultrasound During a Preload Challenge

The Frank-Starling-Sarnoff curve is clinically important and describes the relationship between cardiac preload and output. This report illustrates a novel method of simultaneous jugular venous and carotid arterial Doppler velocimetry as transient surrogates of cardiac preload and output, respectively; this approach is enabled by wireless, wearable Doppler ultrasound.

A preload challenge (PC) is a clinical maneuver that, first, increases the cardiac filling (i.e., preload) and, second, calculates the change in cardiac ...

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3.3K Views.  Health Sciences North Research Institute. The Frank-Starling-Sarnoff curve is clinically important and describes the relationship between cardiac preload and output. This report illustrates a novel method of simultaneous jugular venous and carotid arterial Doppler velocimetry as transient surrogates of cardiac preload and output, respectively; this approach is enabled by wireless, wearable Doppler ultrasound.

Video: Continuous Venous-Arterial Doppler Ultrasound During a Preload Challenge

Ultrasound Assessment of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery in Clinical Research

The vascular endothelium is a monolayer of cells that cover the interior of blood vessels and provide both structural and functional roles. The endothelium acts as a barrier, preventing leukocyte adhesion and aggregation, as well as controlling permeability to plasma components. Functionally, the endothelium affects vessel tone.
Endothelial dysfunction is an imbalance between the chemical species which regulate vessel tone, thombroresistance, cellular proliferation and mitosis. It is the first step in atherosclerosis and is associated with coronary artery disease, peripheral artery disease, heart failure, hypertension, and hyperlipidemia.
The first demonstration of endothelial dysfunction involved direct infusion of acetylcholine and quantitative coronary angiography. Acetylcholine binds to muscarinic receptors on the endothelial cell surface, leading to an increase of intracellular calcium and increased nitric oxide (NO) production. In subjects with an intact endothelium, vasodilation was observed while subjects with endothelial damage experienced paradoxical vasoconstriction.
There exists a non-invasive, in vivo method for measuring endothelial function in peripheral arteries using high-resolution B-mode ultrasound. The endothelial function of peripheral arteries is closely related to coronary artery function. This technique measures the percent diameter change in the brachial artery during a period of reactive hyperemia following limb ischemia.
This technique, known as endothelium-dependent, flow-mediated vasodilation (FMD) has value in clinical research settings. However, a number of physiological and technical issues can affect the accuracy of the results and appropriate guidelines for the technique have been published. Despite the guidelines, FMD remains heavily operator dependent and presents a steep learning curve. This article presents a standardized method for measuring FMD in the brachial artery on the upper arm and offers suggestions to reduce intra-operator variability.

Endothelial dysfunction is associated with numerous disease states and is predictive of adverse cardiovascular events in humans. Flow-mediated vasodilation (FMD) is a non-invasive ultrasound method of evaluating endothelial function. Methodological choices and operator experience may affect results. A systematic approach to FMD in human studies is discussed here.

The vascular endothelium is a monolayer of cells that cover the interior of blood vessels and provide both structural and functional roles. The ...

A Methodological Approach to Non-invasive Assessments of Vascular Function and Morphology

The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis. Damage to the endothelium may predispose the vessel to atherosclerosis and increase the risk for cardiovascular disease. Assessments of peripheral endothelial function are good indicators of early abnormalities in the vascular wall and correlate well with assessments of coronary endothelial function. The present manuscript details the important methodological steps necessary for the assessment of microvascular endothelial function using laser Doppler imaging with iontophoresis, large vessel endothelial function using flow-mediated dilatation, and carotid atherosclerosis using carotid artery ultrasound. A discussion on the methodological considerations for each of the techniques is also presented, and recommendations are made for future research.

The present article describes the methodological considerations for several non-invasive assessments of vascular function and morphology that are commonly used in medical research to assess different stages of atherosclerosis.

The endothelium is the innermost lining of the vasculature and is involved in the maintenance of vascular homeostasis.  Damage to the endothelium may ...

Ultrasound Assessment of Flow-Mediated Dilation of the Brachial and Superficial Femoral Arteries in Rats

Arterial vasodilation to increases in wall shear rate is indicative of vascular endothelial function. In humans, the non-invasive measurement of endothelial function can be achieved by employing the flow-mediated dilation technique, typically performed in the brachial or superficial femoral artery. Briefly, a blood pressure cuff placed distal to an ultrasound probe is inflated to a suprasystolic pressure, which results in limb ischemia. After 5 min of occlusion the cuff is deflated, resulting in reactive hyperemia and increases in wall shear rate that signal vasodilatory molecules to be released from the endothelium eliciting vasodilation. Despite the thousands of studies performing flow-mediated dilation in humans, surprisingly, no studies have performed this technique non-invasively in living rats. Considering the recent shift in focus to translational research, the establishment of guidelines for non-invasive measurement of flow-mediated dilation in rats and other rodents would be extremely valuable. In the following article, a protocol is presented for the non-invasive measurement of flow-mediated dilation in brachial and superficial femoral arteries of rats, as those sites are most commonly measured in humans.

Non-invasive assessment of endothelial function in humans can be determined by the flow-mediated dilation technique. Although thousands of studies have used this technique, no study has performed this technique non-invasively in rats. The following article describes non-invasive measurement of flow-mediated dilation in the brachial and superficial femoral arteries of rats.

Arterial vasodilation to increases in wall shear rate is indicative of vascular endothelial function. In humans, the non-invasive measurement of ...

Assessment of Pulmonary Capillary Blood Volume, Membrane Diffusing Capacity, and Intrapulmonary Arteriovenous Anastomoses During Exercise

Exercise is a stress to the pulmonary vasculature. With incremental exercise, the pulmonary diffusing capacity (DLCO) must increase to meet the increased oxygen demand; otherwise, a diffusion limitation may occur. The increase in DLCO with exercise is due to increased capillary blood volume (Vc) and membrane diffusing capacity (Dm). Vc and Dm increase secondary to the recruitment and distension of pulmonary capillaries, increasing the surface area for gas exchange and decreasing pulmonary vascular resistance, thereby attenuating the increase in pulmonary arterial pressure. At the same time, the recruitment of intrapulmonary arteriovenous anastomoses (IPAVA) during exercise may contribute to gas exchange impairment and/or prevent large increases in pulmonary artery pressure.
We describe two techniques to evaluate pulmonary diffusion and circulation at rest and during exercise. The first technique uses multiple-fraction of inspired oxygen (FIO2) DLCO breath holds to determine Vc and Dm at rest and during exercise. Additionally, echocardiography with intravenous agitated saline contrast is used to assess IPAVAs recruitment.
Representative data showed that the DLCO, Vc, and Dm increased with exercise intensity. Echocardiographic data showed no IPAVA recruitment at rest, while contrast bubbles were seen in the left ventricle with exercise, suggesting exercise-induced IPAVA recruitment.
The evaluation of pulmonary capillary blood volume, membrane diffusing capacity, and IPAVA recruitment using echocardiographic methods is useful to characterize the ability of the lung vasculature to adapt to the stress of exercise in health as well as in diseased groups, such as those with pulmonary arterial hypertension and chronic obstructive pulmonary disease.

To assess the pulmonary diffusion and vasculature responses to exercise, we describe the multiple-inspired oxygen diffusion capacity technique to determine capillary blood volume and membrane diffusing capacity, as well as agitated saline contrast echocardiography to assess the recruitment of intrapulmonary arteriovenous anastomoses.

Exercise is a stress to the pulmonary vasculature. With incremental exercise, the pulmonary diffusing capacity (DLCO) must increase to meet the increased ...

Closed Chest Biventricular Pressure-Volume Loop Recordings with Admittance Catheters in a Porcine Model

Pressure-volume (PV) loop recording enables the state-of-the-art investigation of load-independent variables of ventricular performance. Uni-ventricular evaluation is often performed in preclinical research. However, the right and left ventricles exert functional interdependence due to their parallel and serial connections, encouraging simultaneous evaluation of both ventricles. Furthermore, various pharmacological interventions may affect the ventricles and their preloads and afterloads differently. 
We describe our closed chest approach to admittance-based bi-ventricular PV loop recordings in a porcine model of acute right ventricular (RV) overload. We utilize minimally invasive techniques with all vascular accesses guided by ultrasound. PV catheters are positioned, under fluoroscopic guidance, to avoid thoracotomy in animals, as the closed chest approach maintains the relevant cardiopulmonary physiology. The admittance technology provides real-time PV loop recordings without the need for post-hoc processing. Furthermore, we explain some essential troubleshooting steps during critical timepoints of the presented procedure. 
The presented protocol is a reproducible and physiologically relevant approach to obtain a bi-ventricular cardiac PV loop recording in a large animal model. This can be applied to a large variety of cardiovascular animal research.

Here we present a closed chest approach to admittance-based bi-ventricular pressure-volume loop recordings in pigs with acute right ventricular dysfunction.

Pressure-volume (PV) loop recording enables the state-of-the-art investigation of load-independent variables of ventricular performance. Uni-ventricular ...

Functional Assessment of the Donor Heart During Ex Situ Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography

Heart transplantation remains the gold standard treatment for advanced heart failure. However, the current critical organ shortage has resulted in the allocation of a growing number of donor hearts with extended criteria. These marginal grafts are associated with a high risk of primary graft failure and may benefit from ex situ perfusion before transplant. This technology allows for extended organ preservation using warm oxygenated blood perfusion with continuous metabolic monitoring. The only NESP device currently available for clinical practice perfuses the organ in an unloaded non-working state, which does not allow for functional assessment of the beating heart. We therefore developed an original platform of NESP in working mode conditions with adjustment of left ventricular preload and afterload. This protocol was applied in porcine hearts. Ex situ functional assessment of the heart was achieved with intracardiac conductance catheterization and surface echocardiography. Along with a description of the experimental protocol, we herein report the main results, as well as pearls and pitfalls associated with the acquisition of pressure-volume loops and myocardial power during NESP. Correlations between hemodynamic findings and ultrasound variables are of major interest, especially for further rehabilitation of donor hearts before transplantation. This protocol aims to improve the assessment of donor hearts to both increase the donor pool and reduce the incidence of primary graft failure.

Functional Assessment of the Donor Heart During Ex Situ Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography

A reliable noninvasive approach for functional assessment of the donor heart during normothermic ex situ heart perfusion (NESP) is lacking. We herein describe a protocol for ex situ assessment of myocardial performance using the epicardial echocardiography and conductance catheter method.

Heart transplantation remains the gold standard treatment for advanced heart failure. However, the current critical organ shortage has resulted in the ...

Assessing Leg Blood Flow in Training Workloads

Doppler Ultrasound-Based Leg Blood Flow Assessment During Single-Leg Knee-Extensor Exercise in an Uncontrolled Setting

Doppler ultrasound has revolutionized the assessment of organ blood flow and is widely used in research and clinical settings. While Doppler ultrasound-based assessment of contracting leg muscle blood flow is common in human studies, the reliability of this method requires further investigation. Therefore, this study aimed to investigate the within-day test-retest, between-day test-retest, and inter-rater reliability of Doppler ultrasound for assessing leg blood flow during rest and graded single-leg knee-extensions (0 W, 6 W, 12 W, and 18 W), with the ultrasound probe being removed between measurements. The study included thirty healthy subjects (age: 33 &#177; 9.3, male/female: 14/16) who visited the laboratory on two different experimental days separated by 10 days. The study did not control for major confounders such as nutritional state, time of day, or hormonal status. Across different exercise intensities, the results demonstrated high within-day reliability with a coefficient of variation (CV) ranging from 4.0% to 4.3%, acceptable between-day reliability with a CV ranging from 10.1% to 20.2%, and inter-rater reliability with a CV ranging from 17.9% to 26.8%. Therefore, in a real-life clinical scenario where controlling various environmental factors is challenging, Doppler ultrasound can be used to determine leg blood flow during submaximal single-leg knee-extensor exercise with high within-day reliability and acceptable between-day reliability when performed by the same sonographer.

Author Spotlight: Assessing the Reliability of Doppler Ultrasound in Measuring Leg Blood Flow 

This test-retest study evaluated leg blood flow measured by the Doppler ultrasound technique during single-leg knee-extensor exercise. The within-day, between-day, and inter-rater reliability of the method was investigated. The approach demonstrated high within-day and acceptable between-day reliability. However, the inter-rater reliability was unacceptably low during rest and at low workloads.

Doppler ultrasound has revolutionized the assessment of organ blood flow and is widely used in research and clinical settings. While Doppler ...

Echocardiographic Assessment Using Subxiphoid-Only Examination for Hypotensive Patients

Point-of-care ultrasound, or POCUS, has gathered significant interest as a tool to augment clinical decision-making in the care of acutely ill patients. Patients with hemodynamic instability, in particular, require immediate intervention and are at high risk for further cardiovascular and/or respiratory decompensation. POCUS examination of these patients, therefore, requires a protocol that is sufficient to answer clinicians' questions while still retaining adequate brevity to be feasible in a short period of time at the bedside. Here, we demonstrate a protocol for obtaining such information by the Echocardiographic Assessment using Subxiphoid-Only - Mean Arterial Pressure, or EASy MAP exam, a focused ultrasonographic assessment of the cardiovascular and respiratory systems. The cardiovascular portion of the examination utilizes the subcostal window to obtain views of the heart and inferior vena cava (IVC); this is then supplemented by anterior upper lung and posterolateral diaphragmatic pleural views for the respiratory portion. All six views (cardiac, IVC, left and right anterior upper lung, and left and right posterolateral pleural) are obtained using a low-frequency phased array transducer. We discuss some of the common pitfalls encountered in obtaining these images and the basics of interpreting the most common findings; also described is a 12-point scale for rating the quality of the images obtained from the cardiac view and a small number of supplementary views that may be considered when clinically relevant.

The protocol here provides a rapid, phenotype-based approach for focused ultrasound evaluation of the hypotensive patient, using subcostal images of the inferior vena cava and heart, with additional views of the upper lungs and pleural spaces.

Point-of-care ultrasound, or POCUS, has gathered significant interest as a tool to augment clinical decision-making in the care of acutely ill patients. ...

Demystifying Venous Excess Ultrasound (VExUS): Image Acquisition and Interpretation

Providers in many medical specialties must accurately assess the hemodynamic circuit to deliver appropriate patient care. Venous congestion is increasingly implicated in a range of multiorgan complications. However, hemodynamic assessment remains challenging because of the complex physiology involved and inconsistent diagnostic accuracy of conventional bedside tools and physical exam maneuvers. While right heart catheterization is regarded as the gold standard for measuring systemic venous pressure, it is invasive and not easily repeatable, and thus, there remains a need for non-invasive alternatives. Even point-of-care ultrasound examinations of the internal jugular vein or inferior vena cava have significant limitations in terms of accuracy of intravascular volume assessment and correlation with central venous pressure. To improve bedside clinicians' accuracy at assessing venous congestion, a protocol was developed and validated that utilizes pulsed-wave (PW) Doppler signals of veins in the liver and kidney to grade the degree of venous congestion present in patients. Although this scoring system, called Venous Excess Ultrasound (VExUS), is being increasingly adopted within certain subspecialties of medicine, such as nephrology and critical care, it remains underutilized in medicine as a whole. This is likely due, at least in part, to knowledge gaps and lack of training in this emerging modality. To address this educational gap, this article will describe VExUS image acquisition and interpretation.

Point-of-care ultrasound (POCUS) is often used to assess the hemodynamic circuit and detect the presence of venous congestion. The Venous Excess Ultrasound (VExUS) scoring system was developed to aid clinicians in predicting the impact of venous congestion on organ dysfunction. This article aims to describe VExUS image acquisition and interpretation.

Providers in many medical specialties must accurately assess the hemodynamic circuit to deliver appropriate patient care. Venous congestion is ...

Peripheral Vascular Exam Using a Continuous Wave Doppler

Source: Joseph Donroe, MD, Internal Medicine and Pediatrics, Yale School of Medicine, New Haven, CT
Peripheral vascular disease (PVD) is a common condition affecting older adults and includes disease of the peripheral arteries and veins. While the history and physical exam offer clues to its diagnosis, Doppler ultrasound has become a routine part of the bedside vascular examination. The video titled &#34;The Peripheral Vascular Exam&#34; gave a detailed review of the physical examination of the peripheral arterial and venous systems. This video specifically reviews the bedside assessment of peripheral arterial disease (PAD) and chronic venous insufficiency using a handheld continuous wave Doppler.
The handheld Doppler (HHD) is a simple instrument that utilizes continuous transmission and reception of ultrasound (also referred to as continuous wave Doppler) to detect changes in blood velocity as it courses through a vessel. The Doppler probe contains a transmitting element that emits ultrasound and a receiving element that detects ultrasound waves (Figure 1). The emitted ultrasound is reflected off of moving blood and back to the probe at a frequency directly related to the velocity of blood flow. The reflected signal is detected and transduced to an audible sound with a frequency directly related to that of the received Doppler signal (thus, faster blood flow produces a higher frequency sound).
<img alt="Figure 1" src="/files/ftp_upload/10123/10123fig1.jpg" /> 
Figure 1. Generation of a Doppler signal. The handheld Doppler emits an ultrasound signal, which is then reflected back by moving blood, and finally received by the Doppler probe.
The HHD is easily used in the office or hospital setting to detect pulses, screen for PAD using the ankle brachial pressure index (ABPI), and localize venous insufficiency. This video reviews these procedures; however, it is not intended to be a comprehensive review of non-invasive vascular testing.

Continuous Venous-Arterial Doppler Ultrasound During a Preload Challenge

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