Cardiac output (CO) is a fundamental measure for the assessment of cardiac performance and is applied widely to detect the presence of cardiovascular disease and monitor its progression, as well as to monitor patients in challenging hemodynamic circumstances and to optimize therapy. CO is a key parameter in characterizing a patient’s hemodynamic state. For example, a notable characteristic of chronic heart failure is an impaired CO response to exercise with gradual reduction in cardiac function, culminating in reduced CO even at rest. Measures of both resting and exercise CO have been shown to be important prognostic markers in chronic heart failure.1–4
Despite a plethora of developments over recent decades, there still exists a clear need for highly accurate measures of CO that can be applied in various clinical settings in a cost-effective and scalable fashion. Thermodilution has been the most extensively utilized approach and is considered highly accurate, but inadequacies with this method have been widely reported.5–8 Thermodilution is invasive, time-consuming, and relatively expensive, and requires the attention of a trained physician. Finally, due to its invasive nature— the technique requires the invasive placement of a right heart/pulmonary artery catheter (PAC)—thermodilution comes with a degree of risk and complications. Its use is therefore limited to intensive care units (ICUs), operating rooms and the cardiac catheterization laboratory. As a result, thermodilution is utilized for only a small percentage of patients in whom the measurement of CO could prove useful. With such evident flaws, numerous less invasive methods have been proposed to measure CO. However, it is well documented that these methods—which have included echocardiography, bioimpedence, arterial pulse wave contour analysis, and CO2 rebreathing—are also beset with limitations, specifically regarding their reliability and reproducibility.9–13
More recently, bioimpedence has come to the forefront in the non-invasive arena. This technique was founded on the concept that electrical conducting properties of the thoracic space vary with the amount of blood contained therein. The method entails the measurement of charges in the electrical impedance of the chest cavity, which are subsequently highly related to changes in the amount of blood contained within the aorta. Analysis of the rate of change of aortic blood volume can readily be related to CO. Bioimpedence offers an easy-to-use, cost-effective CO measurement modality that can be scaled to sites of less intensive care, including the emergency room, regular hospital wards, and physician offices.
Provisional studies for this method displayed highly promising results. More recently, however, concerns have surfaced over the levels of accuracy of CO achieved by bioimpedance, particularly in complex hemodynamic patients.10 Furthermore, available bioimpedence devices are not intended for continuous CO monitoring in any setting; rather, they are intended to provide spot measurements with the patient sitting in a chair.
While reasons for these limitations are mostly technical and require a discussion beyond the scope of this review, it is widely believed that bioimpedence yields a relatively low signal-to-noise ratio, which is particularly noticeable in clinical settings rich in ambient radiofrequency noise, for example in hospitals or under other challenging circumstances such as during patient movement, during heavy breathing, and in obese subjects. As bioimpedance-based approaches rely on changes in the amplitude of propagated electrical signals (amplitude modulation, or AM), they are limited in their ability to filter such electrical noise. Therefore, bioimpedence has been found to offer sub-optimal accuracy in ICUs and other settings where significant electrical noise and body motion exist.9,10 In addition, variances in skin conductivity, patient movement, and lack of clinician attention to exact placement of sticker-electrodes may all contribute to inaccurate and variable measurement readings.
It is these problems of achieving both non-invasive and accurate CO measurements that have underpinned the development of a new method, designed specifically to overcome these deficiencies. New Bioreactance™ technology (Cheetah, Medical Inc., Indianapolis, IN) is based on the discovery that changes in aortic blood volume induce small changes in the frequency of electrical signals propagating across the thorax. These small changes are highly correlated with blood flow and can thus be used to report the CO with very high dependability. Similar to bioimpedance-based methods, the Bioreactance system (NICOM™) consists of applying four pairs of double electrode stickers to the patient—two attached on either side of the thorax (positioned marginally below the ribs) and two pairs just below the shoulders (on either side of the mid-axial line) or on the upper back. Each pair of electrodes delivers a low alternating current, sensed for its propagation characteristics along the thorax by the other electrode pairs. The fundamental innovation behind Bioreactance's accuracy across multiple clinical settings lies in the fact that the primary parameter being measured is changes in frequency, not changes in amplitude.
The performance advantage gained from this approach resembles the benefits in fidelity achieved in moving from AM to frequency modulation (FM) radio. This enables a high degree of accuracy, despite patient movement and variations in body types and location of the sticker-electrodes, and allows filtering of the electrical interference noise typically encountered in hospital and physician office settings.
Keren et al. have fundamentally demonstrated the accuracy of the Bioreactance technology in a pre-clinical study. Nine open chest pigs were put on right heart bypass to enable the precise control and adjustment of CO to known values, using a cardiopulmonary bypass pump (CPB). As well as adjusting CO via the CPB, in a secondary phase blood temperature was varied between 38 and 36ºC.14 Changes in temperature induce significant changes in electrical conductivity and thus impose a relatively rigorous test on the system performance independent of physical factors. The results of this study showed the measurements of Bioreactance (NICOM) technology and cardiopulmonary bypass pump to correlate with each other (r=0.84), even in the setting of large variations in CO and temperatures (see Figure 1). Other preclinical studies performed with Bioreactance-based systems captured a tight correlation between dX/dt, which reflects the rate of frequency change during the cardiac cycle, and dP/dt, which reflects pressure changes over time as captured with invasive pressure catheters; the latter is an established index of cardiac contractility.
Intensive Care Unit
CO measurements in the ICU setting is usually obtained by thermodilution, an invasive method that requires insertion of a pulmonary arterial catheter.15 Other modalities employ arterial catheters for pulse contour analysis,16,17 an intratracheal tube for partial CO2 re-breathing,18 or an intra-esophageal probe for continuous Doppler velocity flow assessment.19,20
NICOM Bioreactance-based technology has benefits over these existing methods by providing accurate, continuous readings without the obvious drawbacks of invasive methods. In a prospective study by Squara et al.,21 CO measurements obtained from Bioreactance and thermodilution were simultaneously recorded minute-by-minute and compared in 110 adult patients following cardiac surgery.
The aim was to evaluate the accuracy, precision, responsiveness, and reliability of Bioreactance for detecting CO changes. Tolerance for each of these parameters was specified prospectively within acceptable guidelines. The study concluded that CO measured by Bioreactance produced acceptable accuracy, precision, and responsiveness in a wide range of circulatory situations. The study also highlighted the cost, complication profile, and efficiency benefits of NICOM compared with PACs, which may take up to half an hour to insert in a procedure that can be carried out only by a trained physician. In contrast, the NICOM system may be quickly applied by a nurse, thus freeing up physician time. Furthermore, significant safety benefits may be realized by obviating the need for catheter insertion.
Cardiac Care Unit and Heart Failure Unit
There is a clear rationale behind monitoring cardiac function in the cardiac care unit (CCU) and heart failure unit, and where the direct reason for admission is heart disease, the value of realtime information on cardiac function looms even larger. For example, in patients with exacerbation of heart failure, which is the number one reason for hospitalization in the Western world, restoration of cardiac function and reduction of pulmonary vascular congestion—which can be indexed by thoracic fluid content (TFC)— indicate that the patient is responding well to treatment. This type of information is critical given the economics of heart failure and the fact that, in the US, 90-day readmission rates for heart failure hover around 30%: a figure with far-reaching clinical and economical implications. Currently, many patients—especially those in the CCU—are monitored using PACs, which also provide pulmonary artery wedge pressure (PAW). There is, however, a need to reduce the cost and invasiveness of monitoring or, at the very least, to enable earlier withdrawal of invasive PAC while retaining good insights into the patient’s cardiac and hemodynamic status.
While bioimpedance has been used in the CCU, it has often proved inconsistent in its measurement accuracy. The abundant radiofrequency noise and the confounding impact of patient movement can challenge the signal-to-noise profile of bioimpedance, thus reducing its consistency. NICOM has been used in the CCU with similar results as in the ICU (Burkhoff et al., unpublished data) with results showing good tracking of CO as measured by PAC. More studies are needed and are ongoing to assess the potential of using NICOM in the CCU, for example to improve insight into the clinical course of individual patients, optimize time of discharge, and, potentially reduce hospital readmission rates.
Operating Room/Peri-operative Settings/Recovery Floor
High-risk patients who undergo invasive surgical procedures require close post-operative monitoring prior to ambulation to a less intensive site of care. Hemodynamic monitoring is a key component of this paradigm because surgery and recovery impose significant challenges on the cardiovascular, pulmonary, and renal system post-operatively. For example, patients who undergo cardiothoracic surgery often require a few days of observation in the step-down or telemetry unit, where their haemodynamic status is closely monitored. Unfortunately, the use of invasive monitoring modalities such as PAC and arterial lines immobilizes the patient, may augment the risk of complications, and adds to the nursing work-load. From the perspective of the patient—and indeed the healthcare unit—it is important to move the patient to a less invasive site of care. However, in order for this to be achieved the patient must remain without any cardiac monitoring, as invasive catheters may not be used in standard wards—hence the rationale and need for accurate and non-invasive CO monitoring. Utilization of non-invasive CO monitoring may also lead to significant cost savings, derived not only by freeing up expensive ICU space—and ultimately reducing the hours a patient spends in post-operative recovery—but also through foregoing the need to insert a disposable catheter to monitor the patient’s hemodynamic status, with an additional cost benefit of approximately US$100 per patient per day.
Emergency Room
While heart failure remains the number one cause of hospital admission in the West, immediate diagnosis in an emergency room (ER) setting is often problematic. A patient’s dyspnea may be linked to heart failure, bronchitis, emphysema, sepsis, or pulmonary emboli, among others, making immediate diagnosis challenging. In addition, extensive monitoring is needed following diagnosis to decide whether the patient should be sent home, sent to an intensive care unit, or simply hospitalized in a regular ward. The growing utilization of ERs further fuels the need to rapidly assess, treat, monitor, and mobilize patients.
Much research has gone into ER protocols that may help to address this challenge. Of note, a serum test for brain natriuretic peptide (BNP) has been increasingly utilized as a rapid adjunct in differential diagnosis of dyspnea. Very high BNP levels are associated with fluid overload and point to exacerbation of heart failure as the cause of dyspnea, while normal BNP indicates against heart failure as the source.
With the cost of procedural testing low and the cost of ER utilization high, the clinical and financial benefits of accurate monitoring are evident. Rapid BNP measurement in the ER has been shown to improve the evaluation and treatment of patients with acute dyspnea and thereby reduce the time to discharge and the total cost of treatment.22
BNP also has its limitations. First, as it is a blood test, there is the issue of logistics and turnaround time, which can take anything from 10 minutes to one hour. Second, as a blood test it provides a momentary snapshot that represents the status when the test is taken, and is not a monitoring tool. Finally, the serum levels of BNP is a peptide lag behind clinical progression, given the peptide’s serum half-life. Thus, once diagnosis is made, further testing cannot provide short-term, realtime insight on response to treatment, which is critical in the ER.
Recent research has highlighted the value of TFC and CO monitoring to empower quick differential diagnosis of dyspnea in the ER, showing that it can also mitigate the use of erroneous medications and ease efficiency bottlenecks. The common manifestation of dyspnea in the ER, and the high volume of heart-failure patients in particular, can have a significant impact on ER efficiency and economics where a quick and accurate diagnosis is key. A study by Peacock et al.23 of elderly patients presenting with dyspnea to the ER indicated that when changes in working diagnosis were made, these were consistent with the final diagnosis at the time of ER disposition in two-thirds of cases. In addition to changes in diagnosis, ER physicians made medication changes on the basis of impedance cardiography-derived hemodynamic information in 39% of cases.
While Peacock et al. validated the benefits of impedance cardiography, upcoming studies that employ Bioreactance in this setting aim to bring the high accuracy compared with invasive modalities demonstrated in ICU settings to the ER. The ability of Bioreactance to provide good information despite patient movement is also appealing for ER use, as well as for use in the ambulance. Finally, by providing realtime, continuous monitoring, Bioreactance-derived CO along with TFC add an additional and potentially complementary data provided by a BNP level.
Outpatient/Physician Clinic
Cardiologists and primary care physicians have limited means to assess and monitor heart failure patients in the outpatient setting. In contrast to ischemic heart disease, where office diagnostic procedures are common and now include stress testing and nuclear cardiology, heart failure management relies heavily on the traditional clinical evaluation.
Echocardiography may be used as an adjunct input, but provides at best a general view on cardiac function. Moreover, given the trend whereby heart failure with normal ejection fraction (HFNEF) now accounts for approximately 50% of heart failure patients, relying on echo-based ejection fraction is often of marginal clinical utility in assessing the immediate clinical status of a patient presenting with symptomatic heart failure.24
Given the lack of quantitative measures to assess cardiac performance, there is currently no ubiquitous, quantifiable means by which to assess the response of heart failure patients to treatment, overall progression, and prognosis. The main gap is in ascertaining cardiac performance during exercise. The peak CO that can be delivered by the heart is a key parameter with far-reaching implications because, similar to ischemic heart disease, heart failure manifests during stress when the heart is challenged. Indeed, by the time heart failure is symptomatic at rest, the patient may be critically ill.
The only sufficiently validated diagnostic test that provides good insight into CO during stress is cardiopulmonary stress testing (CPX), which measures peak oxygen consumption (VO2max). In fact, this modality has been shown time and again to be the most powerful prognostic tool for heart failure patients.25 However, VO2max has significant logistical and cost issues that have limited its penetration and adoption mostly to large heart failure research and transplant centers. This is unfortunate, because heart failure is becoming a major healthcare and economic concern and physicians require a more scalable and cost-effective solution. Another potential limitation of VO2max is that by measuring oxygen consumption VO2max captures more than just CO, because of skeletal muscle oxygen utilization. Lung performance also contributes to the result. Indeed, Wilson et al. suggested that peak cardiac output is an independent and potentially more accurate prognostic factor in heart failure than VO2max.26
Given reports demonstrating low signal-to-noise ratios with Bioreactance during motion in hospitalized patients, researchers have evaluated its use to derive peak CO during exercise testing. A recent study by Myers et al.27 validated the use of the Bioreactance-based NICOM system during exercise. In the study, 36 patients (23 heart failure patients and 13 patients with other cardiac conditions but no heart failure) underwent cardiopulmonary exercise testing with continuous concomitant CO measurements.
CO and VO2max closely paralleled each other during rest, at peak exercise, and throughout the course of exercise. Of note, the association between peak VO2 and peak cardiac index measured in past studies with direct invasive approaches and peak cardiac index using NICOM were very closely correlated. Myers concluded that a non-invasive measurement of CO during exercise using a novel Bioreactance-based device has potentially important applications as a simple, inexpensive tool to supplement the clinical evaluation of patients with heart failure. The accuracy, ease of use, and cost-effectiveness of CO measurement by Bioreactance in an outpatient setting can provide physicians with clear patient insight and prognosis, and enable the customization of effective treatment programs.
Pacemaker Optimization
When pacemakers—particularly biventricular cardiac resynchronization devices—are inserted in the catheterization unit, a catheter is often used to ensure the pacemaker parameters (such as atrio-ventricular and ventriculo-ventricular delays) are adjusted to the optimal settings for the patient. However, in the subsequent outpatient environment (where catheters are not used) the physician is faced with the problem of how to modify and achieve the optimal setting for the pacemaker, further complicated by the numerous setting options on modern devices. Clearly, the inability to attain accurate cardiac output measurements for pacemaker optimization represents a considerable unmet need in this setting. Bioreactance could alleviate this problem through the provision of robust, accurate monitoring and enable patients to fully benefit from pacemaker optimization.
Dialysis Monitoring
A further application of Bioreactance in this setting is for patients with kidney failure, many of whom require dialysis three or four times per week. As many of these patients suffer from associated conditions, such as ischemic heart disease or congestive heart failure, they may be prone to myocardial infarction, or indeed pulmonary edema in the intervals between dialysis treatment. Much research has been conducted to enhance realtime cardiac monitoring capabilities during dialysis. As it is not possible to use a central pulmonary catheter in a patient up to four times per week, Bioreactance provides an ideal solution in a kidney dialysis unit, or with the portable unit, for self-monitoring during home dialysis.
Home Application and Early Warning of Heart Failure
Patients with heart failure are frequently hospitalized for fluid overload. A reliable method for chronic monitoring of fluid status is therefore desirable. However, the current reliance on patient weight in the home monitoring of heart failure remains a rather unsophisticated and unreliable benchmark. It is widely accepted that the most important means of monitoring heart failure is not weight, but thoracic fluid content. Cheuk-Man Yu et al.28 evaluated an implantable system capable of measuring intrathoracic impedance to identify potential fluid overload before heart failure hospitalisation. This study found that a consistent reduction in intrathoracic impedance occurs over an average of 18 days preceding hospitalization for worsening heart failure. This reduction in intrathoracic impedance predated the onset of symptoms by an average of 15 days, potentially serving as a ‘warning window’ for early intervention. Such findings have led to the development by Medtronic of the implantable biventricular pacemaker with bioimpendance sensors that measure thoracic fluid content. The devices are expensive, however, and benefit only those fitted with the pacemaker. In this capacity, there remains a need for an inexpensive and reliable method for the chronic monitoring of fluid status.
The enhanced accuracy and lower cost permitted by Bioreactance technology could prove a highly beneficial application in this area. Results of a study by Packer et al.29 suggested that when performed at regular intervals in stable patients with heart failure with a recent episode of clinical decompensation, measuring thoracic fluid content and cardiac output with the bioimpedance system can identify patients at increased near-term risk of recurrent decompensation. This indicates that Bioreactance, which offers increased accuracy, will aid the early diagnosis of exacerbation of heart failure. Furthermore, because particular body position and movement do not affect the performance of Bioreactance, patients can perform the test themselves.
Conclusion
There remains a clear unmet need for accurate, non-invasive, realtime and continuous measurement of cardiac output. Existing monitoring devices, both invasive and non-invasive, have notable limitations. For example, the thermodilution technique using a PAC is invasive, risks infection, is time-consuming, and, recently, the use of invasive hemodynamic monitoring has been increasingly criticized because of its uncertain risk–benefit ratio and cost.30–32 As a result, there has been a continuing search for a method of cardiac output measurement that is less invasive than its predecessors yet retains similar accuracy—criteria that impedance cardiography has gone some way to satisfy. However, accuracy concerns with impedance cardiography persist, which has resulted in low physician confidence and, ultimately, poor levels of penetration and adoption in most clinical settings.
The development of Bioreactance technology overcomes these limitations and provides potential solutions in both in- and outpatient settings for the assessment of circulatory function in acute heart failure patients, peri-operative/recovery situations, for routine assessment testing, and in determining appropriate treatment, medication, and discharge decisions.