Abstract
Background:
Central venous pressure (CVP) is measured to assess intravascular fluid status. Although the clinical gold standard for evaluating CVP is invasive measurement using catheterization, the use of catheterization is limited in a clinical setting because of its invasiveness. We developed novel non-invasive technique, enclosed-zone (ezCVPTM) measurement for estimating CVP. The purpose of this study was to assess the feasibility of ezCVP and the relationship between ezCVP and CVP measured by a catheter.
Methods and Results:
We conducted 291 measurements in 97 patients. Linear regression analysis revealed that ezCVP was significantly correlated with CVP (r=0.65, P<0.0001). The Bland-Altman analysis showed that ezCVP had an underestimation bias of −2.5 mmHg with 95% limits of agreement of −14.1 mmHg and 9.6 mmHg for CVP (P<0.0001). The areas under the curves of receiver operating curve with ezCVP to detect the CVP ≥12 cmH2O (8.8 mmHg) and CVP >10 mmHg were 0.81 or 0.88, respectively. The sensitivity, specificity and positive likelihood ratio of ezCVP for the CVP ≥8.8 mmHg and CVP >10 mmHg were 0.59, 0.96 and 14.8 with a cut-off value of 11.9 and 0.79, 0.97 and 26.3 with a cut-off value of 12.7.
Conclusions:
These findings suggest that ezCVP measurement is feasible and useful for assessing CVP.
Central venous pressure (CVP) is often measured in clinical practice to assess intravascular fluid status and cardiac preload. Measurement of CVP is particularly valuable for the management of heart failure (HF).1–4
The prognosis for patients with HF whose CVP remains at an elevated level is poor, even if appropriate guideline-directed therapy is provided.1,5
Even after successful decongestion, measurement of CVP is thought to be useful for detecting exacerbation of HF, which can progress the disease severity and result in a poor prognosis.5,6
Therefore, the measurement of CVP is quite important in the management of HF.
Although the clinical gold standard for evaluating CVP is invasive measurement using right heart catheterization via the central venous cava, the use of heart catheterization is limited in a clinical setting because of its invasiveness. As an alternative, for evaluation of intravascular fluid status, patients can monitor body weight and edema by themselves, and health-care providers can evaluate jugular venous pulsation (JVP), heart sounds and edema. These evaluations play pivotal roles in the management of HF.5,7,8
However, physical assessment involves some uncertainty due to the patient’s condition and health-care provider’s skill. Echocardiographic assessment of respiratory change of the inferior vena cava is also useful for the estimation of CVP,3
but it requires expertise and expensive equipment. The efficacy of remote hemodynamic assessment using implantable devices such as an implantable cardioverter defibrillator and a pulmonary artery monitoring device in a specific populations has been reported,9,10
but the high cost and limited availability will continue to be important considerations in the universal use of such devices. Therefore, the development of a novel technique for measuring CVP that is immediately available, universally feasible, not costly and readily repeatable is required.
We previously demonstrated the utility of measurement of enclosed-zone flow-mediated vasodilation (ezFMD) for evaluation of endothelial function.11–13
Measurement of ezFMD is a new technique for fully automatic measurement of FMD in the brachial artery using an oscillometric method that is widely used for measuring blood pressure. In the process of measurement of ezFMD, a blood pressure cuff is gradually deflated from the pressure that is 50 mmHg higher than systolic blood pressure down to diastolic blood pressure. In this process, we noticed that there is a second peak of oscillatory amplitude at a low cuff pressure near CVP measured by a catheter (Figure 1). The second peak of oscillatory amplitude at a low cuff pressure seemed to reflect brachial, cephalic and basilic venous pressure, which are comparable to CVP because the cuff oscillation reaches a maximum when the cuff pressure is equal to mean the pressure of pulsatile flow. Therefore, we hypothesized that we could estimate CVP from the oscillation of cuff pressure. We named this novel technique for estimating CVP the enclosed-zone CVP (ezCVPTM) measurement. The purpose of this study was to assess the feasibility of ezCVP and the relationship between ezCVP and CVP measured by a catheter.
Methods
Design, Setting and Subjects
This study was a prospective single-center observational study. We included 97 patients who were older than age 20 years and underwent right-heart catheterization at Hiroshima University Hospital from April 2017 to December 2017. The right-heart catheterization studies were conducted to assess hemodynamic conditions of patients with coronary artery disease (n=9), valvular heart disease (n=54), cardiomyopathy (n=30) and other diseases (n=4). Exclusion criteria were as follows: persistent atrial fibrillation, use of positive airway pressure in the right-heart catheterization study, inability of the patient to hold his/her breath at end-expiration for measurement of CVP, and inadequacy of cuff placement around the right upper arm. This study was approved by the ethics committee of Hiroshima University (reference number: C20160070). All participants gave written informed consent for participation. This study was conducted in accordance with the Declaration of Helsinki. The individual de-identified participant data will not be available to the public.
Measurement of Central Venous Pressure
Each patient was placed in the supine position on the angiography system. A 5 Fr Swan-Ganz pulmonary catheter (Zeon Medical Inc., Toyama, Japan) was inserted into the right internal jugular vein and connected to a multimodular monitor via a transducer that was zeroed to the level of the mid-axillary line. After measurements for routine hemodynamic assessment including measurements of pulmonary artery wedged pressure (PAWP), pulmonary artery pressure (PAP), right ventricular pressure (RVP) and cardiac output, the tip of the catheter was placed in the right atrium to measure right atrial pressure (RAP). RAP was measured at end-expiration with breath-holding for 3 cardiac cycles, and the average of 3 measurements of the mean RAP was used as the mean CVP. A 4 Fr sheath was inserted into the left radial artery for coronary angiography and for measurements of left ventricular pressure and arterial blood pressure.
Measurement of ezCVP
Prior to insertion of the Swan-Ganz pulmonary catheter and the radial artery sheath, a blood pressure cuff (Nihon Kohden. Co.) was placed around the right upper arm by medical staff and was connected to a modified bedside monitor and transducer that was zeroed to the level of the mid axillary line (Figure 2). A cuff pressure control algorithm was installed in the modified bedside monitor (PVM-9901, Nihon Kohden. Co.) equipped with a sphygmomanometer pump to control cuff pressure automatically. Measurement of ezCVP was started immediately after the measurements for routine hemodynamic assessment. At first, arterial pressure was measured using the blood pressure cuff. Cuff pressure was maintained at 40 mmHg for 30 s to analyze the respiratory cycle, and then cuff pressure was decreased gradually by 5-mmHg steps every 6 s down to 5 mmHg, as shown in
Figure 1A; therefore, a CVP of less than 5 mmHg could not be measured by this method. Oscillatory amplitudes at each pressure level were recorded for 6 s and then averaged. The cuff pressure with the second peak of oscillatory amplitude was defined as ezCVP, as shown in
Figure 1B. Then, ezCVP was measured three-fold serially by the same investigator and compared to CVP. ezCVP was determined by one investigator who was blinded to any clinical and hemodynamic information for the patients. We excluded 6 patients from analysis because the measurements of CVP varied widely due to body motion, deep respiration and/or arrhythmia during ezCVP measurements.
The cuff pressure control algorithm is based on an oscillometric method for detecting cuff pressure that has a peak amplitude. The algorithm detects the peak amplitude that changes with the change in cuff pressure and calculates the ezCVP value based on the cuff pressure that has a peak amplitude. When there is no peak amplitude and no noise signal, which means that the amplitude is monotonically decreasing during ezCVP measurement, the algorithm declares ezCVP as ‘0’. When the algorithm detects a noise signal, it declares failure in measurement.
Statistical Analysis
Statistical analysis was performed using JMP 13.0 software (SAS Institute Inc., Cary, NC, USA). Results are presented as mean±standard deviation for continuous variables with a normal distribution, and as medians (interquartile ranges) for continuous variables with non-parametric distribution. Categorical variables are presented as numbers (percentages). Correlations between ezCVP and CVP were evaluated using Pearson’s correlation coefficients (r). Bland-Altmann analysis was used to determine the bias and limits of agreement between ezCVP with CVP. Lin’s concordance correlation coefficient (ρc) was calculated to evaluate the strength of agreement: >0.99 indicates almost perfect agreement; 0.95–0.99, substantial agreement; 0.90–0.95, moderate agreement; <0.90, poor agreement. The performance of ezCVP measurement for predicting elevated CVP (CVP ≥10 mmHg or CVP >12 cmH2O that was equal to 8.8 mmHg of CVP)4,14
was assessed using the area under the curve (AUC) of a receiver operating curve (ROC). A P value <0.05 was considered statistically significant.
Results
Clinical Characteristics of the Subjects
In the present study, we conducted 291 measurements in 97 patients. We excluded 19 patients with atrial fibrillation during the measurement of ezCVP from analysis. Overall, 234 measurements in 78 patients were analyzed.
Table
shows the clinical characteristics and hemodynamic status of the study patients. Cardiac output was preserved, but mean PAWP was slightly higher than the normal range. Five patients had severe tricuspid regurgitation.
Table.
Clinical Characteristics and Hemodynamic Status of Participants
| Variables |
n=97 |
| Age, years |
68.5±15.4 |
| Female, n (%) |
33 (42.9) |
| Height, m |
158.7±11.4 |
| Body weight, kg |
59.8±11.9 |
| Body mass index, kg/m2 |
23.7±3.6 |
| Coronary artery disease, n (%) |
9 (9.3) |
| Valvular heart disease, n (%) |
54 (55.7) |
| Cardiomyopathy, n (%) |
30 (30.9) |
| Others, n (%) |
4 (4.1) |
| Hypertension, n (%) |
58 (75.3) |
| Diabetes mellitus, n (%) |
51 (66.2) |
| Dyslipidemia, n (%) |
42 (54.5) |
| Diuretics, n (%) |
32 (41.6) |
| Renin angiotensin system inhibitor, n (%) |
39 (51.7) |
| β-blocker, n (%) |
30 (39.0) |
| Calcium channel blocker, n (%) |
28 (36.4) |
| Left ventricular ejection fraction, % |
52.9±16.5 |
| Severe tricuspid regurgitation, n (%) |
7 (6.6) |
| Hemoglobin, g/dL |
12.8±2.3 |
| Creatinine, mg/dL |
0.9 (0.7–1.3) |
| N-terminal pro-brain natriuretic peptide, pg/mL |
610.5 (237.3–2,274.3) |
| Heart rate, beats/min |
71.9±12.0 |
| Systolic blood pressure, mmHg |
129.5±20.5 |
| Diastolic blood pressure, mmHg |
74.2±14.3 |
| Cardiac index, L/min/m2 |
2.8±0.9 |
| Right atrial pressure, mmHg |
8.0 (6.0–10.0) |
| Systolic pulmonary artery pressure, mmHg |
31.7±10.2 |
| Diastolic pulmonary artery pressure, mmHg |
16.4±6.1 |
| Mean pulmonary artery pressure, mmHg |
22.8±8.0 |
| Mean pulmonary artery wedge pressure, mmHg |
14.7±6.5 |
Results were presented as mean±standard deviation for continuous variables with normal distribution or median (interquartile range) for continuous variables with non-parametric distribution.
Of the total of 234 measurements, ezCVP could be declared in 187 measurements (81.0%) and could not be declared in 47 measurements due to noises being mixed into ezCVP. Therefore, we excluded those 47 measurements from analysis to assess the relationship between CVP and ezCVP.
Figure 3
shows a scatter plot for ezCVP vs. CVP among the remaining 187 measurements. Linear regression analysis revealed that ezCVP correlated with CVP (r=0.65, P<0.0001). Lin’s ρc
was 0.53 and indicated poor agreement between CVP and ezCVP (Figure 3).
Of the 78 patients, ezCVP was declared in all of the 3 measurements in 47 patients (60.2%), in 2 of the 3 measurements in 16 patients (20.5%), in 1 of the 3 measurements in 14 patients (17.9%), and in none of the 3 measurements in 1 patient (1.2%).
When CVP is <5 mmHg, it is below the threshold for ezCVP to quantify CVP. Therefore, to validate the quantitative ability of ezCVP, Bland-Altman analysis between ezCVP and CVP was performed for 63 measurements with CVP of ≥5 mmHg. ezCVP had an underestimation bias of −2.5 mmHg, with 95% limits of agreement of −14.1 mmHg and 9.6 mmHg for CVP (P<0.0001) (Figure 4). The linear regression analysis demonstrated that the difference between CVP and ezCVP significantly correlated with the average in ezCVP and CVP (Figure 4, blue line).
In 108 of the 187 measurements with a 0 reported by ezCVP, CVP was <5 mmHg in 48 measurements.
Detection of Abnormal Elevation of CVP
Figure 5A
and
5B
show ROC curves of ezCVP to discriminate CVP ≥12 cmH2O (8.8 mmHg) and CVP >10 mmHg. The AUC values of ROC curves with ezCVP to detect CVP ≥12 cmH2O (8.8 mmHg) and CVP >10 mmHg were 0.81 and 0.88, respectively. The sensitivity, specificity and positive likelihood ratio (LR+) of ezCVP for CVP ≥8.8 mmHg and CVP >10 mmHg were 0.59, 0.96 and 14.8 with a cut-off value of 11.9, and it was 0.79, 0.97 and 26.3 with a cut-off value of 12.7, respectively.
Discussion
This is the first report about the feasibility and validity of ezCVP measurement. The major findings of this study were as follows: (1) the feasibility of ezCVP measurement was acceptable as an initial attempt; (2) ezCVP significantly correlated with CVP; and (3) the ability of ezCVP to detect abnormal elevation of CVP was good, with high specificity and high LR+.
Principle of Venous Pressure Measurement by the Oscillometoric Method
In the present study, we demonstrated that the oscillometric method was applicable for the measurement of venous pressure in the upper arm. We applied the same principle of the oscillometric method used in the measurement of arterial blood pressure to the measurement of venous pressure. In the measurement of arterial pressure by the oscillometric method, the highest amplitude of cuff pressure oscillation is documented when cuff pressure is equal to the mean arterial pressure. It is presumed that the same phenomenon occurs in the measurement of venous pressure; that is, ezCVP seems to be able to reflect mean venous pressure of the upper arm. In the present study, we confirmed that it is possible to measure the change of venous volume caused by venous pressure variation using the pressure cuff. By the measurement principle, ezCVP should be a multiple of 5 between 40 mmHg and 5 mmHg. However, due to the performance of the sphygmomanometer pump and the control algorithm, it was difficult to make the cuff pressure a multiple of 5 strictly. Therefore, the ezCVP took a value other than a multiple of 5 and formed a similar distribution to a continuous distribution.
Feasibility of the ezCVP Measurement
In the present study, ezCVP could be declared in 187 of the 234 measurements (81.0%) and in all but one of the 78 patients. Body motion, deep respiration and/or arrhythmia during the measurement were thought to be causes of noise mixed into ezCVP. The results are acceptable as an initial attempt, but the current system has room for improvement for clinical use.
Relationship Between ezCVP and CVP
In the present study, we demonstrated that ezCVP was significantly correlated with CVP, with significant underestimation bias. Lin’s coefficient of concordance between CVP and ezCVP was poor. In addition, ezCVP had high specificity, high LR+ and modest sensitivity for detection of elevated CVP. These results were the most important results of the present study. From the viewpoint of clinical implication, the ability to detect elevated CVP is a prerequisite for ezCVP. Health-care providers assess JVP to estimate whether CVP is abnormally high. The LR+ of the JVP examination for detecting CVP of more than 12 cmH2O was reported to be 10.4.14
Therefore, in the present study, we tested the ability of ezCVP to detect CVP of more than 12 cmH2O. The LR+ of ezCVP was better than LR+ of the JVP examination previously reported. We also tested the ability of ezCVP to detect CVP of more than 10 mmHg, which is commonly used in an echocardiographic examination as the cut-off value of elevated CVP.4
ezCVP was useful for qualitative assessment of CVP; therefore, underestimation bias does not seem to be a serious problem in qualitative assessment of CVP.
In 108 of the 187 measurements with a ezCVP of 0, CVP was <5 mmHg in 48 measurements. In those 108 measurements, CVP of <5 mmHg is considered to have been properly evaluated by ezCVP. However, accurate measurement of CVP <5 mmHg is not possible theoretically by current ezCVP because cuff pressure was decreased automatically from 40 mmHg to 5 mmHg by a 5-mmHg step. The improvement of cuff-pressure control algorism and the validation study are needed to measure CVP <5 mmHg.
The cuff pressure for measuring ezCVP was set to reduce the pressure by 5 mmHg, and ezCVP showed various values other than multiples of 5 because it was difficult to strictly reduce cuff pressure by 5 mmHg in each step.
Clinical Perspectives
Self-monitoring of body weight by patients with HF is recommended in the guidelines of HF because monitoring body weight is easy for anyone to do to assess body fluid status and prevent further exacerbation of HF.3,15
In contrast, in some patients with advanced HF, body weight gradually decreases as a result of malnutrition and cardiac cachexia. In those patients, change of body weight cannot be an appropriate indicator of intravascular fluid status. Estimation of CVP plays an important role in the management of body fluid in such cases. Evaluation of JVP can also provide useful information, though it requires expertise. However, ezCVP measurement can allow inexperienced health-care providers to assess CVP.
Study Limitations
There are a number of limitations in this study. First, we excluded patients with atrial fibrillation, which is the most common arrhythmia in HF. We assumed that ezCVP could not be measured accurately in patients with atrial fibrillation. The oscillometric method is potentially inappropriate in patients with atrial fibrillation because CVP fluctuates due to a lack of atrial contraction and an irregular ventricular rhythm. Second, patients were placed in the supine position on the angiography system and medical staff placed the cuff. In the future, ezCVP measurement should be adapted for monitoring CHF status at home.
Conclusions
In conclusion, we demonstrated that a novel method named ezCVP measurement was feasible and useful for assessing CVP. The results of this study warrant further research and development of this technique for future clinical application.
Funding
This study was funded by Nihon Kohden Co. Ltd.
Disclosures
T.H., Y.S., Y.D., H.S., K.N., K.I., S. Kurisu, Y.F., H.H., S.M., S. Kishimoto, M.K., T.M., C.G., K.N., T.T., and Y.K. have no conflicts of interest to declare.
A.N. received grants from TWOCELLS Co. Ltd., MSD K.K., Astellas Pharma Incorporated, and Teijin Pharma Limited, and honoraria from Kyowa Hakko Kirin Co. Ltd. and CHUGAI Pharmaceutical Co. Ltd.
K.N. received honoraria and grants from Daiichi Sankyo Co. Ltd. and MSD K.K., and honoraria from Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co. Ltd., Mochida Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Amgen Astellas BioPharma K.K., Bayer Holding Limited, Boehringer Ingelheim GmbH, Eli Lilly K.K., Astellas Pharma Incorporated, Toa Eiyo K.K., and Abbott Japan Co.Ltd.
Y.H. received consulting fees from Kyowa Hakko Kirin Corporation related to this study, as well as honoraria and grants from Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited, Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corporation, Sanofi K.K., AstraZeneca K.K., Kyowa Hakko Kirin Co. Ltd., Takeda Pharmaceutical Co. Ltd., Astellas Pharma Incorporated, Daiichi Sankyo Co. Ltd., Mochida Pharmaceutical Co. Ltd., Nihon Kohden Corporation, Shionogi Co. Ltd., Nippon Sigmax Co. Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., Unex Corporation, and Kao Corporation, and honoraria from Radiometer Limited, Omron Corporation, Sumitomo Dainippon Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Torii Pharmaceutical Co. Ltd., Kowa Co. Ltd., Fujiyakuhin Co. Ltd., Amgen Astellas BioPharma K.K., Nippon Shinyaku Co. Ltd., Itamar Medical Limited, Bayer Holding Limited, Eli Lilly K.K., and Ono Pharmaceutical Co. Ltd.
Y.K. received honoraria from Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Limited, Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corporation, Sanofi K.K., Astra Zeneca K.K., Takeda Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Kowa Co. Ltd., Nippon Shinyaku Co. Ltd., Bayer Holding Limited, and Ono Pharmaceutical Co. Ltd. Both H.M. and T.U. are employees of Nihon Kohden Co. Y.K. is a member of
Circulation Journal’
s Editorial Team.
References
- 1.
Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. N Engl J Med 2001; 345: 574–581.
- 2.
Drazner MH, Rame JE, Dries DL. Third heart sound and elevated jugular venous pressure as markers of the subsequent development of heart failure in patients with asymptomatic left ventricular dysfunction. Am J Med 2003; 114: 431–437.
- 3.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2016; 37: 2129–2200.
- 4.
Ciozda W, Kedan I, Kehl DW, Zimmer R, Khandwalla R, Kimchi A. The efficacy of sonographic measurement of inferior vena cava diameter as an estimate of central venous pressure. Cardiovasc Ultrasound 2016; 14: 33.
- 5.
Udelson JE, Konstam MA, Zannad F, Pang PS, Burnett JC, Swedberg K, et al. Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: Findings from the EVEREST trial. Eur Heart J 2013; 34: 835–843.
- 6.
Drazner MH, Brown RN, Kaiser PA, Cabuay B, Lewis NP, Semigran MJ, et al. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: A 14-year multi-institutional analysis. J Hear Lung Transplant 2012; 31: 67–72.
- 7.
Brodowicz KG, McNaughton K, Uemura N, Meininger G, Girman CJ, Yale SH. Reliability and feasibility of methods to quantitatively assess peripheral edema. Clin Med Res 2009; 7: 21–31.
- 8.
Metkus TS, Kim BS. Bedside diagnosis in the intensive care unit: Is looking overlooked? Ann Am Thorac Soc 2015; 12: 1147–1150.
- 9.
Adamson PB, Cowart P, Henderson J, Hasan A, Bourge RC, Abraham WT, et al. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Circ Heart Fail 2014; 7: 935–944.
- 10.
Abraham WT, Adamson PB, Bourge RC, Aaron MF, Rosa Costanzo M, Stevenson LW, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: A randomised controlled trial. Lancet 2011; 377: 658–666.
- 11.
Ukawa T, Takayanagi T, Morimoto H, Higashi Y, Idei N, Yoshizumi M, et al. Novel non-invasive method of measurement of endothelial function: Enclosed-zone flow-mediated dilatation (ezFMD). Med Biol Eng Comput 2012; 50: 1239–1247.
- 12.
Idei N, Ukawa T, Kajikawa M, Iwamoto Y, Fujimura N, Maruhashi T, et al. A novel noninvasive and simple method for assessment of endothelial function: Enclosed zone flow-mediated vasodilation (ezFMD) using an oscillation amplitude measurement. Atherosclerosis 2013; 229: 324–330.
- 13.
Morimoto H, Kajikawa M, Oda N, Idei N, Hirano H, Hida E, et al. Endothelial function assessed by automatic measurement of enclosed zone flow-mediated vasodilation using an oscillometric method is an independent predictor of cardiovascular events. J Am Heart Assoc 2016; 5: pii: e004385.
- 14.
McGee S. Inspection of the neck veins. Evidence-Based Physical Diagnosis, 3rd edition. Elsevier Saunders; 2012. doi:10.1016/C2009-0-42449-8.
- 15.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure. J Am Coll Cardiol 2013; 62: e147–e239.
