Printer Friendly

A comparison of pulse contour wave analysis and ultrasonic cardiac output monitoring in the critically ill.

Cardiac output (CO) is a key measure of cardiovascular physiology, providing an index of myocardial function, and global oxygen, nutrient, and drug delivery to the tissues. As such, CO is utilised as an endpoint by many clinicians in the provision of fluid and vasoactive therapy (1), although a role in potentially optimising drug dosing should also be appreciated. Specifically, CO is a major determinant of hepatic and renal blood flow (2), which in turn can directly influence drug metabolism and excretion, depending on the relevant pharmacokinetics (PK) (3). In scenarios where the rate of drug elimination is not limited by intrinsic organ function (e.g. saturable elimination pathways), increased major organ blood flow may potentially result in enhanced excretion through greater delivery of solute to drug eliminating tissues.

Prior research in critically ill postoperative patients has confirmed augmented creatinine clearances in correlation with an increased CO (4), similar to changes encountered in normal pregnancy (5). In the absence of organ dysfunction, increased CO may therefore promote enhanced drug elimination (6,7), predisposing to sub-therapeutic levels (8). In the case of antibacterial therapy, this may promote either treatment failure or the selection of resistant strains (9). Although the influence of altered physiology on antibacterial levels in sepsis is still under investigation, elevated CO has been documented in this setting (10) along with the requirement for timely and accurate antibacterial therapy to achieve clinical success. As such, the influence of changes in CO on antibacterial PK in the critically ill requires ongoing study.

Further emphasising this point, we have recently demonstrated a linear correlation between CO (using a minimally invasive pulse contour technique) and cefazolin clearance in patients undergoing elective or semi-elective open abdominal aortic aneurysm repair (11). Although further validation is required in a critical care environment, this finding reinforces the impact of changes in CO on drug PK and suggests a perhaps previously under-appreciated role for beside assessment of CO in optimising antibacterial doses. This is also in the context of biochemical tests that are routinely used for such purposes, lacking sensitivity to accurately quantify altered organ function in the critically ill (12,13).

Complicating any such clinical application is ambiguity surrounding the most appropriate method of CO estimation in the critically ill (14). Although pulmonary artery catheter (PAC) thermodilution techniques have traditionally been regarded as the 'gold standard', a variety of less invasive techniques have recently been developed (15). These are attractive in a research setting as they require less skilled operators, are less costly and avoid the potentially significant complications associated with PAC insertion.

Two principal types of minimally invasive CO monitors are commonly used in clinical practice. The first group derive CO on the basis of arterial pulse waveform analysis, typically employing proprietary algorithms to determine beat-to-beat estimates of stroke volume and CO, with or without a requirement for external calibration. Currently three monitors are available for clinical use: Vigileo[R] (Edwards Lifesciences, Irvine, CA, USA), PiCCO[R] (PULSION Medical Systems, AG, Munich, Germany), and LiDCOrapid[R] (LiDCO Ltd., London, UK).

The second group of monitors gaining popularity are those which employ ultrasound. Such devices include: the USCOM[R] transthoracic Doppler CO monitor (USCOM Ltd, Sydney, NSW), and the CardioQ-ODM[R] (Deltex Medical, West Sussex, UK) oesophageal Doppler monitor. These techniques typically measure blood-flow velocity either across the aortic valve, or in the descending aorta, following which CO is calculated by multiplying by the estimated cross-sectional area. Of note, USCOM has the principal advantages of being totally noninvasive, does not require the use of costly single-use consumables, and could conceivably be employed on a number of patients concurrently.

Despite the increasing popularity of minimally invasive CO monitoring, there is a significant lack of comparison data between devices leading to uncertainty regarding the utility of any one monitor for use in antibacterial PK studies or clinical dose modification. The aim of this investigation was therefore to examine whether USCOM could provide an accurate and re-usable alternative to Vigileo CO analysis (which has previously been employed in a perioperative environment11), thereby simplifying future clinical or research work in this area.

METHODS

Study population

This investigation was performed in a 30-bed tertiary level intensive care unit, providing a range of organ support to critically ill patients. The only major patient groups not represented include: paediatrics, postoperative cardiothoracic patients and solid organ transplant recipients. Patients were enrolled prospectively as part of a larger study examining antibacterial dosing in at-risk patients (16). As such, this represents a convenience sample of critically ill septic and traumatised patients admitted to this facility. The study protocol was approved by the institutional human research ethics committee (HREC 2007/188) and written informed consent was obtained from either the patient or their substitute decision maker.

Study protocol

This has previously been published in detail elsewhere (16). In brief, Vigileo and USCOM measurements were obtained in all patients at the time of antibacterial dosing, and where possible again at three hours post dose. Analysis of USCOM data was performed by an investigator blinded to the arterial pulse contour CO results. Demographic and treatment data were recorded as part of the protocol.

The Vigileo system, employing second generation software (version 1.10), was connected to an existing intra-arterial catheter (sited in the radial artery) via a Flo Trac[R] (Edwards Lifesciences, Irvine, CA, USA) sensor. Age, gender, body weight and height were entered, following which the sensor was levelled to the phlebostatic axis, and zeroed to atmospheric pressure. Inspection of the arterial waveform was undertaken prior to CO measurement to ensure fidelity of the technique. The Vigileo monitor provides continuous CO data utilising the heart rate (HR), and an index of stroke volume (obtained from the arterial pressure waveform), which is automatically averaged and updated.

The USCOM device allows for beat-to-beat quantitative evaluations of 14 CO parameters, including CO, HR, stroke volume, stroke volume variability and systemic vascular resistance. The transducer is placed on the chest in either the left parasternal position to measure trans-pulmonary blood flow, or the suprasternal position to measure trans-aortic blood flow. The suprasternal position was used for all measurements in the study protocol. Demographic data (including age, height, weight and gender) were entered prior to measurement and used to calculate the aortic valve area.

The flow profile is displayed on the USCOM monitor with the spectral display showing variations of blood flow velocity with time. Algorithms are used to determine flow volumes from the raw Doppler data, independent of two-dimensional echocardiographic measurement of flow diameters. All research personnel received training in the technique prior commencement of the study, though all measurements were performed by the authors.

Statistics

Continuous data are presented as the mean (SD) or median [IQR] as appropriate. Categorical data are presented as counts (%). Correlation was assessed by means of a scatter graph and linear regression. Goodness of fit was determined by a Pearson (r) coefficient. Differences in mean values were assessed by a Paired Students t-test. Precision and bias were determined by a Bland-Altman plot17. The mean of the differences between the two measurements [=[SIGMA](C[O.sub.vigileo]-C[O.sub.USCOM])/N] is referred to as the bias, whereas precision is the SD of the differences. Limits of agreement (LOA) is the range enclosed by [+ or -]1.96 SD. The percentage error was determined using the method described by Critchley and Critchley (18). Differences in bias as a function of admission diagnosis, vasopressor requirement and gender were assessed by means of an independent Students t-test. A P value <0.05 was considered as statistical significance and all analyses were performed using SPSS (Chicago, IL, USA) and MedCalc for Windows (Belgium).

RESULTS

A total of 62 patients were enrolled in the study, all of whom had paired CO measurements obtained at the beginning of the dosing interval. Patients were categorised into two groups according to the primary admission diagnosis: trauma (n=25, 40.3%) and sepsis (n=37, 59.6%). Twenty-one (33.9%) required vasopressors and 59 (95.2%) were mechanically ventilated on the day of the study. The principal demographic, physiological and anthropometric characteristics of the included patients are listed in Table 1. The mean C[O.sub.Vigileo] and C[O.sub.USCOM] for the first paired CO measurements were 8.20[+ or -]2.65 l/minute and 6.84[+ or -]2.57 l/minute respectively (P <0.001).

Across all patients, a significant correlation was observed between the first Vigileo and USCOM CO measurements (r=0.537, P <0.001) (Figure 1A). The bias and precision between the two devices was 1.36[+ or -]2.51 l/minute, with LOA of -3.6 to +6.3 l/minute (Figure 2A). The overall percentage error was 65%. There was an improved correlation in those admitted with sepsis (r=0.639, P <0.001) (Figure 1B), although bias and precision were similar (1.25[+ or -]2.17 l/minute), with LOA of -3.0 to +5.5 l/minute (Figure 2B) and the percentage error was 59%. In contrast, a much poorer correlation (r=0.373, P=0.066) was noted in patients admitted with trauma (Figure 1C). Bias [+ or -] precision was 1.53[+ or -]2.98 l/minute in this group with LOA of -4.3 to +7.4 l/minute (Figure 2C) and a percentage error of 73%.

[FIGURE 1A OMITTED]

[FIGURE 1B OMITTED]

[FIGURE 1C OMITTED]

No significant difference in bias was demonstrated between diagnostic groups (P=0.667), or in those receiving vasopressor infusion (P=0.230). A lower bias was noted in women compared with men 0.39 (2.70) vs 1.90 (2.26) l/minute, P=0.023). This is likely to reflect the observation that women were under-represented in the trauma sub-group (n=4/25, 16%), and had a smaller body-surface area (1.81 vs 2.07 [m.sup.2], P <0.001).

No significant correlation was demonstrated between age (P=0.636), fluid balance (P=0.296), and bias. However a weak positive correlation was noted with body surface area (BSA) (r=0.253, P=0.047) and a weak negative correlation was observed with HR (r=-0.286, P=0.024). This suggests that at increased heart rates USCOM will tend to report higher CO values than those recorded with Vigileo.

[FIGURE 2A OMITTED]

[FIGURE 2B OMITTED]

In 54 patients a second paired CO assessment was obtained at three hours post drug dosing. Figure 3 plots the change in CO between measurements for each device ([DELTA] C[O.sub.Vigileo] vs [DELTA] [C.sub.USCOM]. This demonstrates a weak, although significant, correlation (r=0.377, P=0.005) suggesting that gross trends in CO over time were similar with either device.

DISCUSSION

Recent data in a perioperative setting has suggested the potential utility of minimally in vasive CO measurement in predicting renal drug clearance (11). This current analysis has compared two bedside CO monitors in the context of a larger study examining antibacterial PK in critically ill patients (16). Despite a significant correlation (particularly in the septic subgroup), Bland-Altman analysis demonstrates very poor agreement with percentage errors well outside acceptable margins18. In this respect, our findings clearly indicate that these devices are not simply interchangeable. Given our recent experience with Vigileo in patients undergoing open abdominal aortic aneurysm repair (11), we would favour the application of this device where a PAC is not in situ for future research or clinical practice in this area.

[FIGURE 2C OMITTED]

[FIGURE 3 OMITTED]

To our knowledge, this is the first study comparing Vigileo and USCOM, although previous researchers have employed alternative Doppler based techniques. Concha et al compared transoesophageal echocardiography with Vigileo in patients undergoing laparoscopic surgery, reporting a bias [+ or -] SD of 1.17[+ or -]1.6 l/minute and LOA of -2.02 to 4.37 (19). Similar investigation has been performed in patients undergoing abdominal aortic aneurysm surgery, with improved bias (0.12 l/minute) and LOA (-1.66 to 1.90 l/minute) (20). Others have also reported comparable findings in perioperative patients receiving vasopressor and fluid therapy (21).

More recently, McLean and colleagues compared Vigileo and transthoracic Doppler echocardiography in 53 critically ill patients manifesting shock (22). Compared with our study, their reported percentage error was 49.3%, although improved agreement was demonstrated when patients manifesting atrial fibrillation and aortic stenosis were excluded (percentage error 29.5%) (22).

The greater agreement between Vigileo and Dopper echocardiography, as compared to Vigileo and USCOM in our analysis, is likely related to the assumptions concerning aortic valve area. In this respect, Van den Oever and colleagues have previously evaluated USCOM in comparison with transoesophageal echocardiographic valve measurements in patients undergoing cardiac surgery (23). Importantly, their findings demonstrated that USCOM calculated aortic and pulmonary valve areas did not correlate with measured values, suggesting this is a significant source of error. Of note, patients with known aortic valve disease were excluded from this analysis (23).

Additional sources of error are likely to include difficulty in obtaining adequate acoustic windows, such as in the case of morbid obesity or distorted anatomy. Of interest, the larger bias in traumatised patients is likely to reflect this problem with limited positioning, dressings, and associated thoracic trauma complicating suprasternal Doppler CO assessment. The positive correlation between bias and BSA further highlights this issue. Overall, it must also be noted that USCOM has generally not performed favourably when compared to traditional PAC thermodilution techniques (24,25).

The ability of Vigileo to accurately measure CO in comparison to traditional methods is also uncertain1 with a number of validation studies demonstrating mixed results (26). In particular, initial studies raised concerns regarding the accuracy of the early software (v1.01) (27,28), although subsequent iterations appear to have improved the accuracy of the device (29). Specifically, use of a wider casemix in development, and improved algorithms, appears to have enhanced its application.

Even with these improvements, accuracy of arterial pressure waveform analysis is still likely to be influenced by alterations in the pulse contour, such as in aortic stenosis and regurgitation (30,31). As a limitation in our analysis, we did not actively screen for such lesions. Similarly, periods of haemodynamic instability are also likely to lead to additional errors as has been demonstrated in previous studies (32). Although this may help to explain the weak negative correlation observed between bias and HR, it is interesting to note that we did not identify any significant difference in bias associated with the use of vasopressors.

We have not employed traditional thermodilution CO measurements in this study, as PAC insertion was not available. In this respect, use of Vigileo measurements as the comparator in our analysis is based on the following: 1) in critically ill patients the reported percentage error in comparison to PAC thermodilution is 30% (26) (being the established threshold for acceptable agreement); 2) a concordance rate of 96% has been reported for trends (+/- 30%) in CO when comparing Vigileo and PAC measurements in the critically ill (33); 3) PAC use is declining in modern intensive care practice (34) leading to unfamiliarity with the device, its insertion and results and; 4) for the purposes of antibacterial PK study the risk-benefit and economic considerations do not favour the use of more invasive techniques.

In conclusion, we have compared two minimally invasive CO monitors (Vigileo and USCOM) in the context of an antibacterial PK study in the critically ill. Our findings suggest poor agreement between the techniques, largely due to issues concerning the application of suprasternal Doppler CO assessment in critically ill patients.

REFERENCES

(1.) Vincent JL, Rhodes A, Perel A, Martin GS, Della Rocca G, Vallet B et al. Clinical review: update on hemodynamic monitoring a consensus of 16. Crit Care 2011; 15:229.

(2.) Di Giantomasso D, May CN, Bellomo R. Vital organ blood flow during hyperdynamic sepsis. Chest 2003; 124:1053-1059.

(3.) Roberts JA, Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 2006; 45:755-773.

(4.) Brown R, Babcock R, Talbert J, Gruenberg J, Czurak C, Campbell M. Renal function in critically ill postoperative patients: sequential assessment of creatinine osmolar and free water clearance. Crit Care Med 1980; 8:68-72.

(5.) Mabie WC, DiSessa TG, Crocker LG, Sibai BM, Arheart KL. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994; 170:849-856.

(6.) Jin SJ, Jung JY, Noh MH, Lee SH, Lee EK, Choi BM et al. The population pharmacokinetics of fentanyl in patients undergoing living-donor liver transplantation. Clin Pharmacol Ther 2011; 90:423-431.

(7.) Loirat P, Rohan J, Baillet A, Beaufils F, David R, Chapman A. Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. N Engl J Med 1978; 299:915-919.

(8.) Udy AA, Putt MT, Shanmugathasan S, Roberts JA, Lipman J. Augmented renal clearance in the Intensive Care Unit: an illustrative case series. Int J Antimicrob Agents 2010; 35:606-608.

(9.) Roberts JA, Kruger P, Paterson DL, Lipman J. Antibiotic resistance --what's dosing got to do with it? Crit Care Med 2008; 36:2433-2440.

(10.) Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 1990; 113:227-242.

(11.) Douglas A, Udy AA, Wallis SC, Jarrett P, Stuart J, Lassig-Smith M et al. Plasma and tissue pharmacokinetics of cefazolin in patients undergoing elective and semielective abdominal aortic aneurysm open repair surgery. Antimicrob Agents Chemother 2011; 55:5238-5242.

(12.) Hoste EAJ, Damen J, Vanholder RC, Lameire NH, Delanghe JR, Van den Hauwe K et al. Assessment of renal function in recently admitted critically ill patients with normal serum creatinine. Nephrol Dial Transplant 2005; 20:747-753.

(13.) Martin JH, Fay MF, Udy A, Roberts J, Kirkpatrick C, Ungerer J et al. Pitfalls of using estimations of glomerular filtration rate in an intensive care population. Intern Med J 2011; 41:537-543.

(14.) Vincent JL. So we use less pulmonary artery catheters but why? Crit Care Med 2011; 39:1820-1822.

(15.) Morgan P, Al-Subaie N, Rhodes A. Minimally invasive cardiac output monitoring. Curr Opin Crit Care 2008; 14:322-326.

(16.) Roberts JA, Roberts MS, Semark A, Udy AA, Kirkpatrick CM, Paterson DL et al. Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/ pharmacodynamics in sepsis and trauma patients. BMC Anesthesiol 2011; 11:3.

(17.) Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1:307-310.

(18.) Critchley LA, Critchley JA. A meta-analysis of studies using bias and precision statistics to compare cardiac output measurement techniques. J Clin Monit Comput 1999; 15:85-91.

(19.) Concha MR, Mertz VF, Cortinez LI, Gonzalez KA, Butte JM. Pulse contour analysis and transesophageal echocardio-graphy: a comparison of measurements of cardiac output during laparoscopic colon surgery. Anesth Analg 2009; 109:114-118.

(20.) Kusaka Y, Yoshitani K, Irie T, Inatomi Y, Shinzawa M, Ohnishi Y. Clinical comparison of an echocardiograph-derived versus pulse counter-derived cardiac output measurement in abdominal aortic aneurysm surgery. J Cardiothorac Vasc Anesth 2012; 26:223-226.

(21.) Meng L, Tran NP, Alexander BS, Laning K, Chen G, Kain ZN et al. The impact of phenylephrine, ephedrine, and increased preload on third-generation Vigileo-FloTrac and esophageal doppler cardiac output measurements. Anesth Analg 2011; 113:751-757.

(22.) McLean AS, Huang SJ, Kot M, Rajamani A, Hoyling L. Comparison of cardiac output measurements in critically ill patients: FloTrac/Vigileo vs transthoracic Doppler echocardiography. Anaesth Intensive Care 2011; 39:590-598.

(23.) Van den Oever HLA, Murphy EJ, Christie-Taylor GA. USCOM (Ultrasonic Cardiac Output Monitors) lacks agreement with thermodilution cardiac output and transoesophageal echocardiography valve measurements. Anaesth Intensive Care 2007; 35:903-910.

(24.) Boyle M, Steel L, Flynn GM, Murgo M, Nicholson L, O'Brien M et al. Assessment of the clinical utility of an ultrasonic monitor of cardiac output (the USCOM) and agreement with thermodilution measurement. Crit Care Resusc 2009; 11:198-203.

(25.) Thom O, Taylor DM, Wolfe RE, Cade J, Myles P, Krum H et al. Comparison of a supra-sternal cardiac output monitor (USCOM) with the pulmonary artery catheter. Br J Anaesth 2009; 103:800-804.

(26.) Mayer J, Boldt J, Poland R, Peterson A, Manecke GR Jr. Continuous arterial pressure waveform-based cardiac output using the FloTrac/Vigileo: a review and meta-analysis. J Cardiothorac Vasc Anesth 2009; 23:401-406.

(27.) Mayer J, Boldt J, Wolf MW, Lang J, Suttner S. Cardiac output derived from arterial pressure waveform analysis in patients undergoing cardiac surgery: validity of a second generation device. Anesth Analg 2008; 106:867-872.

(28.) Zimmermann A, Kufner C, Hofbauer S, Steinwendner J, Hitzl W, Fritsch G et al. The accuracy of the Vigileo/FloTrac continuous cardiac output monitor. J Cardiothorac Vasc Anesth 2008; 22:388-393.

(29.) Zimmermann A, Steinwendner J, Hofbauer S, Kirnbauer M, Schneider J, Moser L et al. The accuracy of the Vigileo/FloTrac system has been improved - follow-up after a software update: a blinded comparative study of 30 cardiosurgical patients. J Cardiothorac Vasc Anesth 2009; 23:929-931.

(30.) Lorsomradee S, Lorsomradee S, Cromheecke S, De Hert SG. Uncalibrated arterial pulse contour analysis versus continuous thermodilution technique: effects of alterations in arterial waveform. J Cardiothorac Vasc Anesth 2007; 21:636-643.

(31.) Manecke GR. Edwards FloTrac sensor and Vigileo monitor: easy, accurate, reliable cardiac output assessment using the arterial pulse wave. Expert Rev Med Devices 2005; 2:523-527.

(32.) de Waal EEC, Kalkman CJ, Rex S, Buhre WF. Validation of a new arterial pulse contour-based cardiac output device. Crit Care Med 2007; 35:1904-1909.

(33.) McGee WT, Horswell JL, Calderon J, Janvier G, Van Severen T, Van den Berghe G et al. Validation of a continuous, arterial pressure-based cardiac output measurement: a multicenter, prospective clinical trial. Crit Care 2007; 11:R105.

(34.) Wiener RS, Welch HG. Trends in the use of the pulmonary artery catheter in the United States, 1993-2004. JAMA 2007; 298:423-429.

A. A. UDY *, M. ALTUKRONI ([dagger]), P. JARRETT ([double dagger]), J. A. ROBERTS ([section]), J. LIPMAN **

Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital and Burns, Trauma and Critical Care Research Centre, University of Queensland, Brisbane, Queensland, Australia

* BHB, MB, ChB, PGCert (AME), FCICM, Staff Specialist and Senior Lecturer.

([dagger]) MB, BS, JBIM, FCCM, Senior Medical Officer.

([double dagger]) RN, Research Nurse, Department of Intensive Care Medicine.

([section]) BPharm (Hons), PhD, FSHP, Clinical Pharmacist and National Health and Medical Reasearch Council Training Fellow, Departments of Intensive Care Medicine and Pharmacy.

** MB, BCh, DA, FFA, MD, FCICM, Director and Professor.

Address for correspondence: Department of Intenisve Care Medicine, Level 3 Ned Hanlon Building, Royal Brisbane and Women's Hospital, Butterfield street, Herston, Queensland 4029, Australia.
Table 1
Demographic characteristics of all enrolled patients (n=62)

Age, y, mean (SD) 43.6 (17.8)

Male/female, n (%) 40 (64.5)/22
 (35.5)

Weight, kg, median [IQR] 80 [74.5-91.25]

Height, cm, mean (SD) 171.4 (10.5)

Body surface area, [m.sup.2], mean (SD) 1.98 (0.26)

Body Mass Index, kg/[m.sup.2], mean (SD) 29.5 (7.91)

Vasopressor requirement, n (%) 21 (33.9)

Mechanical ventilation, n (%) 59 (95.2%)

Trauma patients, n (%) 25 (40.3)

Sepsis patients, n (%) 37 (59.7)

Heart rate, beats/min, mean (SD) 101.6 (21.3)

Fluid balance, ml, mean (SD) 778.8 (1903.2)

APACHE II, median [IQR] 18.0 [14-25]

SOFA 7.06 (2.64)

IQR=interquartile range, APACHE=Acute Physiological
and Chronic Health Evaluation Score, SOFA=Sequential
Organ Failure Assessment.
COPYRIGHT 2012 Australian Society of Anaesthetists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2012 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Original Papers
Author:Udy, A.A.; Altukroni, M.; Jarrett, P.; Roberts, J.A.; Lipman, J.
Publication:Anaesthesia and Intensive Care
Article Type:Report
Geographic Code:8AUST
Date:Jul 1, 2012
Words:3915
Previous Article:Observations on the assessment and optimal use of videolaryngoscopes.
Next Article:Ventilation--how often are we correct?
Topics:

Terms of use | Privacy policy | Copyright © 2022 Farlex, Inc. | Feedback | For webmasters |