Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension

Accepted Manuscript Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension

Abdullah Alkhodair, Michael Y.C. Tsang, John Cairns, John R. Swiston, Robert D. Levy, Lisa Lee, Victor F. Huckell, Nathan W. Brunner PII: DOI: Reference:

S0167-5273(17)34444-3 https://doi.org/10.1016/j.ijcard.2018.01.076 IJCA 25940

To appear in: Received date: Revised date: Accepted date:

30 July 2017 28 November 2017 18 January 2018

Please cite this article as: Abdullah Alkhodair, Michael Y.C. Tsang, John Cairns, John R. Swiston, Robert D. Levy, Lisa Lee, Victor F. Huckell, Nathan W. Brunner , Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Ijca(2017), https://doi.org/10.1016/j.ijcard.2018.01.076

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Comparison of thermodilution and indirect Fick cardiac outputs in pulmonary hypertension Abdullah Alkhodair MD, 1Michael YC Tsang MD, 1 John Cairns MD, 2John R Swiston MD, 2Robert D Levy MD, 2Lisa Lee, 1Victor F Huckell MD, 1 Nathan W Brunner MD

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Divisions of 1Cardiology and 2Respirology, University of British Columbia Nathan Brunner 2775 Laurel Street Vancouver, BC Canada V5Z 1M9 [email protected]

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Corresponding author:

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Disclosure:

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The authors report no relationships that could be construed as a conflict of interest.

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Word Count:2363 Max Words: 3000

ACCEPTED MANUSCRIPT Abstract: Background: The accurate measurement of cardiac output (CO) is required in patients with pulmonary hypertension (PH). While both the thermodilution (TDCO) and indirect Fick (IFCO) methods are commonly used, there is little data

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comparing them in patients with PH.

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Methods:

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We performed a retrospective analysis of patients evaluated at our center. All patients who had right heart catheterization (RHC) within 3 months of an echocardiogram, and CO assessment by both TDCO and IFCO

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methods were included. Bland-Altman analysis was used to assess agreement between the two methods. We

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further evaluated their agreement in each sex, and within tertiles of age, BMI and TR severity. We investigated the correlation between each method of CO and objective parameters of right ventricular function on

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echocardiography.

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Results:

In a cohort of 168 patients, the correlation between IFCO and TDCO was modest at (r=0.61). On average, values

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for CO were lower with IFCO than with TDCO, by 0.62 L/min (95%CI -0.82, -0.40). This difference was greater for females: 0.86 L/min (95% CI -1.08, -0.63) and in the highest tertile of BMI: 0.97 L/min (95%CI -1.4, -0.55).

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Moderate and severe TR did not in general result in lower TDCO values. Echocardiographic parameters of right

Conclusion:

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ventricular function were correlated more strongly with TDCO than with IFCO.

In PH patients, IFCO was substantially lower than TDCO on average, suggesting that these two techniques cannot be used interchangeably. TDCO correlated more strongly with echocardiographic measures of RV function, suggesting that it may be preferred over IFCO.

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ACCEPTED MANUSCRIPT Abbreviations:

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BSA: body surface area. CHD PH: congenital heart disease associated pulmonary hypertension CTD PH: connective tissue disease associated pulmonary hypertension CTEPH: chronic thromboembolic pulmonary hypertension HIV PH: HIV associated pulmonary hypertension IFCO: Indirect Fick method of calculating cardiac output IVC diameter: inferior vena cava diameter LVEDP: left ventricular end diastolic pressure LVEF: left ventricular ejection fraction LVEI: left ventricular eccentricity index PAP: pulmonary artery pressure RAP: right atrial pressure 2: maximum oxygen consumption. NYHA: New York heart association PVR: pulmonary vascular resistance PH: pulmonary hypertension PH LHD: pulmonary hypertension due to left heart disease PVOD: pulmonary occlusive disease RA volume (MOD): right atrial volume by method of disc RHC: right heart catheterization. RV- FAC: right ventricular fractional area change RVSP: right ventricular systolic pressure sPAP: systolic pulmonary artery pressure TAPSE: tricuspid annular plane systolic excursion TDCO: thermodilution cardiac output TR: tricuspid regurgitation

ACCEPTED MANUSCRIPT Introduction:

Right heart catheterization (RHC) remains essential for establishing the diagnosis of pulmonary arterial hypertension (PAH) and for estimating prognosis1-2. An important

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part of this assessment is the measurement of cardiac output (CO), which is associated

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with clinical outcomes3-4 and is required for the calculation of pulmonary vascular resistance (PVR). While the gold standard technique for measuring CO is the direct Fick

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method, this requires the cumbersome measurement of oxygen consumption and is rarely

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used in clinical practice1. There are two methods in common clinical use for measuring cardiac output; the indirect Fick (IFCO)5-6 method and the thermodilution (TDCO)7

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method. While early studies suggested a good correlation between these methods, these

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studies were small and generally not done in populations with PH8-9. Moreover, a

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correlation between methods does not imply equivalence of the results. Recent studies

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have shown that these two measures of CO commonly provide substantially different

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values when performed on the same patient10-11.

Though the recent 5th World Symposium on Pulmonary Hypertension and the ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension suggested that TDCO be used1-2, this recommendation is based on expert opinion and there is a paucity of literature available to support this choice. Thus, clinical studies such as this one are needed to identify which is the superior measure of CO. In pre-capillary PH, the cardiac

ACCEPTED MANUSCRIPT output should be proportional to the right ventricular stroke volume, and thus right ventricular function on echocardiogram. Comparing the correlation between CO and RV

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function should help to identify which method of estimating CO is more useful.

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At our institution, our pattern of practice has been to use both methods of measuring CO

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in all patients undergoing RHC for evaluation of pulmonary hypertension. We compared

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cardiac output as determined using both the IFCO and TDCO methods and investigated their association with prognostic parameters of right ventricular function on

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echocardiography.

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Methods:

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We performed a retrospective analysis at our large tertiary PH referral centre from 2008-

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2014, of all patients followed who had RHC within 3 months of transthoracic

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echocardiography. Eligible patients were identified through a structured chart review of all clinic records by study authors (AA, NWB). All adult patients who met diagnostic criteria for PH on RHC [mean pulmonary artery pressure (MPAP) > 25 mmHg] were included. Patients were excluded if either IFCO or TDCO had not been reported at RHC, or if they had not had an echocardiogram at our institution within 3 months prior to RHC. Patients with uninterpretable echocardiograms, missing hemodynamic data, or known

ACCEPTED MANUSCRIPT unrepaired intracardiac shunts were excluded. The study was approved by the Clinical Research Ethics Board at the University of British Columbia (H14-01309)

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Right heart catheterization:

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All RHC were performed by a single operator with an annual experience of over 250

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hemodynamic catheterizations. All RHC were carried out using a 7-F balloon-tipped

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Swan-Ganz catheter 4-7, usually inserted in the right femoral vein. The zero level was taken as the midaxillary line. Standard RHC evaluation included a shunt run to identify

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left to right shunting, followed by measurement of pressures in the right atrium, right

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ventricle, pulmonary artery and pulmonary artery wedge position. The cardiac output was

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then measured. At the discretion of the operator, left heart catheterizations were then

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carried out for measurement of left ventricular end-diastolic pressure (LVEDP).

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For calculation of IFCO, saturations were measured in the pulmonary artery, systemic

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artery, and pulmonary artery wedge position if possible. If the PA wedge saturation could not be obtained, it was assumed to be the same as the systemic arterial saturation. The difference between the arterial and venous oxygen saturations was calculated by subtracting the PA saturation from the systemic artery or PA wedge saturation (whichever was highest).

ACCEPTED MANUSCRIPT The oxygen consumption (VO2) was estimated using the method of LaFarge12. The thermodilution cardiac output (TDCO) was measured by injecting 10 mL of room temperature normal saline into the proximal port of the Swan-Ganz catheter, and

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observing the rate of temperature change at the distal tip with time, according to standard

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techniques6. The measurement was performed in triplicate. Further measurements were

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performed if discrepant values were obtained. The reported TDCO was the mean of three

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measures that agreed within variability of less than 15%.

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Echocardiography:

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All echocardiograms were reviewed by trained readers (AA and MT), to extract variables

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associated with right ventricular function and prognosis in pulmonary arterial

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hypertension (PAH). These variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular fractional area change (RV-FAC), indexed right atrial volume

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(RAV), and the systolic left ventricular eccentricity index (LVEI). Other variables,

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including the basal right ventricular diameter (RVd), the maximal tricuspid regurgitation (TR) velocity, and the TR severity were also extracted.

Key echocardiographic variables were measured in accordance with the American Society of Echocardiography's Guidelines for the echocardiographic assessment of the right heart in adults13. TAPSE was measured using an M-mode tracing through the lateral

ACCEPTED MANUSCRIPT tricuspid valve annulus if available, or otherwise from the 2D apical four chamber view14,15. The agreement between these two techniques has been previously validated14. The LVEI was measured using the left ventricular anteroposterior (parallel) dimension

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over the septolateral (perpendicular) dimension in systole at the papillary muscle

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level16.The right ventricular systolic pressure was estimated from the tricuspid

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regurgitation jet velocity using standard techniques12.

Clinical Data:

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Clinical data were collected from a structured chart review, including age, sex, body mass

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index (BMI), and category of pulmonary hypertension according to the WHO

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classification as determined by the treating pulmonary hypertension specialist. Ethics

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Statistical Analysis:

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approval was obtained from our institutional research ethics board.

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Descriptive data are presented as means and standard deviations. P-values of less than 0.05 were taken to be significant. In a subset of patients, the echocardiograms were measured by 2 different trained observers to obtain measures of interobserver variability. This is expressed using intra-class correlation coefficients (ICC). The correlation between IFCO and TDCO is expressed in terms of Pearson’s correlation coefficient. BlandAltman analysis was used to describe the agreement between the IFCO and TDCO

ACCEPTED MANUSCRIPT methods of measuring cardiac output17. Agreement (bias) was expressed as the mean of the differences obtained by the different technique and its upper/lower limits and the 95% confidence intervals (CIs). We compared the agreement between IFCO and TDCO for

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all cases and for either gender and between tertiles of age, TR severity and BMI.

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We performed simple linear regression to estimate the unadjusted association between

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each measure of CO with TAPSE (mm), the RV fractional change (RV-FAC), RA

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volume and LVEI. In order to evaluate these associations in a more uniform population with purely pre-capillary pulmonary hypertension, these analyses were then repeated for

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a pre-specified subgroup comprising patients established to have WHO Group 1, 3 or 4

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PH.

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Results:

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We identified 190 patients who met the inclusion criteria. Of these, we excluded 18

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patients due to missing data and 4 patients with CHD and possible intracardiac shunting. The mean age was 63 ±15. years, and 64% of the patients were female. The demographic characteristics of our study population are shown in Table 1. WHO Group I PH was present in 71 (42%) of patients, WHO Group II in 63 (37%), Group III in 101 (60%) and Group IV in 29 (17%). The PH specialists classified patients according to the either the 4th or 5th World Symposium on pulmonary hypertension, appropriate to when the patient

ACCEPTED MANUSCRIPT was seen in clinic1. Some patients (38%) were felt to have multifactorial pulmonary hypertension. It was therefore possible for patients to be included in more than one

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group.

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We noticed an overall good reproducibility of the echocardiographic measures that were

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used in this study between two trained observers. TAPSE proved to have the highest

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reproducibility with intra-class coefficient value of 0.9. The reproducibility of the other echocardiographic measures tested was good as well, with ICC of 0.83, 0.84 and 0.70 for

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RV-FAC, RA volume and LVEI, respectively.

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The overall mean IFCO was 4.2 ± 1.5 L/min and the mean TDCO was 4.8 ± 1.6 L/min. The Pearson correlation coefficient between IFCO and TDCO was found to be 0.61

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(p<.001) with a coefficient of determination (r2) of 0.38, indicating only modest

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correlation (Figure 1). Bland-Altman analysis (Figure 2) indicates that IFCO was

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significantly lower than TDCO by (0.6 L/min), with 95% CI of (-0.8, -0.4) in keeping with statistically significant bias. We found that 90 patients (53%) had a discrepancy between the values from IFCO and TDCO of greater than 20%. This discrepancy rate was not different between patients with high CO (>5 L/min) and those with low CO (<5 L/min).

ACCEPTED MANUSCRIPT We further evaluated the correlation and agreement of both CO methods within each sex, and within tertiles of age and BMI. We also compared correlation and agreement for those with mild TR vs. moderate or severe TR. The difference between the two methods

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was of higher magnitude for females, with IFCO 0.86 L/min lower than TDCO on

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average (95% CI -1.05, -0.61) compared to only 0.2 L/ min (95% CI -0.63, -0.2)

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difference in males. The mean difference was not significantly different among all three

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age tertiles; at -0.71 L/min (95% CI -1.1, -0.23), -0.63 L/min (95% CI -1.0, -0.2) and 0.53 L/min (95% CI -0.76, -0.30) for the first, second and third tertiles, respectively. A

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similar analysis was carried out by tertile of BMI, and the agreement between methods

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was worse with higher BMI; at -0.7 L/min (95% CI -1.1, -0.23), -0.55 L/min (-0.87, -

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0.23) and -0.97 L/min (95% CI, -1.4, -0.55) for the first, second and third tertiles of BMI, respectively. In patients with mild TR, IFCO was lower than TDCO by 0.83 L/min (95%

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CI -1.2, -0.46). In contrast, in patients with moderate or severe TR, IFCO was lower than

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TDCO by 0.44 L/min (95% CI -0.67, -0.2).

In the analysis of the associations between methods of measuring CO and echocardiographic parameters of RV function, both IFCO and TDCO were positively correlated with TAPSE (Table 2). However, the correlation appeared stronger with TDCO (r=0.29 vs. 0.49 for IFCO vs. TDCO). RV-FAC was not significantly correlated with IFCO (r=0.07, P=0.3), though it was for TDCO (r=0.2, P=0.01). Similarly, LVEI

ACCEPTED MANUSCRIPT was not associated with IFCO (r=-0.11, P=0.1), but was associated with TDCO (r=-0.19, P=0.01). RA volume did not correlate with either measure of cardiac output. The stronger correlation between the TDCO and the echocardiographic measures of RV

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function persisted in our subgroup analysis of patients identified to have WHO Group 1,

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III or IV PH.

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Discussion:

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Variability in techniques used in right heart catheterization limits the generalizability of

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measurements done in different laboratories, and may introduce bias in multicentre studies that rely on pooled hemodynamic data. One source of variability is the estimation

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of cardiac output, for which IFCO and TDCO are in common clinical use. Identifying

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which technique is preferable is an important prerequisite for further standardization in

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right heart catheterization.

Though evidence is generally dated and scant, both the IFCO and TDCO methods have been previously shown to have strengths and weaknesses. The gold standard is the direct Fick method which requires measurement of VO2, which is not routinely used due to its complexity and the time restraints in most laboratories. The indirect Fick method uses an

ACCEPTED MANUSCRIPT estimate of resting VO2 derived from conventional formulae12. These formulae have been shown to be less accurate in certain populations, such as severely obese individuals18. In contrast, the TDCO method cannot be used in the context of intracardiac

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shunting, and there have been concerns regarding its accuracy in patients with severe

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tricuspid regurgitation20.

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Recently, a large study evaluated IFCO and TDCO in 2 cohorts with a large proportion of patients with left heart disease. Over half of the population in this study had mean PA

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pressure >25 mmHg. As in our study, the agreement between IFCO and TDCO was

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modest in both cohorts. TDCO was a better predictor of mortality21. Another large study

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comparing IFCO and TDCO included only a subset of patients with pulmonary hypertension. Although the correlation coefficient between the two methods was

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(r=0.55), there were significant differences between TDCO and IFCO, bias was −0.39

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L/min and the limits of agreement were between −4.44 L/min and +3.66 L/min using the

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Bland-Altman analysis for repeated measures10. Another study, done in critically ill patients, also showed suboptimal agreement between IFCO and TDCO22.

Our study represents the largest comparison of IFCO and TDCO done exclusively in patients with PH. As in the above studies, we found the correlation between IFCO and TDCO to be modest. The disagreement between IFCO and TDCO in our study was more

ACCEPTED MANUSCRIPT marked than what was seen in other studies10,21, with the two measures disagreeing by over 20% in over half the subjects. This represents a clinically relevant difference, especially in lower CO values. In our study, IFCO was more often lower in magnitude

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with TDCO. This contrasts somewhat with other studies, that showed the mean IFCO to

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be either minimally reduced compared to the mean TDCO, or the mean IFCO to be

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greater than the mean TDCO10,21. It is important to recognize that these other studies

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were done in general catheterization laboratory populations rather than in PH-specific populations. This discrepancy could therefore be explained on the basis of differences in

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the study populations. However, all studies agree on the lack of strong agreement in

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these 2 commonly used methods of measuring VO2.

The disagreement between IFCO and TDCO was particularly pronounced for women and

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for those with higher BMI, arguing for a high degree of caution when comparing CO

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calculated using different techniques in these patient groups. It is possible that the

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equations used for estimating VO2 are less accurate in these conditions, as these populations may have been underrepresented in the derivation cohort. It is also possible that the estimated VO2 did not adequately reflect the increased metabolic demands experienced by some patients. Some recent studies have investigated methods for refining the estimate of VO219, and these may eventually prove useful for calculation of CO.

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Contrary to popular belief, we found that severe TR did not result in worse agreement

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between IFCO and TDCO. However, two smaller, older studies also found no impact of

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severe TR on the accuracy of TDCO23-24. While it is generally accepted that TDCO is

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less accurate with severe TR19, these findings suggest that the clinical impact of severe

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TR on the accuracy of TDCO may be less important in clinical practice.

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Parameters of right ventricular function on echocardiography are known to correlate with

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cardiac output in pulmonary hypertension15. Therefore, the superior measure of CO

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should correlate more strongly with measures of RV function on cardiac imaging. The echo parameters of TAPSE, RV-FAC and LVEI showed a significantly stronger

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association with TDCO compared to IFCO. Our findings therefore may support TDCO as

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the superior measure. TDCO correlated more strongly with RV function not just for the

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overall study population, but for the subset identified to have only pre-capillary PH (WHO Groups 1, 3 and 4). In these cases, the left ventricle would not be expected to influence the cardiac output in a substantial manner. To our knowledge, our work represents the first study to compare the degree of correlation between commonly used quantitative methods of measuring RV function on echocardiography and measures of cardiac output.

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Limitations: This was a single center retrospective study, and thus the sample size was insufficient to

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test our hypothesis in different pulmonary hypertension subtypes. The gold standard

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method of assessing CO is the direct Fick method, which requires the measurement of

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oxygen consumption at the time of catheterization. This is not routinely done in our lab

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and therefore, we cannot comment on how IFCO and TDCO correlated with the direct Fick method. In our study population, 38% of patients were felt to belong to more than

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one WHO Group. While this is a large proportion of patients with multifactorial PH, all

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assessments were made by trained and experienced PH physicians. This is felt to reflect

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a real world population where PH often cannot be attributed to a single WHO Group alone. Also, we could not evaluate other important variables of interest such as clinical

Conclusion:

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and BNP.

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outcomes, such as mortality, and other surrogate endpoints such as 6MWD, peak VO2

In patients evaluated for pulmonary hypertension, IFCO was on average, significantly lower than TDCO. The magnitude of the difference was clinically meaningful, suggesting that these two techniques cannot be used interchangeably. The correlation with echocardiographic measures of RV function was superior for TDCO, suggesting that

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TDCO may be the preferred method for assessing cardiac output.

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ACCEPTED MANUSCRIPT Table 1: Baseline characteristics (n=168) Mean ± SD

63.6 ± 15

BMI (kg/m2)

28.3 ± 7.1

IFCO (L/min)

4.2 ± 1.5

TDCO (L/min)

4.8 ± 1.6

TAPSE (mm)

17.1 ± 5.8

RV-FAC (%)

30.2.1 ± 10.4

Mean PA Pressure (mmHg)

41.7 ± 14.5

Mean RA Pressure (mmHg)

10.6 ± 6.1

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Age (yrs)

16 ± 8.2

TR velocity (m/sec)

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WHO group 1 (%)

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PAWP (mmHg)

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WHO group 2 (%)

4 ± 2.4 71 (42) 63 (37)

WHO group 3 (%)

101 (60)

WHO group 4 (%)

29 (17)

WHO group 5 (%)

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BMI=body mass index, IFCO=indirect Fick cardiac output, TDCO=thermodilution cardiac output, TAPSE= tricuspid annular plane systolic excursion, RV-FAC= right ventricular fractional area change, TR= tricuspid regurgitation, mPA= mean pulmonary artery pressure, mRA= mean right atrial pressure, PAWP= pulmonary artery wedge pressure.

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Table 2: Correlation between Indirect Fick CO/TD CO and selected echocardiographic

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variables. (n=168)

IFCO p-val

TDCO r

TDCO p-val

TAPSE

0.29

<0.01

0.49

<0.01

RV-FAC

0.07

0.34

0.2

0.01

RA volume

-0.08

0.28

-0.07

0.38

LV EI

-0.11

0.14

-0.19

0.01

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IFCO r

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TAPSE= tricuspid annular plane systolic excursion, RV-FAC= right ventricular fractional area change, RA vol= right atrial volume, LV EI systole= left ventricular eccentricity index in systole, IFCO r= Indirect Fick cardiac output correlation coefficient, TDCO r= thermodilution cardiac output correlation coefficient.

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Figure 1:

Figure 1: a scatter plot indicates a linear relationship with Pearson correlation coefficient between IFCO and TDCO of 0.61 and R2 value of 0.38. Figure 2:

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Figure 2: BA plot suggests Fick CO is lower than TD CO, on average, by 0.6 L/min, with upper/lower limits of agreement equal to -3.3, 2.1.

ACCEPTED MANUSCRIPT Highlights

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 Standardization of cardiac output measurement is important  We found the indirect Fick method gave lower cardiac outputs than thermodilution  Thermodilution correlated more strongly with echo measures of RV function