Comparison of cardiac function index derived from femoral and jugular indicator injection for transpulmonary thermodilution with the PiCCO-device: A prospective observational study

Introduction Cardiac function index (CFI) is a trans-pulmonary thermodilution (TPTD)-derived estimate of systolic function. CFI is defined as the ratio of cardiac output divided by global end-diastolic volume GEDV (CFI = CO/GEDV). Several studies demonstrated that the use of femoral venous access results in a marked overestimation of GEDV, while CFI is underestimated. One study suggested a correction formula for femoral venous access that markedly reduced the bias for GEDVI. Therefore, the last PiCCO-algorithm requires information about the CVC-position which suggests a correction of GEDV for femoral access. However, a recent study demonstrated inconsistencies of the last PiCCO algorithm using incorrected GEDV to calculate CFI despite obvious correction of GEDV. Nevertheless, this study was based on mathematical analyses of data displayed in a total of 15 patients equipped with only a femoral, but not with a jugular CVC. Therefore, this study compared CFI derived from the femoral indicator injection TPTD to data derived from jugular indicator injection in 28 patients with both a jugular and a femoral CVC. Methods 28 ICU-patients with PiCCO-monitoring were included. Each dataset consisted of three triplicate TPTDs using the jugular venous gold standard access and the femoral access with and without information about the femoral indicator injection to evaluate, if correction for femoral GEDV also pertains to CFI. (CFI_jug: jugular indicator injection; CFI_fem: femoral indicator injection; CFI_fem_cor: femoral indicator injection with correct information about CVC-position; CFI_fem_uncor: femoral indicator injection with uncorrect information about CVC-position; CFI_fem_uncor_form = CFI_fem_uncor * (GEDVI_fem_uncor/GEDVI_fem_cor)). Results CFI_fem_uncor was significantly lower than CFI_jug (4.28±1.70 vs. 5.21±1.91 min-1; p<0.001). Similarly, CFI_fem_cor was significantly lower than CFI_jug (4.24±1.62 vs. 5.21±1.91 min-1; p<0.001). This is explained by the finding that CFI_fem_uncor was not different to CFI_fem_cor (4.28±1.70 vs. 4.24±1.62 min-1; p = 0.611). This suggests that correction for femoral CVC does not pertain to CFI. Calculative correction of CFI_fem_uncor by multiplying CFI_fem_uncor by the ratio GEDVI_fem_uncor/GEDVI_jug resulted in CFI_fem_uncor_form which was slightly, but significantly different from the gold standard CFI_jug (5.51±2.00 vs. 5.21±1.91 min-1; p = 0.024). The agreement of measurements classified in the same category of CFI (decreased (<4.5), normal (4.5–6.5) and increased (>6.5 min-1)) was high for CFI_jug and CFI_fem_uncor_form (identical categories in 26 of 28 comparisons; p = 0.49). By contrast, the agreement with CFI_jug was significantly lower for CFI_fem_cor (14 out of 28; p<0.001) and CFI_fem_uncor (15 out of 28; p<0.001). Conclusions While the last PiCCO algorithm obviously corrects GEDVI for femoral indicator injection, this correction is not applied to CFI. Therefore, femoral TPTD indicator injection results in substantially lower values for CFI compared to TPTD using a jugular CVC. Necessarily, uncorrected CFI-values derived from femoral TPTD are misleading and have to be corrected.


Introduction
Accurate haemodynamic monitoring is essential for the diagnosis and therapeutic management of critically ill patients with circulatory failure [1]. Different methods and techniques can be used to estimate the left ventricle (LV, Table 1) contractile fraction and the LV ejection function (LVEF). Doppler echocardiography is the gold standard imaging technique for measuring LVEF [2, 3], but repeated measurements are often not feasible due to the lack of experienced examiners on a 24/24h basis. Therefore, trans-pulmonary thermodilution (TPTD) has been suggested to assess cardiac systolic function [4][5][6][7]. In addition to stroke volume (SV) and cardiac output (CO) the preload parameter global end-diastolic volume (GEDV) and the marker of pulmonary edema extravascular lung water (EVLW) as well as a number of calculated ratios have been suggested to facilitate the interpretation of numerous parameters provided by TPTD and pulse contour analysis (PCA) [5,8,9]. Two of these parameters have been associated to cardiac contractility and with systolic function when compared to echocardiography or other gold-standard techniques (see overview of studies; Table 2) [4][5][6][7][10][11][12].: Cardiac function index (CFI) and global ejection fraction (GEF). Both have been shown to accurately assess LVEF and its response to inotropic substances, volume depletion, resuscitation and impairment of contractility by verapamil [4,10,11,13]. Previous studies also confirmed that a low CFI identified cardiac dysfunction in both acute heart failure and septic patients [4,7,10].
Based on their mathematical derivation, CFI (CO/GEDV) and GEF (4 Ã SV/GEDV) necessarily depend on an accurate determination of GEDV. However, several studies demonstrated that GEDV is markedly overestimated in case of using a femoral venous access for TPTD-indicator injection instead of a jugular or subclavian access [14][15][16]. Consequently, CFI is underestimated in case of femoral indicator injection [17]. One of these studies suggested a formula to correct GEDVI for femoral venous access that markedly reduced the bias for GEDVI in a small validation group [15]. Consequently, the last PiCCO-algorithm requires information about the central venous catheter (CVC)-position that results in correction of GEDVI if the information of a femoral access is given. However, at least two studies suggest inconsistencies of the last PiCCO-algorithm using uncorrected GEDV to calculate CFI and pulmonary vascular permeability index (PVPI) despite obvious correction of GEDVI in case of femoral indicator injection [17,18]. Nevertheless, these studies were based on mathematical analyses of data displayed in a total of 15 patients equipped with only a femoral, but not with a jugular CVC.
Another recent study in patients equipped with both jugular and femoral CVCs demonstrated that the last PiCCO-algorithm corrects GEF, but not PVPI which resulted in a substantial underestimation of PVPI in case of femoral indicator injection [19]. However, in the study performed by Huber et al. the CFI was not analyzed [19].
Therefore, we have compared in the present study CFI values of 28 patients equipped with both jugular and femoral CVCs: Two triplicate measurements with femoral indicator injection with and without giving the information of femoral indicator injection were compared to the gold-standard of CFI derived from jugular indicator injection.

Materials and methods
This prospective observational study was conducted in a ten-bed general ICU at a university hospital between October 6, 2016 and March 31, 2017. The study was approved by institutional review board approved (Ethikkommission; Fakultät für Medizin; Technische Universität München 3049/11s). Written informed consent was obtained by all patients (18 years of age or older) or their legal representatives. All patients had to be equipped with PiCCO device and with both jugular and femoral catheter. The indication for PiCCO monitoring was made independently from the study by the ICU physician in charge None of the patients had been included in one of the previous studies or databases comparing TPTD-parameters derived from jugular to femoral indicator injection [14,15,[17][18][19]. After fulfilling above-mentioned criteria no patient was excluded. The abbreviations and nomenclature of haemodynamic parameters used in this paper are summarized in Table 1.
28 datasets including triplicate TPTD with 15 ml cold saline solution were recorded in 28 patients equipped with both jugular and femoral CVC. The jugular venous access was used as the gold standard TPTD_jug. Furthermore, two triplicate TPTDs were performed via the femoral access with (TPTD_fem_cor) or without (TPTD_fem_uncor) the information about the femoral indicator injection. This was done to evaluate, if correction for femoral GEDV pertains to CFI_fem.
The three TPTDs were performed in a random order with the intention to avoid a systematic bias by repeated triplicate TPTDs with a total volume of 9 Ã 15 ml.
All measurements were performed in patients equipped either with conventional jugular and femoral CVC or conventional CVC and a dialysis catheter irrespective of the study. According to the local standard CVCs or dialysis catheters were inserted in different positions (one in the superior vena cava and the other one in the inferior vena cava).
Medical ICU Significant differences for CFI and GEF between patients with sepsis and AHF. Significant association of CFI and GEF with left ventricular stroke work index derived from PAC in patients with sepsis and AHF. Significant association of CFI with mixed venous oxygen saturation.
Trepte et al. [11] 16 pigs; 64 measurements before and after induction of hypovolaemia as well as before and after verapamil.
Animal study CFI and GEF detect changes in preload independent cardiac contractility induced by verapamil. Both reflect changes of contractility induced by decrease of preload.

Statistical analyses
All data were controlled for input data error. Continuous variables are expressed as mean ±standard deviation. Categorical variables are expressed as percentages. Wilcoxon-test for paired samples was used to compare continuous variables.
Bland-Altman analysis was used for the analysis of the agreement between CFI derived from jugular vs. femoral venous catheter sites for CFI and to compute the percentage error (PE).
All statistical analyses were performed using the IBM SPSS Statistics software version 23 (SPSS Inc., Chicago, IL, USA).
Sample size calculation. The sample size calculation based on the finding of the previous study by Beitz et al. with CFI-values calculated for jugular indicator-injection of 5.1 ±1.8 min -1 and significantly lower values of 3.8±1.6 min -1 derived from uncorrected femoral indicator injection, using an online statistical power calculator (https://www. dssresearch.com/KnowledgeCenter/toolkitcalculators/statisticalpowercalculators.aspx) Sample sizes of n = 12 and n = 16 would provide statistical powers of 80% and 90% respectively [17]. However, the data by Beitz et al. were calculatorily derived from 95 datasets from only 10 patients [17]. A larger number of patients might have resulted in a stronger standard deviation of the CFI-value measured after femoral indicator injection. Therefore, we assumed the same mean values for CFI, but for power calculation a higher standard deviation of 2.1 min -1 instead of 1.6 min -1 in the study by Beitz et al.. This resulted in a sample size of n = 28 to provide a statistical power of 90% and an alpha-error of 5% (two-tailed test). Table 3 shows the patients characteristics.

Fig 1. Boxplots plots comparing cardiac function index (CFI) derived from jugular indicator injection (CFI_jug), from femoral injection without activation of a potential correction by the device (CFI_fem_uncor), from femoral injection with activation of a potential correction by the device (CFI_fem_cor) and from femoral injection without activation of a potential correction by the device, but corrected by the previously suggested formula (CFI_fem_uncor_form).
CFI_fem_uncor_form was corrected using the formula suggested for correction of femoral indicator injection derived GEDVI: GEDVI corrected [ml/m 2 ] = 0.539 Ã GEDVI uncorrected -15.17 + 24.49 Ã CI uncorrected 2.311 Ã BW ideal. CFI_fem_uncor_form was calculated by multiplying CFI_fem_uncor with the ratio GEDV uncorrected / GEDV corrected . GEDV(I): global end-diastolic volume (index). https://doi.org/10.1371/journal.pone.0200740.g001 Comparison of cardiac function index derived from femoral and jugular indicator injection using a PiCCO-device Despite a slightly significant difference between CFI_fem_uncor_form and CFI_jug with questionable clinical relevance, ex-post correction of CFI_uncor resulted in significantly lower amount of the bias |CFI_fem_uncor_form-CFI_jug| vs. |CFI_fem_uncor-CFI_jug| (0.49±0.71 vs. 0.93±0.60 min -1 ; p = 0.005).

Discussion
TPTD-derived CFI is a bedside surrogate of LV systolic function. CFI is strongly associated with echocardiography-derived LVEF and facilitates guidance of inotropic therapy and fluid Comparison of cardiac function index derived from femoral and jugular indicator injection using a PiCCO-device management. Repeated CFI measurement is readily available and independent of the examiner. Changes in CFI over time provide dynamic information that might be superior to single measurements, particularly when interpreted in the light of a clinical situation. According studies with their findings are summarised in Table 2.
However, the validity of CFI calculation relies on the accurate determination of CO and GEDV. Several recent studies suggest marked overestimation of GEDV/GEDVI and CFI in case of using a femoral CVC for indicator injection, compared to the gold standard of jugular or subclavian injection. Interestingly, a similar phenomenon was found in case of misplacement of subclavian central venous catheter tip into the jugular vein [22].
One study suggested a correction formula for GEDVI derived from femoral indicator injection. This correction is based on GEDVI and CI obtained from femoral access and on ideal bodyweight [15]. Several studies suggest that a similar formula has been integrated to the last Comparison of cardiac function index derived from femoral and jugular indicator injection using a PiCCO-device  Comparison of cardiac function index derived from femoral and jugular indicator injection using a PiCCO-device PiCCO-2-algorithm [17,18]. However, based on mathematical analyses of the data displayed for CFI and GEF, one recent study suggested that CFI obviously is not corrected for femoral injection [17]. Since analyses were performed in small cohorts with only femoral CVCs, the final proof of these results in patients equipped with both jugular and femoral catheters remained to be demonstrated.
This study demonstrates that the correction formula for femoral venous access is not applied to correct CFI. The resulting underestimation of this value would have had a consequence for around 50% of our patients as demonstrated by the wrong classification of CFI in 14 out of 28 measurements. Therefore, measurement of CFI in patients with femoral venous access for indicator injection at present is misleading and has to be replaced by echocardiography as long as the correction formula is not implemented in the TPTD-algorithm. This problem might also apply to the other commercially available TPTD-device EV-1000 (Edwards Lifesciences, Irvine, USA), since at least one study suggests that this device does not correct GEDVI, PVPI and GEF for femoral indicator injection [14].
Unless an appropriate correction is implemented in the PiCCO and the EV-1000, in patients with femoral central venous access echocardiography should be performed to assess left ventricular contractility. Irrespective of the central venous access, echocardiography enables to exclude isolated right heart failure which might impede the use of CFI and GEF also in case of a jugular or subclavian central venous access [10].
However, repeated echocardiography is time consuming and requires the continuous availability of experienced investigators. On the other hand, TPTD is straightforward and reliable even when performed by different investigators. Furthermore, it provides additional extra-cardiac parameters such as EVLWI and calibrates continuous measurement of CI, GEF and CFI.

Practical implication
Although a correction formula for femoral venous access markedly reducing the bias for GEDVI has been published 7 years ago, and despite several studies gave hints for inconsistencies of the correction of GEDVI, PVPI, GEG and CFI, our data demonstrate that the most recent algorithm of the PICCO still does not apply this correction to CFI. Therefore, in patients with femoral venous access CFI has to be classified as misleading and may result in wrong therapeutic interventions due to substantial underestimation and wrong categorization of CFI.
From a practical viewpoint, there are two options to overcome this dilemma in addition to the use of echocardiography: 1. As demonstrated by this study, ex post correction by the previously suggested formula to correct GEDVI appropriately corrects CFI_fem with acceptable bias, percentage error and categorization according to clinical thresholds.
2. Since this mathematical correction maybe cumbersome in clinical routine, GEF can be used instead of CFI. At least two studies suggest that GEF is appropriately corrected for femoral indicator injection by the most recent PiCCO algorithm [18,19].

Limitations of the study
This study included a small number of patients and has been conducted as a single-centre study. Furthermore, all measurements were performed in critically ill patients and not in healthy persons.

Conclusion
While the last PiCCO algorithm obviously corrects GEDVI for femoral indicator injection, this correction is not applied to CFI. Therefore, femoral TPTD indicator injection results in