Comparison of global end-diastolic volume index derived from jugular and femoral indicator injection: a prospective observational study in patients equipped with both a PiCCO-2 and an EV-1000-device

Transpulmonary thermodilution (TPTD)-derived global end-diastolic volume index (GEDVI) is a static marker of preload which better predicted volume responsiveness compared to filling pressures in several studies. GEDVI can be generated with at least two devices: PiCCO and EV-1000. Several studies showed that uncorrected indicator injection into a femoral central venous catheter (CVC) results in a significant overestimation of GEDVI by the PiCCO-device. Therefore, the most recent PiCCO-algorithm corrects for femoral indicator injection. However, there are no systematic data on the impact of femoral indicator injection for the EV-1000 device. Furthermore, the correction algorithm of the PiCCO is poorly validated. Therefore, we prospectively analyzed 14 datasets from 10 patients with TPTD-monitoring undergoing central venous catheter (CVC)- and arterial line exchange. PiCCO was replaced by EV-1000, femoral CVCs were replaced by jugular/subclavian CVCs and vice-versa. For PiCCO, jugular and femoral indicator injection derived GEDVI was comparable when the correct information about femoral catheter site was given (p = 0.251). By contrast, GEDVI derived from femoral indicator injection using the EV-1000 was obviously not corrected and was substantially higher than jugular GEDVI measured by the EV-1000 (846 ± 250 vs. 712 ± 227 ml/m2; p = 0.001). Furthermore, measurements of GEDVI were not comparable between PiCCO and EV-1000 even in case of jugular indicator injection (p = 0.003). This is most probably due to different indexations of the raw value GEDV. EV-1000 could not be recommended to measure GEDVI in case of a femoral CVC. Furthermore, different indexations used by EV-1000 and PiCCO should be considered even in case of a jugular CVC when comparing GEDVI derived from PiCCO and EV-1000.

Several studies demonstrated the usefulness of trans-pulmonary thermodilution (TPTD)-derived global enddiastolic volume (GEDV) and its indexed value (GEDVI), which is adjusted to body surface area (BSA). GEDVI is a static marker of preload which better predicted volume responsiveness compared to filling pressures in a number of studies [1][2][3][4] . Furthermore, GEDVI is part of several algorithms with potential to improve outcome [5][6][7] . GEDVI can be measured with at least two commercially available devices: the PiCCO and the EV-1000. In general, both devices use similar methodologies and algorithms to obtain the thermodilution curve. Only the derivation of GEDV and extravascular lung water EVLW is slightly different between the two devices: the calculations based on the downslope time used by the PiCCO-system have been replaced by a "proprietary function" of the maximum ascending and descending slopes of the thermodilution curve in the EV-1000 [8][9][10] .
TPTD can be performed using superior or inferior vena cava access. However, several previous studies (supplementary Table S1) have shown a marked overestimation of GEDVI when performing TPTD indicator injection using a femoral venous access due to the additional volume of the vena cava inferior and the prolonged transit time of the cold bolus (supplementary Table S1) [11][12][13][14][15] . Since about 20-35% of all CVC insertions are located in the femoral vein [16][17][18] , the significance of incorrect measurements based on CVC site is substantial. Two recent studies have suggested a correction formula for GEDVI based on data derived from femoral TPTD and biometric information 12,13 . Consequently, the manufacturer of the PiCCO device introduced a new software requiring information about the CVC site, and correction for femoral indicator injection can be assumed 19 .
So far, only one case investigated femoral indicator injection using the EV-1000 13 . Therefore, we compared the agreement of GEDVI sequentially derived by femoral as well as jugular indicator injection using the EV-1000 and the PiCCO device in 10 patients equipped with both jugular and femoral venous access.

Methods
This prospective observational study was conducted in a general ICU between January and March 2017. The institutional review board approved the study (Ethikkommission; Fakultät für Medizin; Technische Universität München; 5384/12). The study was registered at ISRCTN (https ://www.isrct n.com/ISRCT N8262 9192, ISRCTN82629192). The research was performed in accordance with relevant guidelines/regulations. All patients or their legal representatives gave written informed consent.
Patients could be included, if a treating physician not involved in the study decided to perform a change of CVC and arterial line in patients with pre-existing and continuing need for TPTD-monitoring. This decision was made irrespectively of the study according to local standards regarding suspected blood stream infection. Only hemodynamic stable patients without vasopressors or with a constant vasopressor-dosage could be included.
We prospectively recorded 14 datasets from 10 patients with both jugular and femoral CVC (Multicath 5, Vygon; Aachen, Germany) or with a CVC and a dialysis catheter (Gambro Gam Cath Dolphin; Gambro Hospal GmbH, Gröbenzell, Germany). In general, CVCs or dialysis catheters were inserted in different positions (in the vena cava superior and in the vena cava inferior, respectively). The arterial TPTD curve was generated as previously described 4,20 .
The measurements with both devices were sequentially performed without an interruption. To avoid a systematic bias due to a potential increase in preload for the last series by repeated TPTDs, the five triplicate TPTDs were performed in random order. The five series of three TPTD-measurements per patient were performed without an interruption, except for changing the position of indicator injection. All patients were stable during the total experimental period of about 15 min. There were no changes in vasoactive substances and fluid supply during the entire period of measurements. The jugular venous access was used as the gold standard (Table 1). Indicator injection via femoral access was separately performed with (assumed) activation of a correction for femoral Scientific Reports | (2020) 10:20773 | https://doi.org/10.1038/s41598-020-76286-w www.nature.com/scientificreports/ measurements and without (de-activation of the correction for femoral measurements due to selecting the wrong information "jugular/subclavian CVC" in the PiCCO-device equipped with the most recent V3.1 algorithm).
Objectives and endpoints. This experimental setting allowed the investigation of the following questions: Statistical analyses. Continuous variables were analyzed using Wilcoxon's matched-pairs test. Bland-Altman analysis was used to evaluate the agreement between variables derived from jugular and femoral venous catheter sites and to calculate the percentage error. The agreement of classification of GEDVI was analyzed using Kendall's tau-b coefficient and Fisher's exact test. The percentage-error was calculated by dividing 1.96*SD by the mean of the compared variables: percentage-error = 1.96*SD/0.5*(GEDVI_A + GEDVI_B) with GEDVI_A and GEDVI_B being two different techniques to measure GEDVI, and SD being the standard deviation of their difference (GEDVI_A -GEDVI_B). A p value of p < 0.05 was considered significant.
Sample size calculation. The sample size calculation was based on the findings of the previous study by Saugel et al. with gold-standard GEDVI-values derived from jugular indicator-injection of 793 ± 18 ml/m 2 and significantly higher values of 1094 ± 235 ml/m 2 for GEDVI derived from femoral indicator injection with the PiCCO-device 12 . Based on the online statistical power calculation, sample sizes of n = 5 and n = 10 would provide statistical powers of 90% and 100% respectively (https ://www.stati stica lsolu tions .net/pssZt est_calc.php). Considering a slightly different setting also validating a second device (EV-1000), we chose a sample size of n = 10.
Ethical approval. The institutional review board approved the study (Ethikkommission; Fakultät für Medizin; Technische Universität München 5384/12). All patients or their legal representatives gave written informed consent.

Results
Patient's characteristics. Table 2 shows the patients characteristics.

Comparisons of GEDV(I) derived from different TPTD injection sites using the PiCCO or the EV-1000 device.
Since most users prefer indexed values, we started our analyses with comparisons of GEDVI derived from PiCCO versus EV-1000 using jugular or femoral TPTD injection. Based on this approach, we tried to address the following questions: 1. 1Does femoral indicator injection result in different values for GEDVI, if the correction function in the PiCCO is not activated?
By contrast, the agreement of classifications of GEDVI_PiC_FF with those of GEDVI_PiC_JUG was 12 out of 14 (86%; Kendall-tau-b coefficient of correlation 0.786; p = 0.002), which was not significantly different (p = 0.482; Fisher's exact test; Table 3).

Is this correction appropriate?
With regard to a low bias, acceptable limits of agreement (Fig. 1C) and classification in the same category for 12 of 14 measurements (agreement of 86%; p = 0.482; Fisher's exact test; Kendal tau-b of 0.685; p < 0.001; Table 3) the correction can be considered appropriate.
The lack of correction for femoral indicator injection resulted in a markedly different distribution of GEDVI for GEDVI_EV_JUG versus GEDVI_EV_FEM ( Table 4).
The agreement of the classifications of GEDVI_EV_JUG with those of GEDVI_EV_FEM was only 7 out of 14 (50%). The classification was significantly different compared to the gold standard of GEDVI_EV_JUG (p = 0.006; Fisher's exact test; Kendall-tau-b coefficient of 0.580; p = 0.024). Also considering a large bias of 135 ± 115 ml/ m 2 and limits of agreement of 359 and − 90 ml/m 2 (Fig. 2B), the differences between GEDVI_EV_FEM and GEDVI_EV_JUG are of high clinical relevance. To overcome the difference between jugular and femoral GEDVI measurements we used the correction formula for EV-1000 as suggested by Saugel, Huber et al. for the PiCCO device. The correction of GEDVI_EV_FEM by the formula resulted in GEDVI_EV_FEM_CORRECTED which was not significantly different from GEDVI_EV_JUG (690 ± 148 vs. 712 ± 227 ml/m 2 ; p = 0.551), with a small bias of − 15 ± 126 ml/m 2 and a percentage-error of 2% (Fig. 2E,F).
Furthermore, in 4 out of 14 cases (29%), GEDVI was differently classified (Table 4). Although the classifications were not significantly different according to Fisher's exact test (p = 0.098), the Kendall-coefficient of correlation was at best moderate (0.560; p = 0.026).
Also considering the bias of − 93 ± 116 ml/m 2 , the differences between GEDVI_EV_JUG and GEDVI_PiC_ JUG are clinically relevant, in particular in obese patients.  GEDV values for both devices were obtained by multiplication of GEDVI with predicted body surface area (BSA_pred for PiCCO) or with actual body surface area (BSA_act for EV-1000). Table 5 demonstrates that predicted versus actual bodyweight (BW) and predicted BSA versus actual BSA were substantially different for several patients.
These findings suggest that the difference between GEDVI_PiC_JUG and GEDVI_EV_JUG is caused by different indexations.

Do jugular measurements of PiCCO and EV-1000 provide comparable results for unindexed GEDV in case of jugular injection?
We compared unindexed GEDV_PiC_JUG and GEDV_EV_JUG which were not significantly different (1511 ± 383 vs. 1478 ± 483 ml; p = 0.542) with a bias of − 33 ± 201 ml and a percentage-error of 2% (Fig. 3E,F).
With regard to a small bias of − 33 ± 201 ml, a percentage-error of 2%, limits of agreement of 361 and − 427 ml and an acceptable agreement of classifications in 10 out of 14 measurements (71%) (p = 0.098; Fisher's exact test, Kendal tau-b of 0.736; p < 0.001; supplementary Table S2), GEDV can be considered comparable between PiCCO and EV-1000 in case of jugular indicator injection.

Discussion
Two previous studies suggested interchangeability of GEDVI derived from the two devices 9,10 . However, both studies did not report on the use of femoral CVCs for indicator injection, which results in an overestimation of GEDV(I) 12 . Therefore, we compared the results from patients equipped with both PiCCO and EV-1000 as well as with femoral and jugular CVCs.
Based on this approach our study shows three main results: • GEDVI-values derived from femoral indicator injection with the EV-1000 are significantly higher compared to GEDVI-values derived from jugular CVC indicator injection. GEDVI-values are falsely classified in 50% of measurements when using the EV-1000 with femoral indicator injection.
• Surprisingly, GEDVI from jugular indicator injection was different between EV-1000 and PiCCO, most probably due to different indexations. • Finally, the current PiCCO-algorithm appropriately corrects for femoral indicator injection.
At first glance these findings might be surprising, since based on two previous studies in 11 pigs 9 and 72 critically ill patients 10 , "interchangeability of the two methods" has been claimed 10 .
This is most probably related to the different design of those two studies. In the animal study, all CVCs for indicator injection were placed into the jugular vein 9 . No femoral indicator injections were performed. Therefore, no conclusions about interchangeability in case of femoral indicator injection can be drawn.
In the clinical study by Kiefer and co-workers no details about the CVC-position were given 10 . However, even if femoral CVCs would have been used in part in this study, interchangeability of wrong GEDV-values can be assumed, since the authors used the old PiCCO-algorithm 8.0.0.6 which was not yet correcting GEDV(I) for femoral indicator injection. The newer PiCCO algorithm V3.1 requiring information about the venous catheter site and correcting for femoral indicator injection became commercially available in parallel with the publication of that study (2012). Therefore, even in case of femoral CVC indicator injection the uncorrected GEDV-values of both devices would have been interchangeable despite a substantial overestimation in case of femoral indicator injection, since the old PiCCO-algorithm did not correct GEDV(I) for femoral CVC site.
By contrast, our findings of a substantial overestimation of GEDVI by the EV-1000 in case of femoral indicator injection are in line with the only one case report addressing this issue 13 . Both studies demonstrate that the  www.nature.com/scientificreports/ slightly different algorithm of the EV-1000 to derive raw GEDV from the thermodilution curve is not capable to correct for femoral indicator injection resulting in an increase in the mean transit time due to the additional volume of the inferior vena cava 15,19 . In case of femoral indicator injection the two devices are not interchangeable even in case of use of unindexed GEDV due to the absence of a correction in the EV-1000. Schmidt and co-workers demonstrated that this results in a shift of the thermodilution (TD)-curve to the right, while the curve is otherwise nearly unchanged. This shift to the right is caused by a prolonged time of the horizontal part of the TD-curve, before the first changes in blood temperature induced by the thermo-bolus can be detected by the arterial thermistor. By contrast, the derivation of GEDV in the EV-1000 was not based on the initial horizontal part of the TD-curve, but on the maximum up-slope and on the maximum down-slope of the curve [8][9][10] . Necessarily, the "proprietary algorithm" of the EV-1000 cannot eliminate the changes of the TPTD-curve due to a prolonged indicator transit time to the thermistor before the "up-slope". The more surprising finding in our study was that indexed GEDVI-values were significantly different between PiCCO and EV-1000 even in case of jugular indicator injection. Regarding this issue, both previous studies comparing PiCCO versus EV-1000 do not allow conclusions, since both studies were restricted to the analysis of GEDV, but not of GEDVI. A closer look to the manufacturers' handbooks provides the information that the EV-1000 calculates BSA based on the actual bodyweight, whereas the PiCCO algorithm uses predicted bodyweight. While the discrepancy of indexation has a limited impact in case of normal weight patients, it results in large differences in GEDVI in obese patients. The finding that 2 out of 14 GEDVI measurements (14%) were classified completely different, i.e. GEDVI_PiC_JUG was elevated, whereas the corresponding GEDVI_EV_JUG was decreased, evidences this. This problem has also been discussed by Beutler and co-workers based on the patient with an actual bodyweight of 220 kg 21 .
While non-correction for femoral indicator injection can be considered as a substantial deficiency of the EV-1000, clinically relevant differences between GEDVI derived from PiCCO and EV-1000 should be interpreted cautiously regarding superiority of one approach. A recent large database analysis investigating 3812 TPTD measurements in 234 patients suggests slightly higher coefficients of correlation with unindexed GEDV for BSA_pred compared to BSA_act 22 . Furthermore, the ROC-AUC regarding a decreased GEDV < 1260 ml was larger for BSA_pred than for BSA_act (AUC = 0.842 vs. AUC = 0.733) in this study 22 . Despite these slight differences further investigations are required to optimize indexation as well as normal ranges of GEDV and other haemodynamic parameters.

Clinical implications and strengths
The findings of our study question the use of EV-1000 to measure GEDV(I) in case of femoral indicator injection. Furthermore, in obese patients the differences between the indexations used by PiCCO and by EV-1000 should be taken into account, until more specific and consistent indexations are available 23 . Both findings should be considered to improve the role of GEDV(I) as marker of preload.

Limitations of the study
This study is limited by a low number of patients and its monocentric design. GEDV(I) alterations over time were not investigated in this study. This is a limitation, since observation of changes over time sometimes facilitates the interpretation of data with inappropriate indexations or questionable normal ranges.

Conclusions
1. While the last PiCCO-software appropriately corrects GEDV(I) for femoral CVC-site, femoral indicator injection in the EV-1000 results in a substantial overestimation of GEDVI. Therefore, the EV-1000 could not be recommended to measure GEDVI in case of a femoral CVC. 2. Due to different indexations, GEDVI-values are not comparable between PiCCO and EV-1000 even in case of jugular indicator injection.

Data availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.