Vaquer et al. Ann. Intensive Care (2019) 9:61 https://doi.org/10.1186/s13613-019-0537-4 RESEARCH Open Access Influence of changes in ventricular systolic function and loading conditions on pulse contour analysis‑derived femoral dP/dtmax Sergi Vaquer1,2,3,4* , Denis Chemla4,5, Jean‑Louis Teboul3,4, Umar Ahmad3,4, Flora Cipriani3,4, Joan Carles Oliva6, Ana Ochagavia1, Antonio Artigas1,7, Francisco Baigorri1,7 and Xavier Monnet3,4 Abstract Background: Femoral dP/dtmax (maximum rate of the arterial pressure increase during systole) measured by pulse contour analysis has been proposed as a surrogate of left ventricular (LV) dP/dtmax and as an estimator of LV systolic function. However, femoral dP/dtmax may be influenced by LV loading conditions. In this study, we evaluated the impact of variations of LV systolic function, preload and afterload on femoral dP/dtmax in critically ill patients with cardiovascular failure to ascertain its reliability as a marker of LV systolic function. Results: We performed a prospective observational study to evaluate changes in femoral dP/dtmax, thermodilution- derived variables (PiCCO2—Pulsion Medical Systems, Feldkirchen, Germany) and LV ejection fraction (LVEF) meas‑ ured by transthoracic echocardiography during variations in dobutamine and norepinephrine doses and during volume expansion (VE) and passive leg raising (PLR). Correlations with arterial pulse and systolic pressure, effective arterial elastance, total arterial compliance and LVEF were also evaluated. In absolute values, femoral dP/dtmax devi‑ ated from baseline by 21% (201 ± 297 mmHg/s; p = 0.013) following variations in dobutamine dose (n = 17) and by 15% (177 ± 135 mmHg/s; p < 0.001) following norepinephrine dose changes (n = 29). Femoral dP/dtmax remained unchanged after VE and PLR (n = 24). Changes in femoral dP/dtmax were strongly correlated with changes in pulse pressure and systolic arterial pressure during dobutamine dose changes (R = 0.942 and 0.897, respectively), norepi‑ nephrine changes (R = 0.977 and 0.941, respectively) and VE or PLR (R = 0.924 and 0.897, respectively) (p < 0.05 in all cases). Changes in femoral dP/dtmax were correlated with changes in LVEF (R = 0.527) during dobutamine dose vari‑ ations but also with effective arterial elastance and total arterial compliance in the norepinephrine group (R = 0.638 and R = − 0.689) (p < 0.05 in all cases). Conclusions: Pulse contour analysis-derived femoral dP/dtmax was not only influenced by LV systolic function but also and prominently by LV afterload and arterial waveform characteristics in patients with acute cardiovascular failure. These results suggest that femoral dP/dtmax calculated by pulse contour analysis is an unreliable estimate of LV systolic function during changes in LV afterload and arterial load by norepinephrine and directly linked to arterial waveform determinants. Keywords: Haemodynamic monitoring, Waveform analysis, Ejection fraction, Preload, Afterload, Thermodilution *Correspondence: sergivaquer@gmail.com 1 Servei de Medicina Intensiva, Centre de Crítics, Corporació Sanitària Universitària Parc Taulí, Parc Taulí 1, 08208 Sabadell, Spain Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 2 of 10 Background Corporació Sanitària Parc Taulí CEIC2013616 and Com- Current haemodynamic monitoring devices performing ité pour la Protection des Personnes Ile-de-France VII arterial pulse contour analysis can measure and monitor 2011A01696-35). All patients or next of kin gave their the maximum rate of rise of arterial pressure (dP/dtmax). consent to participate to the study. Data in this manu- By analogy with the left ventricle (LV) dP/dtmax, arterial script are presented following the “Strengthening the dP/dtmax is supposed to reflect LV systolic function [1–8]. Reporting of Observational Studies in Epidemiology” Several studies have suggested that measurements of (STROBE) criteria for observational studies [15]. arterial dP/dtmax obtained from radial [7, 9] and femo- ral [7, 10] arterial pressure waveforms were comparable Patients to LV dP/dtmax and, in some cases, might be useful for Inclusion criteria were age older than 18 years old and predicting patient outcome [11]. However, conflicting presence of at least one of the following signs of haemo- results regarding the comparability of LV dP/dtmax and dynamic failure in the context of acute illness: arterial dP/dtmax have also been presented in both adults and children [12, 13]. Despite these uncertainties, arte- rial dP/dtmax is most often presented as a marker of LV • Systolic arterial pressure ≤ 90 mmHg or decreases of systolic function in many off-the-shelf haemodynamic more than 50 mmHg in the last 3 h or mean arterial monitoring systems. Supportive literature is based on the pressure ≤ 65 mmHg observed good correlation between LV and arterial dP/ • Oliguria ≤ 0.5 mL/kg/h for more than 2 h dtmax during periods of haemodynamic stability [7–9, 12]. • Blood lactate ≥ 2 mmol/L (or 22 mg/dL) However, these good correlations documented on stable • Central venous oxygen saturation ≤ 60% patients do not necessarily imply that femoral dP/dtmax • Skin mottling provides an adequate evaluation of changes in LV systolic function during haemodynamic challenges. Patients had to be monitored with a transpulmonary Many physiological factors other than LV systolic func- thermodilution device (PICCO2, Pulsion Medical Sys- tion may influence arterial dP/dtmax, including the timing tems, Feldkirchen, Germany) and must present the need of the measurement relative to aortic valve opening, and for a change in the dose of norepinephrine or dobu- the potential influences of cardiac preload and afterload tamine, or for volume expansion or a PLR test [14], as (including its resistive and pulsatile components). To be decided by the attending physicians. considered a reliable marker of LV systolic function, arte- Exclusion criteria were the evidence of a significant rial dP/dtmax should be unaffected by changes in these aortic stenosis with echocardiography (mean pressure variables and should consistently respond to directional gradient of the aortic valve ≥ 25 mmHg) and conditions changes in LV systolic function. precluding measurements of femoral dP/dtmax of suf- Therefore, to assess the validity of arterial dP/dtmax as ficient quality such as over-damping or under-damping an index of LV systolic function and the relative contri- of the arterial pressure signal persisting after repeated bution of changes in cardiac preload and afterload on its flushes of the arterial line. measurement, we studied the responses of femoral dP/ dtmax during changes in the dose of dobutamine and nor- Recorded variables epinephrine, during passive leg raising (PLR) manoeuvre Arterial pressure was measured through an arterial [14] and after intravascular fluid administration in criti- catheter inserted in the femoral artery (PV2015L20-A, cally ill patients with circulatory shock. We also com- Pulsion Medical Systems, Feldkirchen, Germany). The pared these changes with markers of left ventricular catheter was connected to a PiCCO2 device, which auto- afterload and with left ventricle ejection fraction (LVEF) matically and continuously calculated femoral dP/dtmax. measured by transthoracic echocardiography. With this device, dP/dtmax was obtained from the upris- ing portion of the arterial curve, representing the steep- est incline of the arterial trace in systole, and averaged Methods over 12 s. After zeroing the arterial pressure transducer We performed a prospective observational study in two system and before each measurement, the arterial wave- adult intensive care units (Servei de Medicina Intensiva, form signal quality was checked visually using a fast flush Corporació Sanitària Universitària Parc Taulí, Sabadell, test to assess the adequacy of its damping [16]. In case Spain, and Service de Médecine intensive-réanimation, of damping, repeated flushes were performed until suf- Hôpital de Bicêtre, Le Kremlin-Bicêtre, France). The ficient signal quality was acquired. Data were recorded study was approved by local ethics committees of both automatically by the PICCO2 device, and synchronisa- institutions (Comitè Ètic d’Investigació Clínica de la tion of measurements with interventions was performed Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 3 of 10 manually and required the presence of the investigator stabilisation of pulse contour-derived CI (for dobu- team. tamine) or of mean arterial pressure (for norepinephrine). Transthoracic echocardiography was performed with a Patients could be included in the study as many times as CX 50 device (Philips Healthcare, DA Best, The Nether- therapeutic interventions were indicated by the attending lands) and used to estimate LV ejection fraction (LVEF). physicians. Multiple measurements on the same patient Measurements were taken by the same observer in all could only be performed after sufficient time had passed cases (SV) using the Simpson’s method from two- and between different manoeuvres to allow for stabilisation of four-chamber apical views. Endocardial contours were haemodynamic variables and provided that the haemo- hand-drawn, and volumes were automatically averaged dynamic status of the patient had significantly changed out over three consecutive cardiac cycles by the software when assessing the same type of interventions. to calculate LVEF. All patients were equipped with a central venous cath- Data analysis eter in the superior vena cava territory. Thermodilution During norepinephrine dose variations, changes in Ea, measurements were taken by injection of a 15-mL cold TAC and SVRi were used to identify changes in arterial saline bolus (< 8 °C) through the central venous catheter. loading properties, while changes in systolic and mean The results of three consecutive thermodilution meas- arterial pressure were used to estimate changes in LV urements were averaged [17]. Cardiac output and stroke afterload. During dobutamine dose variations, changes volume were measured through transpulmonary ther- in LVEF, CI and CFI were used to estimate changes in modilution [18] and indexed to body surface to provide LV systolic function. Finally, during PLR and volume cardiac index (CI), stroke volume index (SVI) and global expansion, changes in central venous pressure (CVP) and end-diastolic volume index (GEDVi). Cardiac function GEDVi were used to track changes in LV preload. index was obtained directly from the PiCCO2 device as a We considered changes in femoral dP/dtmax induced by calculated variable (CFI = CI/GEDVi) [19]. dobutamine dose variations as the main study variable. To evaluate the resistive component of the arterial Using previous published data [10] and assuming a mini- load, we calculated the systemic vascular resistance mum required threshold of 10%, an α risk of 5% and a β index (SVRi) as SVRi = (mean arterial pressure − central risk of 20%, we estimated that the minimum number of venous pressure)/cardiac index. To evaluate the pulsatile paired measurements required for detecting a significant component of arterial loading, we calculated the total change in femoral dP/dtmax during variations in the dose arterial compliance (TAC = stroke volume/arterial pulse of dobutamine was seven. We continued inclusions in the pressure) [20]. Pulse pressure was calculated as the sys- other study groups (changes in the dose of norepineph- tolic minus the diastolic arterial pressure. The effective rine and PLR/VE) until this number was reached in both arterial elastance was used as a global index of arterial dobutamine subgroups (dose increases and decreases). load as previously described (Ea = 0.9 × systolic arterial Normality of variables was assessed using the Kolmog- pressure/stroke volume) [21]. orov–Smirnov test. Data are presented as mean ± stand- ard deviation (SD) or medians and 25th–75th percentile, Study design as appropriate. Data from norepinephrine and dobu- Data were collected before and after haemodynamic tamine dose changes were pooled (absolute values of interventions. Volume expansion was performed by increases and decreases were evaluated together and infusing 500 mL 0.9% saline solution over 10 min. averaged), and absolute deviations from baseline val- Although other fluids might be considered for volume ues (called “changes” or “variations”) were presented as expansion [22], 0.9% saline solution was used in the units mean differences. Statistical comparisons were made at the time the study was performed. A PLR test was per- using the paired Student’s t test or Wilcoxon rank test as formed by moving the patient from the semi-recumbent appropriate. Percentages of change, rather than raw val- position to a position where the trunk is horizontal and ues alone, were presented in order to normalise baseline the legs are elevated at 45°, as previously described [14]. values. Correlation of changes in study variables during In patients receiving fluid, the post-intervention meas- interventions was performed using Pearson’s correlation urements were taken immediately after the end of vol- test. In order to evaluate the potential impact of repeated ume expansion. In patients in whom a PLR test was measurements of the same type on a single patient, we performed, these measurements were taken at the time studied changes in femoral dP/dtmax during interventions when the maximal PLR-induced change in CI, if any, had using only one measurement per patient. Manoeuvres occurred. This usually occurs within 1 min [14]. After with the highest norepinephrine or dobutamine dose the change in dose of norepinephrine or dobutamine, change were selected, as well as the first volume expan- the post-interventions recording was performed after sion or PLR performed in each patient. All statistical Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 4 of 10 calculations were done using SPSS version 22 (Interna- Results tional Business Machines, Armonk, NY, USA). Values of Patients p < 0.05 were considered statistically significant. Nineteen patients were included (68% male subjects) between March 2013 and January 2015, in whom 72 therapeutic interventions were analysed (162 data Table 1 Baseline demographic and clinical characteristics points). Arterial line damping problems were observed of included patients in five patients, representing nine interventions. In all cases, repeated flushing of the arterial line led to res- Clinical variable All patients (n = 19) olution of the damping effect, so that no patient was Weight (kg) 81 ± 19 excluded due to this problem. Two interventions had Height (cm) 166 ± 10 to be rejected given repeatedly doubtful validity of the Age (years) 71 ± 9 data due to patient movement and incorrect acquisi- Apache II (points) 25 ± 10 tion procedure (Additional file 1: Figure S1). The dis- VT (mL) 406 ± 71 tribution of medical interventions was as follows: RR ­(min−1) 20 (18–25) norepinephrine dose increase: 9 (13%), norepinephrine FiO2 0.37 ± 0.08 dose decrease: 20 (29%), PLR: 12 (17%), volume expan- PaO2/FiO2 257 ± 101 sion: 12 (17%), dobutamine dose increase: 7 (10%), dob- PEEP ­(cmH2O) 6 (5–8) utamine dose decrease: 10 (14%). On average, 3.7 ± 2.0 Pplat ­(cmH2O) 19 ± 5 interventions were collected in each patient (Addi- NE (µg kg−1 min−1) 0.92 ± 0.93 tional file 1: Figure S1). Case demographics and clinical DBT (µg kg−1 min−1) 5.39 ± 4.9) characteristics are presented in Table 1 and Additional WBC (× 103 dL−1) 18.6 (11–23) file 1: Table S1. Baseline haemodynamic characteristics CRP (mg dL−1) 24 ± 11.5 are presented in Table 2. The majority of interventions Cr (mg dL−1) 2.4 ± 1.2 occurred during septic shock (54 cases; 77%), followed Bil (mg dL−1) 1.1 (0.4–3.4) by cardiogenic shock (10 cases; 14%) and hypovolemic Lactate (mg dL−1) 48.3 ± 30 shock (6 cases; 9%). During 55 (79%) therapeutic inter- Data are presented as mean ± SD or median (25th–75th%) ventions, patients were mechanically ventilated, in VT, tidal volume; RR, respiratory rate; ­FiO2, inspired oxygen fraction; P ­ aO2, arterial 25 (45%) of which patients were not fully adapted to oxygen partial pressure; PEEP, positive end-expiratory pressure; Pplat, plateau mechanical ventilation. In 44 cases (67%), sinus rhythm pressure; NE, norepinephrine; DBT, dobutamine; WBC, white blood cells; CRP, C was present. reactive protein; Cr, creatinine; Bil, total bilirubin Table 2 Haemodynamic variables at baseline Haemodynamic variable DBT (n = 17)a NE (n = 29)a VE/PLR (n = 24)a All interventions (n = 70)a Femoral dP/dtmax (mmHg s−1) 1049 ± 347 1319 ± 371 1162 ± 336 1199 ± 365 HR (beats min−1) 89 ± 14 92 ± 18 90 ± 15 90 (74–104) SAP (mmHg) 117 ± 17 137 ± 25 123 ± 14 127 ± 21 MAP (mmHg) 75 ± 7 84 ± 16 78 (75–84) 78 (70–86) PP (mmHg) 66 ± 17 80 ± 18 70 ± 11 73 ± 17 CVP (mmHg) 9±4 9 (8–12) 11 ± 4 9 (8-12) GEDVi (mL m−2) 749 ± 120 773 (684–878) 773 ± 146 750 (671–846) CI (L min−1 m−2) 2.7 ± 0.6 3.1 ± 1.2 3 (2.5–3.5) 3 (2.2–3.4) SVI (mL m−2) 31 ± 9 35 ± 14 32 (24–45) 32 (25–44) CFI ­(min−1) 3.9 ± 1.2 4.3 ± 1.6 4.4 ± 1.7 4.2 ± 1.6 LVEF (%) 43 ± 11 57 (42–61) 54 ± 17 50 ± 14 Ea (mmHg ml−1) 2 ± 0.5 2 (1.3–2.4) 1.9 (1.4–2.2) 1.9 (1.4–2.3) TAC (ml mmHg−1) 0.9 ± 0.3 0.8 (0.6–1.2) 0.8 (0.8–1.1) 0.8 (0.7–1.1) SVRi (dynes s cm−5 m−2) 1774 (1657–2379) 2241 ± 1078 1739 (1575–2172)b 1775 (1627–2404)b Data are presented as mean ± SD or median (25th–75th%) NE norepinephrine, VE/PLR volume expansion/passive leg raising, DBT dobutamine, HR heart rate, SAP systolic arterial pressure, MAP mean arterial pressure, PP pulse pressure, CVP central venous pressure, GEDVi global end-diastolic volume index, CI cardiac index, SVI stroke volume index, CFI cardiac function index, LVEF left ventricle ejection fraction, Ea effective arterial elastance, TAC​total arterial compliance, SVRi systemic vascular resistance index a n value refers to cases Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 5 of 10 Effects of dobutamine doses are presented in Additional file 1: Table S2 in the Changes in the dose of dobutamine (n = 17 interven- Supplemental Material. tions; absolute dose variation = 4.3 ± 1.3 µg kg−1 min−1) The dobutamine-induced per cent changes in femoral induced an absolute deviation from baseline in femo- dP/dtmax were significantly correlated with the per cent ral dP/dtmax of 21% and were correlated with changes changes in CFI, LVEF and CI, but presented the highest in femoral dP/dtmax (R = 0.62; p = 0.008). Changes from correlation with systolic arterial pressure and pulse pres- baseline were also observed in CFI (7%), LVEF (20%), sure (Additional file 1: Table S3). CI (12%) and heart rate (5%) (Table 3). SVI remained unchanged. While systolic arterial pressure and mean Effects of changes in norepinephrine dose arterial pressure values did not vary, pulse pressure Changes in the dose of norepinephrine changed by 20%. SVRi changed by 5%; however, Ea and (n = 29 interventions; absolute dose varia- TAC presented no significant change. GEDVi and CVP tion = 0.19 ± 0.16 µg kg−1 min−1) induced an abso- also remained unchanged (Table 3). lute change from baseline in femoral dP/dtmax of 15% When only one intervention per patient was con- and were correlated with changes in femoral dP/dtmax sidered, changes in the dose of dobutamine induced (R = 0.47; p = 0.011). Arterial systolic, mean and pulse an absolute deviation from baseline in femoral dP/ pressure also changed from baseline by 14, 11 and 9%, dtmax of 17% (1068 [748–1480] vs. 1254 [812–1672] respectively. There were no significant variations in heart ­mmHg−1 s−1; n = 8; p = 0.036). rate, CI and CFI (Table 3). LVEF presented a 11% change Increases in the dose of dobutamine increased femo- from baseline. Although SVI presented a significant ral dP/dtmax by 20% (Fig. 1; Additional file 1: Table S2) change of 4%, CI remained unchanged. CVP and GEDVi and reductions in the dose led to a decrease in femo- also remained at baseline levels. Estimated Ea, TAC and ral dP/dtmax of 28% (Fig. 1; Additional file 1: Table S2). SVRi changed by 9, 17 and 5%, respectively (Table 3). Additional data from haemodynamic changes obtained When only one intervention per patient was consid- before and after increases and decreases in dobutamine ered, changes in the dose of norepinephrine induced an absolute change from baseline in femoral dP/dtmax of 11% Table 3 Changes in haemodynamic variables during monitored interventions Haemodynamic variable DBT changes NE changes VE/PLR a a Mean P Mean P Mean Pa difference ± SD difference ± SD difference ± SD Femoral dP/dtmax (mmHg s−1) 201 ± 298 0.013 177 ± 136 < 0.001 59 ± 304 0.355 CFI ­(min−1) 0.3 ± 0.4 0.013 0.1 ± 0.2 0.124b 0.2 ± 0.4 0.042 LVEF (%) 7±5 < 0.001 5 ± 13 0.025b −1±4 0.309b CI (L min−1 m−2) 0.3 ± 0.5 0.031 0.1 ± 0.2 0.112 0.1 ± 0.4 0.153b b SVI (mL m ) −2 0.7 ± 3.7 0.163 1.2 ± 3 0.040 1.9 ± 4.1 0.028b HR (beats min ) −1 4±8 0.027 1±3 0.079 −2±5 0.019b SAP (mmHg) 7 ± 15 0.065 18 ± 14 < 0.001 11 ± 22 0.027 MAP (mmHg) 3±7 0.089 9±7 < 0.001 5 ± 14 0.092b PP (mmHg) 13 ± 10 < 0.001 6 ± 12 < 0.001b 6 ± 16 0.072 CVP (mmHg) 0±2 0.748 1±2 0.099b 3±3 0.001 GEDVi (mL m−2) 61 ± 244 0.535b 3 ± 86 0.380b − 17 ± 74 0.268 Ea (mmHg mL−1) 0.05 ± 0.2 0.403 0.18 ± 0.2 < 0.001b 0 ± 0.4 0.339b TAC (mL mmHg ) −1 0.01 ± 0.1 0.696 0.15 ± 0.1 0.001 0.03 ± 0.2 0.394b −5 −2 SVRi (dynes s cm m ) 94 ± 157 0.025 109 ± 210 0.009 32 ± 272 0.574 In norepinephrine and dobutamine cases, absolute mean differences are presented. These were calculated as absolute results from increases and decreases in catecholamine dose NE norepinephrine, VE/PLR volume expansion/passive leg raising, DBT dobutamine, CFI cardiac function index, LVEF left ventricle ejection fraction, CI cardiac index, SVI stroke volume index, HR heart rate, SAP systolic arterial pressure, MAP mean arterial pressure, PP pulse pressure, CVP central venous pressure, GEDVi global end- diastolic volume index, Ea effective arterial elastance, TAC​total arterial compliance, SVRi systemic vascular resistance index Significant results (p < 0.05) are highlighted in italics a Calculated with Student’s T test unless indicated b Calculated with Wilcoxon’s rank test Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 6 of 10 Fig. 1 Changes in femoral dP/dtmax. Femoral dP/dtmax before and after clinical interventions. Skewers indicate minimum and maximum value. NE norepinephrine, DBT dobutamine, VE/PLR volume expansion, passive leg raising. *p < 0.05; **p < 0.01 (1134 [909–1457] vs. 1265 [1028–1623] ­ mmHg−1 s−1; n = 13; p = 0.001). Increases in the dose of norepinephrine increased femoral dP/dtmax by 16% (Fig. 1 and Additional file 1: Table S2) and reductions in the dose led to a decrease in femoral dP/dtmax of 8% (Fig. 1 and Additional file 1: Table S2). Additional data from haemodynamic changes obtained before and after increases and decreases in norepinephrine doses are presented in Additional file 1: Table S2 (Fig. 2). The norepinephrine-induced per cent changes in fem- oral dP/dtmax were correlated with per cent changes in arterial systolic pressure, arterial pulse pressure, Ea and TAC (Additional file 1: Table S3). Effects of volume expansion and passive leg raising The PLR test and volume expansion (n = 24 interven- tions) did not induce significant changes in femoral dP/ dtmax. Heart rate decreased by − 3%, and systolic arterial pressure increased by 9%, while mean arterial pressure Fig. 2 Femoral dP/dtmax versus pulse pressure. Correlation between and pulse pressure remained unchanged. LVEF did not femoral dP/dtmax and pulse pressure (all interventions pooled) change, but CFI significantly increased by 4%. In this sub- group, CI did not change from baseline but SVI increased significantly by 5%. CVP increased by 30%, while GEDVi changes in pulse pressure and systolic arterial pressure remained at baseline values. Calculated Ea, TAC and (Additional file 1: Table S3). SVRi also remained unchanged (Table 3). When only one intervention per patient was consid- ered, PLR and volume expansion did not modify femo- Discussion ral dP/dtmax (1161 [858–1404] vs. 1218 [1105–1379] The present study evaluated changes in pulse contour ­mmHg−1 s−1; n = 14; p = 0.470). analysis-derived femoral dP/dtmax following haemody- The PLR and volume expansion-induced changes in namic interventions aimed at modifying LV systolic func- femoral dP/dtmax presented the highest correlation with tion and LV loading conditions (afterload and preload) Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 7 of 10 in critically ill patients with acute circulatory failure. and should therefore be more sensitive to changes in LV Changes in femoral dP/dtmax were strongly and consist- afterload. Our results support this hypothesis by evidenc- ently correlated with changes in arterial pressure wave- ing not only significant changes in femoral dP/dtmax dur- form determinants across all interventions (arterial ing changes in norepinephrine dose, but also significant systolic pressure and pulse pressure). While femoral dP/ correlations between changes in femoral dP/dtmax and dtmax changed during dobutamine infusion, thus suggest- changes in systolic and mean arterial pressure during ing a certain degree of relation with LV systolic function, such interventions. This demonstrates a dependence of femoral dP/dtmax also changed during norepinephrine femoral dP/dtmax with LV afterload, which may invalidate dose variations and was correlated with changes in arte- its utility as a marker of LV systolic function. rial systolic pressure, pulse pressure, TAC and Ea. Our An interesting additional finding of the present study results suggest that femoral dP/dtmax was mainly sensi- was the strong linear correlation observed between tive to ventricular loading conditions, specifically after- determinants of the arterial pressure waveform and fem- load, due to arterial load variations, and highly linked to oral dP/dtmax. Our results indicate that femoral dP/dtmax changes in arterial pressure waveform, thus making it an maintained an almost one-to-one relationship with arte- unreliable tool to estimate LV systolic function in acute rial pulse pressure and systolic arterial pressure, meaning circulatory failure. that any change in the latter inevitably led to a change in the former. In other words, the higher the amplitude of Femoral dP/dtmax and LV systolic function the arterial waveform, the higher the velocity of the pres- Pulse contour analysis is used at the bedside for esti- sure increase, provided that heart rate remains almost mating several haemodynamic variables. In particular, constant and vice versa (constant cardiac cycle dura- the arterial dP/dtmax is automatically displayed and is tion). As observed in our results, this relationship was thought by many to be an indicator of LV systolic func- strong and was observed even in cases where arterial tion. As expected, femoral dP/dtmax changed following loading conditions remained unchanged, such as during dobutamine increases and decreases and was related to volume expansion and PLR. Therefore, any haemody- the direction and magnitude of the dose variation. Fur- namic change affecting pulse pressure and systolic arte- thermore, although LVEF and CFI are not pure estima- rial pressure should, in principle, affect femoral dP/dtmax tors of LV systolic function, femoral dP/dtmax changed without any corresponding changes in LV contractility. It coherently with these markers during dobutamine dose has been previously described that arterial system com- variations. Note that we assessed the LV systolic func- pliance, pulse wave reflection and arterial system imped- tion not only with CFI, which is only an estimation of ance affect the peripheral arterial waveform [26–29]. We LVEF and which might be mathematically coupled with did not study pulse reflection waves in our patients, but GEDVi [23], but also more directly, with LVEF measured we were able to confirm this hypothesis in our study by by echocardiography. These results would suggest that identifying a strong correlation of femoral dP/dtmax with femoral dP/dtmax retains a certain degree of relationship determinants of arterial load (as estimated by Ea, TAC with LV systolic function. Also, it has been previously and SVRi) during norepinephrine dose variations. observed in animal models that LV dP/dtmax reflects car- diac contractility when adequate LV filling is achieved Femoral dP/dtmax in clinical practice [24, 25]. In our study, femoral dP/dtmax remained Our study challenges the previous belief that femoral unchanged during VE or PLR, which could be explained dP/dtmax could be used as a reliable marker of LV sys- by an optimised LV preload status at the time of the tolic function at the bedside. This belief was based on intervention. This finding would suggest that, similarly to the observed good correlation between LV and arterial what has been previously observed [24, 25], femoral dP/ dP/dtmax during periods of haemodynamic stability [7, 9, dtmax is independent from cardiac preload changes, as it 12]. However, correlations alone lack the sufficient value would be expected from a marker of LV systolic function. to inform on the responses of femoral dP/dtmax to treat- ments during cardiovascular failure. The evaluation of Femoral dP/dtmax, LV afterload and arterial load dynamic changes during haemodynamic challenges in Our results also indicated that femoral dP/dtmax is mark- our study demonstrates that although femoral dP/dtmax is edly influenced by changes in LV afterload (as estimated not completely independent from changes in LV systolic by changes in systolic and mean arterial pressure) during function, it is significantly affected by peripheral arterial changes in the dose of norepinephrine. Unlike LV dP/ properties and waveform characteristics. dtmax, which is measured during the isovolumetric phase Previous reports have also identified a strong relation- of LV contraction before aortic valve opening [2], femo- ship between femoral dP/dtmax and LV dP/dtmax during ral dP/dtmax takes place during the LV ejection phase isolated changes in LV systolic function, independently Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 8 of 10 from changes in LV loading conditions [10, 30]. In a interventions when only one measurement per patient recent study on healthy animals, Monge Garcia et al. was evaluated. Fifth, in order to obtain better informa- [31] presented a thorough evaluation of arterial dP/dtmax tion of potential causality and to homogeneously spread and its relation to LV dP/dtmax and other markers of LV the interventions across patients, it would have been systolic function during changes in cardiac inotropic better to have followed a crossover interventional study state, preload and afterload. Authors documented a posi- design. However, this would have been unethical, since tive relationship between femoral dP/dtmax and changes patients would have had to receive intravenous fluids, in LV systolic function, but also reported + 24% and norepinephrine and dobutamine regardless of any clini- − 33% changes in femoral dP/dtmax during increases or cal indication to receive such treatments. Sixth, respira- decreases in LV afterload induced by epinephrine and tory cycle variations may alter LVEF. This potential nitroprusside infusion, respectively, and a 20% reduc- source of bias was not taken into account when perform- tion in femoral dP/dtmax during acute preload reductions ing measurements. However, LVEF measurements were induced by bleeding. Although authors conclude that the averaged over three cardiac cycles, which attenuated most relevant factor of femoral dP/dtmax was the change any respiratory variation. Furthermore, measurements in LV systolic function, these observations also show the were obtained during periods of haemodynamic stability relevant effect of loading conditions on femoral dP/dtmax and under controlled mechanical ventilation or non-dis- and corroborate our findings. tressed spontaneous ventilation, such that the respira- Therefore, it is only in cases in which one could reason- tory variation of LVEF was probably negligible. Finally, a ably expect that arterial loading properties and LV after- potential mathematical coupling between the measure- load are unchanged, that LV systolic function is the only ment of femoral dP/dtmax and systolic arterial pressure factor modified and that femoral dP/dtmax might be used or pulse pressure could be a point of concern. However, as a marker of LV systolic function. It must be admitted with the PiCCO2 device used in our study, femoral dP/ that such cases are uncommon in a constantly changing dtmax was calculated at the moment of maximal pressure critically ill patient. rise in the systolic phase of the arterial curve and was not averaged during a time segment of the curve. This Limitations approach likely discarded any potential mathematical The present study has some limitations that warrant coupling. further discussion. First, the number of cases was small and the inclusion rate slow due to the need for specific recording equipment and need for manual synchronisa- Conclusions tion between interventions and data acquisition. Second, Femoral dP/dtmax calculated by pulse contour analysis we did not compare measurements of femoral dP/dtmax is an unreliable estimate of LV systolic function as it is with LV dP/dtmax. Nevertheless, the objective of the pre- markedly sensitive to LV afterload variations and changes sent study was to evaluate the responses of femoral dP/ in arterial loading properties during acute changes in dtmax during haemodynamic challenges, and values of LV norepinephrine, and directly linked to arterial waveform dP/dtmax would not have helped to fulfil such objective. characteristics. Furthermore, LV catheterisation for the only purpose of the study would not have been acceptable from an ethi- cal point of view. Alternatively, the estimation of LV dP/ dtmax by echocardiography could have been performed. Additional file However, such an estimation at the bedside in critically ill patients is far from easy and may have provided unreli- Additional file 1. This file contains a patient and interventions flow chart, additional information on population characteristics, pre- and post-inter‑ able measurements. Third, we did not use any device to vention values of haemodynamic variables for the norepinephrine and evaluate and compensate damping of the arterial pres- dobutamine groups, as well as a correlation matrix between femoral dP/ sure signal as utilised by previous authors [7]. However, dtmax and other haemodynamic variables during studied interventions. such devices present their highest utility when high reso- lution of the arterial waveform is required, for example, Abbreviations for resonance wave analyses, which was not the case in LV: left ventricle; PLR: passive leg raising; LVEF: left ventricle ejection fraction; CI: cardiac index; SVI: stroke volume index; GEDVi: global end-diastolic volume our study. Furthermore, the absence of under- and over- index; SVRi: systemic vascular resistance index; TAC​: total arterial compliance; damping phenomena was checked at the beginning of Ea: effective arterial elastance; CVP: central venous pressure; SD: standard recordings. Fourth, while repetition of measurements on deviation. the same patient could be considered as a source of bias, Acknowledgements we obtained the same pattern of responses to clinical None. Vaquer et al. Ann. Intensive Care (2019) 9:61 Page 9 of 10 Authors’ contributions 6. Sugawara M, Senda S, Katayama H, et al. Noninvasive estimation of left SV designed the study, collected data, analysed results and wrote the manu‑ ventricular Max(dP/dt) from aortic flow acceleration and pulse wave script. DC and XM analysed results and reviewed the manuscript. JLT reviewed velocity. Echocardiography. 1994;11:377–84. the manuscript. UA and FC collected data and reviewed the manuscript. JCO 7. Scolletta S, Bodson L, Donadello K, et al. Assessment of left ventricular provided statistical expertise and reviewed results and the manuscript. AO, AA function by pulse wave analysis in critically ill patients. Intensive Care and FB all reviewed the manuscript. XM and FB also oversaw the develop‑ Med. 2013;39:1025–33. ment of the study and mentored SV. All authors read and approved the final 8. Yang F, Iacobelli R, Ming J, et al. Assessment of cardiac function in infants manuscript. with transposition of the great arteries after surgery: comparison of two methods. World J Pediatr. 2018;14:373–7. Funding 9. Tartiere J-M, Logeart D, Beauvais F, et al. Non-invasive radial pulse wave This study was supported by the clinical institutions in which it was devel‑ assessment for the evaluation of left ventricular systolic performance in oped. The research team performed this study as part of their regular clinical heart failure. Eur J Heart Fail. 2007;9:477–83. work. 10. De Hert SG, Robert D, Cromheecke S, et al. Evaluation of left ventricular function in anesthetized patients using femoral artery dP/dt(max). J Availability of data and materials Cardiothorac Vasc Anesth. 2006;20:325–30. The datasets used and/or analysed during the current study are available from 11. Tartière JM, Tabet JY, Logeart D, et al. Noninvasively determined radial the corresponding author upon request. dP/dt is a predictor of mortality in patients with heart failure. Am Heart J. 2008;155:758–63. Ethics approval and consent to participate 12. Kim J, Bang J, Park CS, et al. 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