Journal of Critical Care 72 (2022) 154141

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Journal of Critical Care

journal homepage: www.journals.elsevier.com/journal-of-critical-care

Dynamic changes of pulse pressure but not of pulse pressure variation

during passive leg raising predict preload responsiveness in critically
ill patients with spontaneous breathing activity
Rui Shi, MD, PhD a,b, Francesca Moretto, MD a, Dominique Prat, MD c, Frederic Jacobs, MD c,
Jean-Louis Teboul, MD, PhD a,b, Olfa Hamzaoui, MD c,⁎
a
Université Paris-Saclay, AP-HP, Service de médecine intensive-réanimation, Hôpital de Bicêtre, DMU CORREVE, FHU SEPSIS, Le Kremlin-Bicêtre, France
b
INSERM-UMR_S999 LabEx - LERMIT, Hôpital Marie-Lannelongue, 92350 Le Plessis Robinson, France
c
Service de réanimation polyvalente, Hôpital Antoine Béclère, AP-HP Université Paris-Saclay, Clamart, France

a r t i c l e i n f o a b s t r a c t

Article history: Purpose: To evaluate whether the changes in arterial pulse pressure (PP) and/or pulse pressure variation (PPV)
Received 14 July 2022 during passive leg raising (PLR) can be used to evaluate preload responsiveness in patients with spontaneous
Received in revised form 17 August 2022 breathing activity.
Accepted 22 August 2022 Materials and methods: Patients ventilated with pressure support mode or totally spontaneously breathing were
Available online xxxx
prospectively included. The values of PP and PPV were recorded before and at the end of PLR. The changes in car-
diac index (CI) or the velocity-time integral (VTI) of the left ventricular outflow tract during PLR were tracked by
Keywords:
Pulse pressure
the pulse contour analysis or transthoracic echocardiography. Patients exhibiting an increase in CI ≥ 10% or VTI ≥
Fluid responsiveness 12% during PLR were defined as preload responders.
Heart-lung interaction Results: Among 33 patients included, 28 (80%) received norepinephrine and 14 were preload responders. The in-
crease in PP > 2 mmHg in absolute value (4% in percentage) during PLR (PLRPP) predicted preload responsiveness
with an area under the receiver operating characteristic (AUROC) of 0.76 ± 0.09 (p = 0.003 vs. AUROC of 0.5).
The changes in PPV during PLR, however, failed to predict preload responsiveness (p = 0.82 vs. AUROC of 0.5).
Conclusion: In patients with full spontaneous breathing activity, PLR-induced changes in PP had a fair ability to
assess preload responsiveness even when norepinephrine was administered.
Registration number:ClinicalTrials.gov (NCT04369027).
© 2022 Elsevier Inc. All rights reserved.

1. Introduction ventilated patients if the tidal volume is at least 8 mL/kg, and is no lon-
ger valid if patients develop spontaneous breathing activity [3]. In such
Current guidelines recommend using dynamic over static parame- cases, PLR is the only test, among all the indices/tests, that can be used
ters to predict fluid responsiveness after the initial phase of resuscita- [4,5]. However, PLR needs a real-time cardiac output measurement to
tion [1]. Pulse pressure variation (PPV), passive leg raising (PLR), and assess its hemodynamic effect [6] which makes its use restricted to a
end-expiratory occlusion test are frequently used to predict preload re- limited category of patients. Nevertheless, recent studies showed that
sponsiveness at the bedside in critically ill patients [2]. However, one the decrease in PPV during PLR could help to discriminate preload re-
should be aware that every test has its advantages and its limitations sponders from non-responders in situations where PPV alone failed to
[2]. PPV is a reliable indicator of fluid responsiveness in mechanically do it, such as low tidal volume ventilation [7,8] or persistent spontane-
ous breathing activity during mechanical ventilation [9]. In addition, we
Abbreviations: AUROC, Area under the receiver operating characteristic; CI, Cardiac know from physiology that arterial pulse pressure (PP) reflects stroke
index; Crs, Compliance of the respiratory system; FiO2, Fraction of inspired oxygen; IAP, volume for a constant aortic compliance [10] and that changes in PP
Intra-abdominal pressure; ICU, Intensive care unit; PLR, Passive leg raising; PP, Pulse pres- after fluid infusion are correlated to changes in cardiac index [11]. Ex-
sure; PPV, Pulse pressure variation; ROC, Receiver operating characteristic; TTE, trapolating all these results to patients with spontaneous breathing,
Transthoracic echocardiography; VTI, Velocity-time integral.
⁎ Corresponding author at: Service de Réanimation Polyvalente, Hôpital Antoine
our current study aims at investigating the ability of a decrease in PPV
Béclère, 157, rue de la porte de Trivaux, 92141 Clamart, France. during PLR (PLRPPV) and of an increase in PP during PLR (PLRPP) for
E-mail address: olfa.hamzaoui@aphp.fr (O. Hamzaoui). predicting preload responsiveness.

https://doi.org/10.1016/j.jcrc.2022.154141
0883-9441/© 2022 Elsevier Inc. All rights reserved.
R. Shi, F. Moretto, D. Prat et al. Journal of Critical Care 72 (2022) 154141

2. Materials and methods 2.4. Statistical analysis

This is a prospective study conducted in the intensive care unit (ICU) Demographic variables are presented as frequency (percentage) and
from two tertiary hospitals (Bicêtre and Antoine Béclère). The study was mean ± standard error (SD) or median (interquartile range) as appro-
approved by the local ethics committee -Comité de Protection des priate. The results of receiver operating characteristic (ROC) data were
Personnes, Ile-de-France X, N°: 2018-A00727–48) and was registered presented as the area under the ROC curve (AUROC) ± SD (with a
on ClinicalTrials.gov (NCT04369027). Informed consent was obtained 95% confidence interval), sensitivity (with a 95% confidence interval),
from all patients or next-of-kin. and specificity (with a 95% confidence interval). The AUROC of the
changes in PPV was 0.78 for the prediction of preload responsiveness
in the study by Hamzaoui et al. in ventilated patients with spontaneous
2.1. Patients ventilation cycles [9]. We thus calculated the sample size requirement
for comparing the expecting AUROC (from the previous study) curve
We included adult patients with acute circulatory failure admitted with the null hypothesis of 0.50, assuming an α error of 0.05 and
into ICU. All the included patients needed to be already equipped with power of 80%. In total, at least 30 cases were required to be included.
either a pulse contour analysis device (PiCCO2 Getinge, Sweden) or if Comparisons between time points were performed by a paired Student
not, a radial or femoral arterial line. Patients could be either ventilated t-test or a Wilcoxon rank-sum test. The ROC curves were used to deter-
with a pressure support mode or non-intubated and spontaneously mine the predictive performance of the studied indices to discriminate
breathing. Exclusion criteria were: age ≤ 18 years; pregnancy; agitation; between PLR+ and PLR- cases. The AUROC curve and 95% of confidence
the presence of arrhythmia; venous compression stockings; poor interval were given. Comparisons between AUROC curves were per-
echogenicity if using the echocardiography, defined as the inability to formed by using Delong et al. method [15]. The Youden index (sensitiv-
correctly align the Doppler beam to obtain reliable Doppler measure- ity + specificity − 1) was used to define the optimal cut-off values for
ments. each variable. The gray zone analyses were performed to define the
values presenting with either sensitivity <90% or specificity <90% (di-
2.2. Measurements agnosis tolerance of 10%) [16]. A p-value <0.05 was considered statisti-
cally significant. Statistical analysis was performed using MedCalc
In patients already equipped with a PiCCO2 device, the continuous 11.6.0 software (Mariakerke, Belgium).
pulse contour analysis-derived cardiac index (CI) was obtained. In pa-
tients with no PiCCO2 device, the velocity-time integral (VTI) of the 3. Results
left ventricular outflow tract was measured by using transthoracic echo-
cardiography (TTE). The ventilator settings if any, the fraction of in- 3.1. Patient characteristics
spired oxygen (FiO2), and the flow rate of high flow nasal cannula,
simple mask, or nasal cannula were adjusted by the attending We prospectively included 35 patients (mean age: 64 ± 15 years,
physician. Demographic and other hemodynamic parameters, 57% of men) with acute circulatory failure between September 2019
including heart rate, and arterial blood pressure were recorded. The and April 2022. The mean time interval between admission and inclu-
use of vasopressors and their dosage and blood lactate concentrations sion in the study was 2 (0–6) days. Nine patients (26%) were under me-
were also collected. chanical ventilation with a pressure support mode, five patients (14%)
were under high-flow oxygen therapy, four patients (11%) had a nasal
cannula or a face mask, and 17 patients (49%) were under the room
2.3. Design of the study air. Most of the patients received norepinephrine (n = 28; 80%). The
main patient characteristics at baseline were presented in Table 1.
For every patient, PLR was performed as described in the previous
literature [6]. The patient was orally informed about what this maneu- 3.2. Detection of preload responsiveness
ver consisted of. The changes in CI during PLR were tracked by using
the pulse contour analysis if the PiCCO2 device was in place. If not, Fourteen patients had a positive PLR test and were thus defined as
TTE was performed to track the changes in VTI of the left ventricular preload responders. Baseline hemodynamic parameters were not differ-
outflow tract during PLR. Considering the average threshold value ent in PLR+ group and PLR- group (Table 2). PPV detected preload re-
found for PLR to define preload responsiveness in the literature (10%) sponsiveness with an AUROC curve of 0.58 ± 0.10 (0.40–0.75, p =
[12] and knowing that the least significant change is higher for VTI 0.41 vs. AUROC of 0.5) (Fig. 1) There was no difference observed be-
(11% with one operator) [13] than for pulse contour CI (<2%) [14], an tween PLR+ and PLR- regarding the PLRPPV (−0.8 ± 3.7 vs. 0.4 ± 3.4,
increase in pulse contour CI ≥ 10% or in VTI ≥ 12% defined a positive
PLR test (PLR+) (i.e., preload responsiveness). The absence of an in-
Table 1
crease in pulse contour CI ≥ 10% or in VTI ≥ 12% defined a negative PLR General characteristics of patients.
test (PLR-) (i.e., preload unresponsiveness). At baseline, patients were
Variables All patients
in the semi-recumbent position. At baseline and during PLR, we col-
(n = 35)
lected heart rate, systolic arterial pressure, diastolic arterial pressure,
and mean arterial pressure. Arterial PP was calculated as the systolic ar- Age (years) 65 ± 15
Male (n, %) 20 (57)
terial pressure minus the diastolic arterial pressure. The value of PPV
Sepsis/septic shock (n, %) 31 (88)
was automatically calculated and directly displayed on the screen of Hypovolemic shock (n, %) 3 (9)
the monitors. Baseline hemodynamic data were collected just before Body mass index (kg/m2) 25.0 (21.5–26.3)
the PLR test. Then, PLR was performed by raising the lower limbs and SAPS II at admission 46 ± 16
Lactate at admission (mmol/L) 1.6 (1.3–2.7)
lowering the upper body in the meantime using an automatic bed ele-
Use of vasopressors (n, %) 28 (80)
vation technique [15]. At the end of one minute of PLR, the second set Norepinephrine dose (mcg/kg/min) 0.30 (0.13–0.53)
of measurements was recorded. The ventilator settings if any and the ICU length of stay (days) 8 (5–19)
vasoactive therapies were kept constant throughout the study period. ICU mortality (n, %) 7 (28)
Only one operator at each center (RS and OH) performed echocardiog- Values are expressed as mean ± SD or median (interquartile range) or number (percent-
raphic measurements. All the analyses were performed offline. age). ICU, intensive care unit; SAPS II, Simplified Acute Physiology Score II.

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R. Shi, F. Moretto, D. Prat et al. Journal of Critical Care 72 (2022) 154141

Table 2
Evolution of hemodynamic variables in preload responsive cases (PLR+) and non-respon-
sive cases (PLR-).

Variables PLR+ (N = 14) PLR- (N = 21)

Baseline End Baseline End

HR (beats/min) 103 ± 19 101 ± 16 95 ± 19 94 ± 19

SAP (mmHg) 115 ± 16 125 ± 14* 121 ± 20 124 ± 21*
DAP (mmHg) 54 ± 10 58 ± 10* 54 ± 9 56 ± 9*
MAP (mmHg) 74 ± 7 80 ± 9* 78 ± 11 80 ± 11*
Pulse pressure (mmHg) 60 ± 16 67 ± 16* 68 ± 19 69 ± 20
PPV (%) 10 ± 5 9±4 13 ± 8 12 ± 7
PCCI (L/min/m2)** 2.76 ± 0.89 3.25 ± 1.05* 3.17 ± 1.13 3.17 ± 1.19
VTI (cm)*** 16 ± 4 20 ± 4* NA NA

Values are expressed as mean ± SD or median (interquartile range) or number (percent-

age). DAP, diastolic arterial pressure; HR, heart rate; MAP, mean arterial pressure; PCCI,
pulse contour cardiac output index; PLR, passive leg raising; PPV, pulse pressure variation;
SAP, systolic arterial pressure; VTI, the velocity-time integral of the left ventricular outflow
tract. *P < 0.05 End vs. Baseline; ¤ p < 0.05 PLR+ vs. PLR-; ** N = 7 in PLR+ group ***N = 7
in PLR+ group.

p = 0.77). The PLRPPV failed to discriminate between PLR+ and PLR- Fig. 2. Sensitivity and specificity of the changes in pulse pressure induced by the passive
cases with an AUROC curve of 0.52 ± 0.11 (0.35–0.70, p = 0.82 vs. leg raising. Gray zone represents uncertain zone with cut-off values with a sensitivity of
AUROC of 0.5) (Fig. 1). The changes in PP in the group of PLR+ were sig- <90% or a specificity of <90%.
nificantly higher than the changes in the group of PLR- (7.3 ± 9.3 vs. 1.0
± 3.9, p = 0.009). The PLRPP helped to discriminate between PLR+ and
PLR- cases with an AUROC of 0.76 ± 0.09 (0.59–0.89) with a cut-off (44%–98%) and a specificity of 88% (62%–98%) (p = 0.001 vs. AUROC
value of >2 mmHg (increase by >4% in percentage as compared with of 0.5).
the baseline value) (sensitivity: 71% (42%–92%); specificity: 76% (53%–
92%); p = 0.003 vs. AUROC of 0.5, p = 0.041 vs. AUROC of PLRPPV).
The gray zone ranged between 0 and 6, in which 17 (49%) patients 4. Discussion
were situated (Fig. 2). The baseline and change during PLR of the stud-
ied hemodynamic variables are given in Table 2. The main findings of our study are that in patients with spontaneous
When only non-intubated patients (26/35) were considered, the breathing activity, the increase in PP of equal to or higher than 2 mmHg
AUROC for PLRPP was 0.83 ± 0.10 (0.63–0.95) with a sensitivity of 80% during PLR may be helpful to discriminate preload responders from
non-responders with fair accuracy. However, the absolute decrease in
PPV values during PLR failed to make such discrimination.
Among all the indices of preload responsiveness, PPV has been one
of the most studied and the most used in patients who receive mechan-
ical ventilation. Nevertheless, several conditions limit the interpretation
of PPV [3,17] and thus its utility in some specific settings in clinical prac-
tice. The two major limitations that hinder the applicability of PPV are
the use of low tidal volume ventilation and, the existence of spontane-
ous breathing activity in non-intubated patients [18] or under pressure
support mode [19]. To overcome the misleading interpretation of PPV,
Taccheri et al. showed that in patients under controlled mechanical ven-
tilation but with a low tidal volume, a decrease in PPV during PLR (here
used as a preload challenge) nearly perfectly predicted fluid responsive-
ness (mean AUROC = 0.98) while PPV did not (mean AUROC = 0.66)
[9]. We also recently investigated whether the dynamic changes in
PPV during PLR might help to assess preload responsiveness in patients
under mechanical ventilation but with persistent spontaneous breath-
ing activity [9]. We found that a decrease in PPV during PLR in such pa-
tients significantly better predicted preload responsiveness than
baseline PPV alone, with a mean AUROC of 0.78 vs. 0.61, respectively
[9]. In our present study, the decrease in PPV during PLR failed to dis-
criminate preload responders from non-responders (mean AUROC =
0.52). This may be explained by the fact that spontaneous breathing
alone or in a pressure support mode is characterized by irregular respi-
ratory cycles with variable amplitude and then variable effects on intra-
thoracic pressure making it difficult to unmask preload responsiveness
[20]. Besides, the influence of respiratory muscle activity should also
be considered as spontaneous inspiratory efforts might increase intra-
abdominal pressure (IAP) due to active compression of abdominal mus-
Fig. 1. Receiver operating characteristic (ROC) curves showing the predictive ability of cles, exaggerating the preload response [21]. In this regard, Monge
baseline pulse pressure variation (PPV baseline), changes of pulse pressure during passive
leg raising (PLRPP) and changes of pulse pressure variation during passive leg raising
Garcia et al. tried to use PPV calculated during a Valsalva maneuver to
(PLRPPV) to discriminate between preload responsive patients and non-responsive predict fluid responsiveness [22]. They found that PPV during a 10-s of
patients. Valsalva maneuver had a very good predictive performance with an

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R. Shi, F. Moretto, D. Prat et al. Journal of Critical Care 72 (2022) 154141

AUROC of 0.98 ± 0.03 [22]. Similarly, Préau et al. reported a very good were considered into analysis, the predictive performance of PLRPP
predictive performance of PPV (AUROC = 0.95 ± 0.05) in patients remains good, although further studies designed for this specific group
with strictly spontaneous breathing activity by using a deep inspiration of patients are warranted to confirm the results.
maneuver [23]. Such results were confirmed thereafter in another study
[24]. Thus, to overcome the limitation of PPV in patients with strictly 5. Conclusion
spontaneous breathing, it may be possible to use a forced respiratory
maneuver. However, such a forced respiratory maneuver is hard to be In patients with spontaneous breathing activity, PLR-induced
standardized in all patients, particularly in patients suffering from respi- changes in PP had a fair ability to assess preload responsiveness even
ratory failure. Recently, Mallat et al. conducted a multicentre, observa- when norepinephrine is administered. However, the changes in PPV
tional, prospective study [7], including patients who were during PLR are unreliable to assess preload responsiveness.
mechanically ventilated either on volume-controlled mode or on pres-
sure support mode. The study showed that changes in PPV induced by Funding
PLR had an excellent predictive performance with an AUROC of 0.92
[7], confirming the results reported by Taccheri et al. in a single-center No applicable.
study [8]. It is noteworthy that in the Mallat et al. study, 32 patients
(12%) were on pressure support ventilation with spontaneous breath-
Authors' contributions
ing activity, and the results in this subset of patients were also good
[7]. In our present study, only nine patients (26%) were invasively ven-
O·H conceived the study, R.S., F.M.,D.P., F.J., and O·H performed the
tilated with a pressure support mode and due to this low number of pa-
collection of data, R.S. and O·H analyzed and interpreted the data, and
tients, we cannot provide any statistics and thus give firm conclusion for
drafted the manuscript. J.-L.T. contributed to the conception, to the in-
this category of patients. It is noteworthy that Mallat et al. also were
terpretation of the data, and to drafting the manuscript.
cautious for the interpretation of changes in PPV during PLR in patients
All authors read and approved the final manuscript.
under pressure support ventilation [7].
The interesting finding of our study is that the increase in PP during
PLR predicted preload responsiveness with a fair mean AUROC of 0.77 CRediT authorship contribution statement
and with a relatively large gray zone. Préau et al. conducted a study in
34 non-intubated patients suffering from sepsis and severe pancreatitis Rui Shi: Data curation, Formal analysis, Investigation, Software,
[25]. In this study, an increase in PP ≥9% during a PLR test, was able to Writing – original draft. Francesca Moretto: Investigation, Data
distinguish fluid responders from non-responders with a good accuracy curation. Dominique Prat: Investigation, Data curation. Frederic Ja-
(mean AUC = 0.86) [25]. It is noteworthy that most of their patients re- cobs: Investigation, Data curation. Jean-Louis Teboul: Conceptualiza-
ceived no vasopressors, which might explain the better performance of tion, Supervision, Validation, Writing – review & editing. Olfa
PLR-induced changes in PP in their study [25] in comparison with our Hamzaoui: Conceptualization, Data curation, Investigation, Methodol-
study where 80% of patients received norepinephrine. As we know ogy, Project administration, Supervision, Validation, Writing – review
from physiology, the main determinants of aortic PP are SV and aortic & editing.
compliance [10]. Therefore, changes in PP might reflect changes in SV
if aortic compliance remains constant. However, norepinephrine by Declaration of Competing Interest
augmenting the reflection wave phenomenon [26] may augment the
aortic PP for a given SV so that changes in aortic PP may overestimate Dr. Olfa Hamzaoui is a member of the medical advisory board of
changes in SV induced by norepinephrine. Monnet et al. evaluated the AMOMED.
ability of peripheral PP to be used as a surrogate of cardiac output for Dr. Jean-Louis Teboul is a member of the medical advisory board of
assessing the effects of a fluid challenge and of norepinephrine [11]. In Pulsion/Getinge.
the subgroup of 228 patients who received fluids, the fluid-induced
changes in PP were fairly correlated to those in CI. In the subgroup of References
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