Arterial pressure allows monitoring the changes in cardiac output

induced by volume expansion but not by norepinephrine*

Xavier Monnet, MD, PhD; Alexia Letierce, PhD; Olfa Hamzaoui, MD; Denis Chemla, MD, PhD;
Nadia Anguel, MD; David Osman, MD; Christian Richard, MD; Jean-Louis Teboul, MD, PhD

Objective: To evaluate to which extent the systemic arterial
pulse pressure could be used as a surrogate of cardiac output for
assessing the effects of a fluid challenge and of norepinephrine.
Design: Observational study.
Setting: Medical intensive care unit.
Patients: Patients with an acute circulatory failure who received
a fluid challenge (228 patients, group 1) or in whom norepinephrine
was introduced or increased (145 patients, group 2).
Interventions: We measured the systolic, diastolic, and mean
arterial pressure, pulse pressure, and the transpulmonary ther-
modilution cardiac output before and after the therapeutic inter-
ventions.
Main Results: In group 1, the fluid challenge significantly
increased cardiac output by 24% ! 25%. It significantly increased
cardiac output by >15% ("35% ! 27%) in 142 patients (“re-
sponders”). The fluid-induced changes in cardiac output were
correlated with the changes in pulse pressure (r # .56, p <
.0001), systolic arterial pressure (r # .55, p < .0001), diastolic
arterial pressure (r # .37, p < .0001), and mean arterial pressure
(r # .52, p < .0001). At multivariate analysis, changes in pulse
pressure were significantly related to changes in stroke volume
(multiple r # .52) and to age (r # .12). A fluid-induced increase
in pulse pressure of >17% allowed detecting a fluid-induced
increase in cardiac output of >15% with a sensitivity of 65[56 –
72]% and a specificity of 85[76 –92]%. The area under the receiver
operating characteristic curves for the fluid-induced changes in
mean arterial pressure and in diastolic arterial pressure was
significantly lower than for pulse pressure. In group 2, the intro-
duction/increase of norepinephrine significantly increased car-
diac output by 14% ! 18%. The changes in cardiac output
induced by the introduction/increase in the dose of norepineph-
rine were correlated with the changes in pulse pressure and
systolic arterial pressure (r # .21 and .29, respectively, p # .001)
but to a significantly lesser extent than in group 1.
Conclusions: Pulse pressure and systolic arterial pressure
could be used for detecting the fluid-induced changes in cardiac
output, in spite of a significant proportion of false-negative cases.
By contrast, the changes in pulse pressure and systolic arterial
pressure were unable to detect the changes in cardiac output
induced by norepinephrine. (Crit Care Med 2011; 39:000 – 000)
KEY WORDS: fluid challenge; volume expansion; norepinephrine;
vasopressors; arterial pressure; cardiac output; arterial compli-
ance; pulse wave amplification

I n patients with an acute circula-
tory failure, the question whether
cardiac output should be moni-
tored or not is still a matter of
debate. Recent guidelines recommend to
*See also p. 000.
From the Service de Réanimation médicale (XM,
OH, NA, DO, CR, J-LT) and Unité de Recherche clinique
(AL), Hôpital de Bicêtre, AP-HP, Le Kremlin-Bicêtre;
Faculté de Médecine Paris-Sud (XM, OH, DC, NA, DO,
CR, J-LT), Univ Paris-Sud, Le Kremlin-Bicêtre; and
Service de Physiologie (DC), Hôpital Antoine Béclère,
AP-HP, Clamart, France.
Supplemental digital content is available for this ar-
ticle. Direct URL citations appear in the printed text and
are provided in the HTML and PDF versions of this article
on the journal’s Web site (http://www.ccmjournal.com).
Dr. Monnet and Dr. Teboul consulted for Pulsion.
The remaining authors have not disclosed any poten-
tial conflicts of interest.
For information regarding this article, E-mail:
xavier.monnet@bct.aphp.fr
Copyright © 2011 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e31820edcf0
measure cardiac output in patients with
ventricular failure or persistent shock de-
spite adequate fluid resuscitation (1). Al-
though these recommendations are not
supported by a high level of evidence,
they suggest that a “basic” hemodynamic
monitoring based on the sole arterial
pressure might be sufficient for monitor-
ing initial fluid resuscitation but insuffi-
cient for monitoring later resuscitation
with fluid and vasopressors (1).
Since it tends to maintain arterial pres-
sure stable while cardiac output varies, the
sympathetic regulation might preclude us-
ing arterial pressure for monitoring the
treatment-induced changes of cardiac out-
put. However, among the different values of
arterial pressure, the pulse pressure (PP,
i.e., the difference between systolic [SAP]
and diastolic [DAP] arterial pressure) is
physiologically related to stroke volume
(2). It might thus be able to reflect the
changes in cardiac output induced by dif-
ferent treatments. Nevertheless, the rela-
tionship between PP and stroke volume is
affected by two physiologic phenomena: the
arterial compliance and, if PP is measured
at the peripheral level, the pulse wave am-
plification phenomenon (3). Since vaso-
pressors might alter both arterial compli-
ance and pulse wave amplification to a
larger extent than volume expansion, the
ability of PP to reflect the changes in stroke
volume (and cardiac output) might be bet-
ter for fluid therapy than for vasopressors,
but this has never been demonstrated.
Thus, in the present study, we inves-
tigated to what extent PP could be used
for indicating absolute values and treat-
ment-induced changes of cardiac output
in a large population of patients with an
acute circulatory failure treated with
fluid and norepinephrine.
METHODS
Patients. This study was approved by our
institutional review board. A deferred consent
was asked from the patient’s surrogate as soon

Crit Care Med 2011 Vol. 39, No. 6 1

Table 1. Patients characteristics at baseline
Characteristic
Gender (no of patients, F/M)
Age (mean " SD, years)
Simplified acute physiology score II (mean " SD)
Type of shock (no of patients, %)
Septic
Hypovolemic
Post cardiac arrest
Drug poisoning
Other
Patients receiving NE at baseline (no. of patients, %)
NE dose at baseline (median &25%–75%
interquartile', #g/kg/min)
Acute respiratory distress syndrome (no. of patients, %)
There was no statistical difference between groups.
NE, norepinephrine.
as possible. As he/she recovered conscious-
ness, a deferred consent was asked from the
patient. If the patient or his/her next of kin
refused to consent, patient’s data were not
entered into analysis.
We included patients (1) if they presented
an acute circulatory failure defined by the
presence of at least one of the following crite-
ria: 1) SAP !90 mm Hg (or fall of SAP "50
mm Hg in patients previously known as hy-
pertensive), 2) urinary flow !0.5 mL/kg/min
for more than 2 hrs, 3) tachycardia "100
beats/min, or 4) presence of skin mottling and
(2) if a fluid challenge was administered
(group 1, n ! 228 patients) or if norepineph-
rine was introduced or its dose was increased
(group 2, n ! 145 patients, different from
patients of group 1), as ordered by the attend-
ing physician. The decision to administer fluid
and to introduce/increase the dose of norepi-
nephrine was based on standard care criteria
(e.g., positive fluid responsiveness indicators
for fluid, low arterial pressure for vasopres-
sors). Patients’ characteristics at baseline are
listed in Table 1. Twenty-two patients were not
ventilated. Among the overall 353 patients
who were intubated, 70 were ventilated in the
pressure support mode. Among the 283 re-
maining patients, all of whom were ventilated
in the assist control mode, 223 exhibited some
spontaneous triggering of the ventilator. In
patients ventilated in the assist-control mode,
tidal volume was 6.5% " 2.1% mL/kg.
Measurements. All patients had an internal
jugular vein catheter and a thermistor-tipped
arterial catheter (PV2015L20N, Pulsion Medi-
cal Systems, Munich, Germany) in the femoral
artery that was connected to a PiCCO-Plus or
a PiCCO-2 device (Pulsion Medical Systems,
Munich, Germany) for measuring cardiac out-
put through transpulmonary thermodilution.
The femoral arterial catheter was connected to
the pressure sensor PV8215 by a PV8215 mon-
2 Crit Care Med 2011 Vol. 39, No. 6
Patients With
Patients Receiving an Introduction/
Volume Expansion Increase of NE
(n ! 228) (n ! 145)
95/133 58/87
63 " 13 63 " 12
52 " 11 43 " 18
193 (85) 145 (100)
14 (6) 0 (0)
8 (4) 0 (0)
7 (3) 0 (0)
6 (2) 0 (0)
212 (93) 86 (59)
0.5 &0.3–1.1' 0.5 &0.2–0.7'
137 (61) 73 (50)
itoring kit (Pulsion Medical Systems, Munich,
Germany) and invasive arterial pressure was
measured by the PiCCO-Plus or PiCCO-2 de-
vice. Before all pressure measurements, the
arterial line was carefully flushed and zeroed
to atmospheric pressure. For the measure-
ment of cardiac output, the values of three
thermodilution measurements were averaged.
The PiCCO-Plus and the PiCCO-2 devices both
measure cardiac output and arterial pressure
in a similar way.
Study Design. Before fluid infusion in
group 1 and before the introduction/increase
in the dose of norepinephrine in group 2, a
transpulmonary thermodilution was per-
formed and the values of cardiac output,
stroke volume, global end-diastolic volume,
and extravascular lung water (all obtained
from transpulmonary thermodilution), the
values of SAP, DAP, mean arterial pressure
(MAP), and PP were recorded.
In group 1, a 500-mL saline bolus was
infused over 20 min. In this group, norepi-
nephrine was administered at baseline (in 228
patients) and its dose was unchanged during
fluid infusion. In group 2, norepinephrine was
introduced (in 59 patients) at a dose of 0.24
(0.13– 0.48) #g/kg/min or its dose was in-
creased (in 86 patients) from 0.48 (0.24 – 0.71)
#g/kg/min to 0.62 (0.43–1.07) #g/kg/min.
The values of cardiac output, stroke vol-
ume, global end-diastolic volume, and ex-
travascular lung water, the values of SAP,
DAP, MAP, and PP were also obtained after the
therapeutic intervention, i.e., immediately af-
ter fluid infusion in group 1 and 5 min after
the stabilization of MAP in group 2. Since
predicting fluid responsiveness is an impor-
tant issue in critically ill patients, we separated
patients in group 1 between “fluid responders”
and “fluid nonresponders.” A positive fluid re-
sponse was defined by a treatment-induced
increase in cardiac output of "15% (4 –7). We
also used some other definitions of the fluid
responsiveness: an increase in cardiac output
of "10%, an increase in stroke volume of
"15%, and an increase in stroke volume of
"10%.
Statistical Analysis. All continuous vari-
ables except the dose of norepinephrine were
normally distributed at Kolmogorov-Smirnov
test. Results are expressed as mean " SD, as
median (25%–75% interquartile range) or as
mean (95% confidence interval), as appropri-
ate. Comparisons of variables between before
vs. after fluid administration were assessed by
using a paired Student’s t test. Comparisons
between responders vs. nonresponders were
assessed by using a two-sample Student’s t test
or a Mann-Whitney U test, as appropriate. Cor-
relations were assessed by the Pearson coeffi-
cient and correlation coefficients were com-
pared between group 1 and group 2 using the
Fisher transformation (8). The correlation
analysis was also performed in the four quar-
tiles of age of the total population. A stepwise
regression analysis was performed to look for
independent variables related to the changes
in PP (in %). A p value of $.20 was necessary
for a variable to enter regression analysis.
Elsewhere, a p value of $.05 was considered
statistically significant. In group 1, receiver
operating characteristic (ROC) curves (with
95% confidence intervals) were constructed
for testing the ability of the fluid-induced
changes in SAP, DAP, MAP, and PP to predict
fluid responsiveness. The areas under the ROC
curves were compared using a Hanley-McNeil
test (9). Since the two groups of patients could
have different arterial pressures at baseline, we
also analyzed the data in a subpopulation of
each groups with matched baseline MAP (for
detailed methods, see Supplemental Digital
Content 1, http://links.lww.com/CCM/A228).
The statistical analysis was performed by using
the Statview5.0 software (Abacus Concepts,
Berkeley, CA) and the MedCalc8.1.0.0 software
(Mariakerke, Belgium).
RESULTS
Effects of the Therapeutic Interven-
tions on Hemodynamic Variables. In
group 1 (n ! 228 patients), volume ex-
pansion increased cardiac output by 24%
" 25% (p $ .05). It significantly in-
creased cardiac output of "15% (%35%
" 27%) in 142 patients (“responders”)
(Table 2). In the 86 remaining patients of
group 1 (“nonresponders”), volume ex-
pansion significantly increased cardiac
output by 7% " 5% (Table 2). In the
whole group 1, volume expansion in-
creased SAP, DAP, MAP, and PP by 15%
" 19%, 9% " 16%, 13% " 17%, and
21% " 29%, respectively (Table 2). The
magnitude of these changes was signifi-
cantly larger in responder than in nonre-
sponder patients (Table 2).
Table 2. Hemodynamic variables in patients receiving volume expansion (n ! 228)
Variable
Heart rate (mean "SD, beats/min)
Systolic arterial pressure (mean " SD, mm Hg)
Diastolic arterial pressure (mean " SD, mm Hg)
Mean arterial pressure (mean " SD, mm Hg)
Pulse arterial pressure (mean " SD, mm Hg)
Global end-diastolic volume (mean " SD, mL/m2)
Extravascular lung water (mean " SD, mL/kg
predicted body weight)
Cardiac index (mean " SD, L/min/m2)
“Responders” refers to patients in whom volume expansion increased cardiac index by "15% (n !
86). “Nonresponders” refers to the other patients (n ! 142).
a
p $ .05 vs. before volume expansion (comparisons in rows); bp $ .05 vs. nonresponders
(comparisons in columns).
Table 3. Hemodynamic variables in patients with an introduction/increase of norepinephrine
(n ! 145)
Variable
Heart rate (mean " SD, beats/min)
Systolic arterial pressure (mean " SD, mm Hg)
Diastolic arterial pressure (mean " SD, mm Hg)
Mean arterial pressure (mean " SD, mm Hg)
Pulse arterial pressure (mean " SD, mm Hg)
Global end-diastolic volume (mean " SD, mL/m2)
Extravascular lung water (mean " SD, mL/kg
predicted body weight)
Cardiac index (mean " SD, L/min/m2)
a
p $ .05 vs. before introduction/increase in NE (comparisons in rows).
In group 2 (n ! 145 patients), the
introduction/increase in dose of norepi-
nephrine increased cardiac output by
14% " 18% (p $ .05) (Table 3). In the
whole group 2, the introduction/
increase in the dose of norepinephrine
significantly increased SAP, DAP, MAP,
and PP by 46% " 30%, 9% " 16%,
38% " 24%, and 41% " 23%, respec-
tively (Table 3).
Relationship Between the Changes in
Arterial Pressure and the Changes
in Cardiac Output and Stroke Volume. In
group 1, the fluid-induced changes (in
%) in cardiac output were correlated
with the changes (in %) in PP (r ! .56,
p $ .0001) (Fig. 1), SAP (r ! .55, p $
.0001), DAP (r ! .37, p $ .0001), and
MAP (r ! .52, p $ .0001). The fluid-
induced changes (in %) in stroke vol-
Crit Care Med 2011 Vol. 39, No. 6
first quartile of age (from 36 to 53 yrs,
n ! 59), r ! .48 (p ! .0001) for the
Before Volume After Volume
second quartile of age (from 54 to 62
Category Expansion Expansion
yrs, n ! 50), r ! .54 (p $ .0001) for the
Nonresponders 92 " 23 90 " 22a third quartile of age (from 63 to 74 yrs,
Responders 98 " 22 96 " 21a,b n ! 70), r ! .68 (p $ .0001) for the
Nonresponders 107 " 24 115 " 26a fourth quartile of age (from 75 to 88
Responders 109 " 21 129 " 23a,b yrs, n ! 49).
Nonresponders 52 " 13 55 " 13a
Responders 53 " 13 59 " 13a,b
In group 2, the changes (in %) in
Nonresponders 71 " 16 75 " 16a cardiac output induced by the introduc-
Responders 71 " 14 82 " 16a,b tion/increase in dose of norepinephrine
Nonresponders 56 " 19 60 " 20a were correlated with the changes (in %)
Responders 56 " 18 70 " 18a,b in PP (r ! .21, p ! .001, Fig. 2), SAP (r !
Nonresponders 703 " 185 808 " 280a
Responders 649 " 203b 766 " 264a,b .29, p ! .004), and MAP (r ! .21, p !
Nonresponders 11 " 5 11 " 5 .01) but not in DAP (r ! .13, p ! .12).
All these correlations were significantly
Responders 10 " 6 10 " 5 lower than in group 1 (p ! .0001, .003,
Nonresponders 3.2 " 1.0 3.4 " 1.1a and .0007 for the changes in PP, SAP,
Responders 2.7 " 0.9b 3.5 " 1.1b
and MAP, respectively). The changes (in
%) in stroke volume induced by the
introduction/increase in dose of norepi-
nephrine were correlated with the
changes (in %) in PP (r ! .17, p ! .04),
SAP (r ! .18, p ! .003), and MAP (r !
.17, p ! .04) but not in DAP (r ! (.01,
p ! .92). All these correlations were
significantly lower than in group 1 (p !
Before Introduction/ After Introduction/ .0007, .007, and .02 for the changes in
Increase of Increase of
PP, SAP, and MAP, respectively). Multi-
Norepinephrine Norepinephrine
variate analysis indicated that the
97 " 22 96 " 21 changes in PP (in %) were related to the
83 " 14 120 " 21a changes (in %) in stroke volume (r !
39 " 7 52 " 9a .17) but not to age.
54 " 8 75 " 10a Ability of the Changes in Arterial
45 " 14 67 " 22a
692 " 137 735 " 154a
Pressure to Detect Fluid Responsiveness
10 " 4 10 " 5 in Group 1. The ability of the changes in
the different values of arterial pressure to
3.1 " 1.0 3.5 " 1.1a detect a fluid-induced increase in cardiac
output of "15% in group 1 is described
in Table 4 and Figure 2. The fluid-
induced changes in PP and in SAP exhi-
bited the best diagnostic values, with
ume were correlated with the changes similar areas under the ROC curves. A
(in %) in PP (r ! .49, p $ .0001), SAP fluid-induced increase in PP of "17%
(r ! .44, p $ .0001), DAP (r ! .25, p ! allowed detecting a fluid-induced in-
.0002), and MAP (r ! .39, p $ .0001). crease in cardiac output of "15% with a
There was not statistical difference be- sensitivity of 65% (95% confidence inter-
tween the r coefficients found for the val: 56%–72%) and a specificity of 85%
correlation between changes in cardiac (95% confidence interval: 76%–92%),
output and change in PP on the one i.e., with 6% and 22% of false-positive
side and for the correlation between and false-negative cases, respectively. The
changes in cardiac output and changes area under the ROC curves for the fluid-
in SAP on the other side. Multivariate induced changes in MAP and for the flu-
analysis indicated that the changes in id-induced changes in DAP was signifi-
PP (in %) were significantly related to cantly lower than for the fluid-induced
the changes in stroke volume (r ! .52) changes in PP (Table 4). The areas under
and to age (r ! .12). When the popula- the ROC curve describing the ability of
tion was divided in 4 quartiles of age, the fluid-induced changes in PP to detect
the changes (in %) in PP were related to a fluid-induced increase in cardiac output
the changes (in %) in stroke volume for of "15% were not different among pa-
all quartiles with different coefficients tients belonging to the first, the second,
of correlation: r ! .40 (p ! .002) for the the third, and the fourth age quartiles
3
 A B DISCUSSION
*
This study suggests that PP and SAP
r = 0.56 r = 0.21
300
n = 228
300
n = 145 could be used for detecting the changes

by the introduction/increase in NE
in cardiac output induced by a fluid chal-
Changes in PP (in %) induced

Changes in PP (in %) induced

250 250
lenge, in spite of a significant proportion
by the fluid challenge

200 200
of false-negative cases in which PP and
150 150
SAP did not change while cardiac output
100 100 increased. By contrast, the changes in PP
50 50 and SAP were unable to detect the
0 0
changes in cardiac output induced by the
norepinephrine.
-50 -50
-50 0 50 100 150 200 250 300 -50 0 50 100 150 200 250 300 When taking care of patients with cir-
Changes in CO (in %) induced Changes in CO (in %) induced culatory shock, the question is frequently
by the fluid challenge by the introduction/increase in NE pending whether cardiac output must be
Figure 1. Correlation between the changes in arterial pulse pressure (PP, in % change from baseline) monitored or if a basic monitoring with
and cardiac output (CO, in % change from baseline) induced by a fluid challenge (A, n ! 228 pairs of the sole arterial pressure will be suffi-
measurements) and by the introduction or increase in dose of norepinephrine. (B, n ! 145 pairs of cient. International guidelines recom-
measurements). *p ! .0001 vs. r in A. mend monitoring cardiac output in pa-
tients with shock refractory to initial
100 fluid therapy (1), but this is not sup-
ported by a substantial scientific back-
ground. The goal of the present study was
80 to provide some physiologic basis to this
guideline.
In the first place, our study indicates
Sensitivity (%)

60
that the different values of arterial pres-
sure are not equivalent for monitoring
the treatment-induced changes in stroke
40
Diagnostic ability of
volume or cardiac output. Physiologi-
the fluid-induced changes (in %) in: PP cally, the changes in MAP are dissociated
20 SAP
from the changes in cardiac output due
to the sympathetic modulation of the ar-
MAP
terial tone, which tends to maintain MAP
0
DAP constant while cardiac output varies (10).
0 20 40 60 80 100 According to this physiologic paradigm,
100-Specificity (%) we found that the changes in MAP were
Figure 2. Receiving Operating Characteristics curves describing the ability of the fluid-induced unable to reflect the changes in cardiac
changes (in %) in arterial pulse (PP) and systolic (SAP), diastolic (DAP), and mean (MAP) arterial output induced either by fluid infusion or
pressure to detect a fluid-induced increase in cardiac index of "15%. by the introduction or increase in norepi-
nephrine. In particular, the introduction/
increase in norepinephrine augmented
(0.81 " 0.05, 0.78 " 0.07, 0.78 " 0.05, Influence of Baseline Arterial Pres- MAP to a large extent, but this was re-
and 0.80 " 0.06, respectively). Similar sure. The analysis of the subsets of groups lated to arterial vasoconstriction and not
results were obtained when using dif- 1 and 2 matched for baseline MAP showed correlated with a simultaneous change in
ferent definitions of fluid responsive- similar results than in the whole popula- stroke volume or cardiac output.
ness (see Supplemental Digital Content tion (see Supplemental Digital Content, Another physiologic paradigm is that,
1, http://links.lww.com/CCM/A228). http://links.lww.com/CCM/A228). in contrast with MAP, PP is directly re-

Table 4. Diagnostic ability of the fluid-induced changes in arterial pressures values to detect a fluid-induced increase in cardiac index of "15% in patients
receiving fluid infusion (group 1)

Area Under the Positive Negative

Receiver Operating p vs. Best Cutoff Predictive Predictive Youden
Variable Characteristic Curve .500 Value Sensitivity Specificity Value Value Index

Changes in arterial pulse pressure 0.784 " 0.03 .0001 17% 65 &56–72' 85 &76–92' 88 &80–93' 59 &50–68' 0.50
Changes in systolic arterial pressure 0.757 " 0.03 .0001 8% 74 &66–81' 67 &57–77' 79 &71–85' 61 &51–71' 0.41
Changes in mean arterial pressure 0.692 " 0.04a .001 13% 46 &38–55' 84 &74–91' 82 &72–90' 49 &40–57' 0.30
Changes in diastolic arterial pressure 0.598 " 0.04a .01 11% 67 &29–45' 83 &73–90' 78 &66–87' 44 &37–52' 0.50

n ! 228, mean " SD or mean &95% confidence interval'.

a
p $ .05 vs. changes in arterial pulse pressure.

4 Crit Care Med 2011 Vol. 39, No. 6

lated to stroke volume (2). In theory, PP
might thus be a better candidate for mon-
itoring the changes in cardiac output at
the bedside (3). However, PP is also in-
versely correlated with arterial compli-
ance, which might differ among patients
and might change over time in a same
patient (11). Furthermore, the propor-
tionality between PP and stroke volume is
physiologically expected at the aortic
level but not at the peripheral arterial due
to the pulse wave amplification phenom-
enon (2). In the present study, we quan-
tified the extent to which these two phys-
iologic issues preclude to use the changes
in PP for detecting the changes in stroke
volume and cardiac output.
In group 1, the fluid-induced changes
in PP were significantly correlated with
the fluid-induced changes in cardiac out-
put. These results are in line with those
of previous small human studies in which
a decrease in PP paralleled the decrease
in stroke volume induced by graded low
body negative pressure (12) or compres-
sion of the right atrium (13). In our
study, the correlation with the fluid-
induced changes in PP was not better for
the fluid-induced changes in stroke vol-
ume than for the fluid-induced changes
in cardiac output, since heart rate was
not decreased to a large extent by volume
expansion in our study population. In
turn, the changes in PP exhibited a good
diagnostic accuracy for detecting fluid re-
sponsiveness. This indicates that PP was
an acceptable surrogate of cardiac output
for assessing the effects of fluid therapy.
Since DAP was only slightly modified by
volume expansion, SAP (i.e., the sum of
DAP and PP) exhibited a similar diagnos-
tic accuracy.
Although the fluid-induced changes in
PP and SAP and in cardiac output were
significantly correlated, these correla-
tions were not excellent (r ! .56 and .55,
respectively). This might be related to the
physiologic issues of arterial compliance
and pulse wave amplification phenome-
non (10). According to this hypothesis,
we found that the coefficient of correla-
tion between changes in PP and in stroke
volume induced by the fluid challenge
was lower in the youngest patients, in
whom the arterial compliance was as-
sumed to be higher and the pulse wave
amplification lower than in the oldest.
In group 2, it is not surprising that
norepinephrine increased DAP and MAP,
which are related to the arterial tone (3).
By contrast, an interesting finding was
that the relationship between PP and car-
Crit Care Med 2011 Vol. 39, No. 6
diac output was poor. This indicates that
changes of mechanical properties of the
arterial system induced by norepineph-
rine, including arterial compliance and
pulse wave amplification, were so marked
that PP could not be used for tracking
trends in cardiac output. Nevertheless, an
important limitation of our study was
that we did not precisely investigate arte-
rial compliance and the pulse wave am-
plification phenomenon.
As a clinical application, the present
study clarifies in which manner clinicians
should use arterial pressure for monitor-
ing therapy during circulatory failure,
with very different attitudes regarding
fluid and vasopressors. The results sug-
gest that when PP increases "17% with
fluid administration, the clinician can be
reasonably confident that a patient is
fluid responsive (6% of false-positive
cases only). By contrast, if PP does not
increase "17%, the high number of
false-negative cases (22%) precludes
drawing any reasonable conclusion con-
cerning fluid responsiveness. This issue
might be particularly relevant when per-
forming repetitive fluid challenges, a pro-
cedure that has been recently revisited
(14). Underestimating the response of
cardiac output to fluid boluses might
clearly lead to fluid under-resuscitation.
Concerning the monitoring of norepi-
nephrine administration, PP cannot be
used for assessing the effects that norepi-
nephrine can exert on stroke volume (15,
16). However, despite our results might
change routine practice, their clinical
relevance is highly limited by the fact
that this study was not designed for evi-
dencing any different impact of arterial
pressure vs. cardiac output monitoring
on outcome. This issue should be inves-
tigated in further studies.
Some monitoring devices use the
physiologic relationship between the am-
plitude of the arterial curve and stroke
volume for estimating cardiac output
from an arterial line. For this purpose,
these devices estimate arterial compl-
iance and vasomotor tone from a complex
analysis of the arterial pressure curve
and, for some of these systems, with help
of an external calibration (17). In accor-
dance with our results, the fact that
changes in arterial compliance and/or va-
somotor tone are more marked with nor-
epinephrine than with fluid therapy
might explain why some systems have
greater difficulty to reliably estimate the
changes in cardiac output when induced
by norepinephrine than by volume expan-
sion (17).
To summarize, the changes in PP or
SAP but not in MAP could help for de-
tecting the hemodynamic effects of a
fluid challenge. If PP increased "17%
during the fluid challenge, one may sup-
pose with acceptable confidence that car-
diac output increased "15%. By contrast,
if PP did not increase "17% during the
fluid challenge, one could not ascertain
that cardiac output did not improve. The
changes in PP or SAP could not be used
for monitoring the effects of norepineph-
rine on cardiac output.
ACKNOWLEDGMENTS
We are greatly indebted to Prof. Lau-
rence Meyer, from the Department of
Epidemiology and Public Health of
Bicêtre Hospital, for her help in statis-
tical analysis.
REFERENCES
1. Antonelli M, Levy M, Andrews PJ, et al: He-
modynamic monitoring in shock and impli-
cations for management. International Con-
sensus Conference, Paris, France, 27–28
April 2006. Intensive Care Med 2007; 33:
575–590
2. Chemla D, Hébert JL, Coirault C, et al:
Total arterial compliance estimated by
stroke volume-to-aortic pulse pressure ra-
tio in humans. Am J Physiol 1998; 274:
H500 –H505
3. Lamia B, Chemla D, Richard C, et al: Clinical
review: Interpretation of arterial pressure
wave in shock states. Crit Care 2005;
9:601– 606
4. Michard F, Boussat S, Chemla D, et al: Rela-
tion between respiratory changes in arterial
pulse pressure and fluid responsiveness in
septic patients with acute circulatory failure.
Am J Respir Crit Care Med 2000; 162:
134 –138
5. Monnet X, Osman D, Ridel C, et al: Predict-
ing volume responsiveness by using the end-
expiratory occlusion in mechanically venti-
lated intensive care unit patients. Crit Care
Med 2009; 37:951–956
6. Monnet X, Rienzo M, Osman D, et al: Esoph-
ageal Doppler monitoring predicts fluid re-
sponsiveness in critically ill ventilated pa-
tients. Intensive Care Med 2005; 31:
1195–1201
7. Monnet X, Rienzo M, Osman D, et al: Passive
leg raising predicts fluid responsiveness in
the critically ill. Crit Care Med 2006; 34:
1402–1407
8. Fisher RA: Statistical Methods for Research
Workers. Fourteenth Edition. Edinburgh,
London, UK, Oliver & Boyd, 1970
9. Hanley JA, McNeil BJ: A method of compar-
ing the areas under receiver operating char-
5
 acteristic curves derived from the same
cases. Radiology 1983; 148:839 – 843
10. Nichols W, O’Rourke M: Contours of pressure
and flow waves in arteries. In: Blood Flow in
Arteries. Nichols W, O’Rourke MS (Eds). London,
UK, Oxford University Press; 1998, pp 170–200
11. O’Rourke B: Evidence for mitochondrial K%
channels and their role in cardioprotection.
Circ Res 2004; 94:420 – 432
12. Convertino VA, Cooke WH, Holcomb JB: Ar-
terial pulse pressure and its association with
reduced stroke volume during progressive
6 Crit Care Med 2011 Vol. 39, No. 6
central hypovolemia. J Trauma 2006; 61:
629 – 634
13. Marquez J, McCurry K, Severyn DA, et al:
Ability of pulse power, esophageal Doppler,
and arterial pulse pressure to estimate rapid
changes in stroke volume in humans. Crit
Care Med 2008; 36:3001–3007
14. Vincent JL, Weil MH: Fluid challenge re-
visited. Crit Care Med 2006; 34:1333–1337
15. Hamzaoui O, Georger JF, Monnet X, et al:
Early administration of norepinephrine in-
creases cardiac preload and cardiac output in
septic patients with life-threatening hypoten-
sion. Crit Care 2010; 14:R142
16. Monnet X, Jabot J, Maizel J, et al: Norepi-
nephrine increases cardiac preload and re-
duces preload dependency assessed by pas-
sive leg raising in septic shock patients Crit
Care Med 2011; In Press
17. Monnet X, Anguel N, Naudin B, et al: Arterial
pressure-based cardiac output in septic pa-
tients: Different accuracy of pulse contour
and uncalibrated pressure waveform devices.
Crit Care 2010; 14:R109