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doi: 10.1093/bja/aev222
Advance Access Publication Date: 6 July 2015
Critical Care
CRITICAL CARE
Department of Anesthesiology and Critical Care Medicine, Centre Hospitalier du Dr. Schaffner de Lens, France,
and 2Department of Anesthesiology and Critical Care Medicine, Centre Hospitalier Universitaire de Lille, France
Abstract
Background: Dynamic indices, such as pulse pressure variation (PPV), are inaccurate predictors of uid responsiveness in
mechanically ventilated patients with low tidal volume. This study aimed to test whether changes in continuous cardiac index
(CCI), PPV, and stroke volume variation (SVV) after a mini-uid challenge (100 ml of uid during 1 min) could predict uid
responsiveness in these patients.
Methods: We prospectively studied 49 critically ill, deeply sedated, and mechanically ventilated patients (tidal volume <8 ml
kg1 of ideal body weight) without cardiac arrhythmias, in whom a uid challenge was indicated because of circulatory failure.
The CCI, SVV (PiCCO; Pulsion), and PPV (MP70; Philips) were measured before and after 100 ml of colloid infusion during
1 min, and then after the additional infusion of 400 ml during 14 min. Responders were dened as subjects with a 15% increase
in cardiac index (transpulmonary thermodilution) after the full (500 ml) uid challenge. Areas under the receiver operating
characteristic curves (AUCs) and the grey zones were determined for changes in CCI (CCI100), SVV (SVV100), and PPV (PPV100)
after 100 ml uid challenge.
Results: Twenty-two subjects were responders. The CCI100 predicted uid responsiveness with an AUC of 0.78. The grey zone
was large and included 67% of subjects. The SVV100 and PPV100 predicted uid responsiveness with AUCs of 0.91 and 0.92,
respectively. Grey zones were small, including 12% of subjects for both indices.
Conclusions: The SVV100 and PPV100 predict uid responsiveness accurately and better than CCI100 (PiCCO; Pulsion) in
patients with circulatory failure and ventilated with low volumes.
Key words: cardiac output; uid therapy; goal-directed therapy; haemodynamics; monitoring; pulse pressure
449
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| Mallat et al.
Methods
This prospective single-centre observational study was conducted
in a general adult intensive care unit (ICU) after approval by our
local institutional ethics committee (Lens Hospital, France).
Informed consent was obtained from each subjects next of kin.
Subjects
We studied deeply sedated and mechanically ventilated patients
without spontaneous breathing (as attested by the ow curve on
the ventilator). Volume therapy was decided by the physician
based on the presence of one or more of the following sign(s) of
acute circulatory failure:18 (i) systolic arterial pressure <90 mm Hg,
mean arterial pressure <65 mm Hg, or the need for vasopressor infusion; (ii) skin mottling; and (iii) lactate concentrations >2 mM or
(iv) urine output <0.5 ml kg1 h1 for 2 h. Subjects had also to be
monitored by the PiCCO device (PiCCO; Pulsion Medical System,
Munich, Germany) as part of routine management of persistent
signs of tissue hypoperfusion. Exclusion criteria were as follows:
tidal volume 8 ml kg1 of IBW {with IBW (in kilograms) determined
as follows: x+0.91[height (in centimetres)152.4], where x=50 for
males and x=45.5 for females}, pregnancy, age <18 yr, moribund,
Measurements
Subject characteristics, the aetiology of acute circulatory failure,
the Simplied Acute Physiology Score (SAPS) II, and the Sequential
Organ Failure Assessment (SOFA) scores were obtained on the day
of enrolment. Ventilator settings with airway pressures and
inspiratory oxygen fraction were recorded. Static respiratory compliance (Crs) was calculated as follows: Crs (in millilitres per centimetre of water)=tidal volume/(plateau pressure end-expiratory
pressure). Driving pressure was determined as the difference between the plateau pressure and the end-expiratory pressure. The
cardiac index was obtained with the PiCCO device by central venous injection of iced 0.9% saline solution (20 ml) in triplicate and
then averaged. We also recorded CCI, which was measured by
pulse-contour analysis after calibration. In addition, heart rate
(HR), systemic arterial pressures, and end-expiratory central
venous pressure (zero referenced to the mid-axillary line) were
collected. The SVV and PPV were obtained online using the
PiCCO monitor and the Philips IntelliVue MP70 monitor (Philips
Medical Systems, Suresne, France), respectively. Transthoracic
echocardiography was performed before the beginning of the
study (EnVisor HD; Philips ultrasound system, Philips Healthcare,
DA Best, The Netherlands), and left ventricular ejection fraction
was determined by the Simpson method.20
Study protocol
The uid challenge was administered via a separate venous line.
A set of cardiovascular measurements was obtained at baseline,
including HR, systemic arterial pressures, central venous pressure, SVV, PPV, CCI ( pulse-contour) and cardiac index (transpulmonary thermodilution). A 100 ml colloid solution (4% human
serum albumin, Vialebex; LFB, Paris, France) was infused during
1 min, and cardiovascular measurements were repeated immediately after this bolus administration. The remaining 400 ml of colloid solution was then infused at a constant rate during 14 min,
and cardiovascular measurements were repeated.
Changes in CCI (CCI100) induced by the mini-uid challenge
were expressed as relative changes. Changes in SVV (SVV100)
and PPV (PPV100) were expressed as absolute differences
( parameter after 100 ml minus parameter before 100 ml), as
previously described.17
Statistical analysis
According to the changes in the thermodilution-derived cardiac
index after 500 ml volume expansion, subjects were classied
as responders (15% increase in cardiac index) or non-responders. Data are expressed as mean (), or as median [2575%
interquartile range (IQR)], as appropriate. Normality was evaluated using the KolmogorovSmirnov test. Differences between
responders and non-responders were assessed by two-tailed Students t-test or MannWhitney U-test, as appropriate. Comparisons within groups were assessed using Students paired t-test
or Wilcoxon test, as appropriate. Analysis of categorical data
used the 2 or Fishers exact test. Correlations were tested by
using the Pearson or the Spearman test, as appropriate. To adjust
for the phenomenon of regression to the mean, absolute changes
in CCI, SVV, and PPV between baseline and after the mini-uid
challenge were also analysed by performing an analysis of covariance (), with the absolute changes in these variables
Changes in pulse pressure variation after a mini-uid challange predict uid responsiveness
of PPV, SVV, and CCI (one value each minute) displayed on the
monitor at times when the haemodynamic status was stable.
The coefcient of variation was then calculated for each collection and averaged for the series of 15 sets. The precision was calculated as two times the coefcient of variation, and the least
signicant change (LSC) as precision time 2. The LSC characterizes the minimal change that a device needs to measure in
order to detect a real change.
Results
We studied 49 subjects, whose characteristics are summarized in
Table 1. The major cause of acute circulatory failure was septic
shock (94%). All subjects were sedated and mechanically ventilated, without spontaneous breathing. Sedation level and vasopressor infusion were kept constant during volume expansion.
No subjects had right ventricular dilatation (dened by the ratio
of right-to-left ventricular diameter >0.6) or paradoxical septal
motion by echocardiography.
There were 22 (45%) responders dened by an increase in the
thermodilution cardiac index of >15% after volume expansion of
500 ml. No signicant differences were found in subject characteristics, heart rate-to-respiratory rate ratio, or tidal volume between
responders and non-responders except for driving pressure,
plateau pressure, and lactate concentrations, which were higher,
and Crs, which was lower in non-responders (Table 1).
Table 1 Characteristics of the population and comparison between responders and non-responders. Crs, respiratory system compliance; FIO2 ,
inspired oxygen fraction; HR, heart rate; IBW, ideal body weight; ICU, intensive care unit; IQR, interquartile range; LVEF, left ventricular
ejection fraction; PaCO2 , arterial carbon dioxide partial pressure; PaO2 , arterial oxygen partial pressure; RR, respiratory rate; SAPS, Simplied
Acute Physiology Score; SBE, standard base excess; SOFA, Sequential Organ Failure Assessment; VT, tidal volume. Data are expressed as
mean (), median (2575% interquartile range), or count (%)
Characteristic
Responders (n=22)
Non-responders (n=27)
P-value
64 (2679)
26.6 (4.6)
29/20
66 (20)
10 (614)
24 (49)
6.8 (6.47.3)
8 (610)
22 (1725)
32.3 (25.146.9)
24 (49)
13.8 (4.6)
4.4 (3.35.4)
55 (9)
7.35 (7.237.38)
5.05 (4.265.32)
30.2 (14.8)
6.2 (9.8 to 1.5)
2.1 (1.23.6)
45 (92)
1.0 (0.31.6)
61 (2679)
25.8 (4.40)
16/6
64 (17)
10 (611)
10 (45)
6.8 (5.67.3)
6 (510)
17 (1425)
45.2 (26.755.9)
6 (27.3)
12.0 (4.6)
4.4 (3.46.0)
57 (9)
7.32 (7.237.38)
4.79 (4.265.32)
34.0 (17.8)
7.8 (9.8 to 1.9)
1.9 (1.03.1)
20 (91)
1.0 (0.41.6)
66 (4778)
27.3 (4.8)
13/14
67 (22)
10 (614)
14 (52)
6.8 (6.47.6)
8 (710)
23 (2027)
28.8 (23.735.7)
18 (66.7)
15.3 (4.2)
4.2 (3.25.0)
52 (9)
7.36 (7.217.39)
5.05 (4.265.45)
26.6 (10.4)
5.0 (11.9 to 1.1)
2.3 (1.44.8)
25 (93)
1.2 (0.31.7)
0.53
0.23
0.08
0.58
0.34
0.12
0.55
0.10
0.008
0.009
0.006
0.012
0.28
0.90
0.84
0.24
0.1
0.39
0.06
1.00
0.78
46 (94)
3 (6)
21 (95)
1 (5)
25 (93)
2 (7)
1.00
1.00
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| Mallat et al.
variables were similar between the two groups (Table 2). Volume
expansion decreased SVV and PPV only in responders. Nevertheless, HR did not change signicantly after volume expansion. The
AUCs for baseline SVV and PPV, when predicting uid responsiveness, were 0.52 [(95% CI: 0.340.66); P=0.84] and 0.62 [(95%
CI: 0.480.76); P=0.12], respectively.
After volume
expansion
Discussion
The main ndings were as follows: (i) CCI100 after a rapid infusion of 100 ml of colloid solution has a reasonable accuracy to
predict a 15% increase in cardiac index after a 500 ml infusion;
(ii) this approach, however, has limited clinical application as reected by a large grey zone including 67% of subjects; and (iii) the
ability of SVV100 and PPV100 induced by mini-uid challenge to
detect uid responsiveness was excellent and higher than
CCI100, with smaller inconclusive zones.
Two recent studies, using echocardiography, suggested that
infusion of a very limited amount of uid during a very short
We found signicant changes between responders and nonresponders after the rst infusion of 100 ml for all tested haemodynamic variables except for HR (Table 3). In responders,
mini-uid challenge increased CCI by 8.6% and decreased PPV
and SVV by 4 and 3%, respectively. The mini-uid challenge induced absolute changes in CCI, PPV, and SVV that were signicantly greater in responders than in non-responders (,
P=0.001, P<0.001, and P<0.001, respectively). Furthermore, after
adjusting to static respiratory compliance and plateau pressure,
these change were still signicantly different between the two
groups (, P=0.005, P<0.001, and P<0.001, respectively).
Before volume
expansion
Changes in pulse pressure variation after a mini-uid challange predict uid responsiveness
| 453
Table 3 Changes in haemodynamic parameters between after and before mini-uid challenge (100 ml of colloid). Data are expressed as
median (2575 interquartile range; IQR) or mean (). All changes in haemodynamic parameters are expressed as relative changes, except for
stroke volume variation and pulse pressure variation, for which absolute differences are reported (see Methods)
Parameter
Responders (n=22)
Non-responders (n=27)
P-value
3 (5 to 2)
4 (4 to 2)
8.6 (4.516.2)
9.5 (5.114.0)
1.8 (4.1)
3.7 (1.5 to 19.8)
4.6 (0.314.6)
6.2 (010.9)
5.1 (011.5)
0 (1 to 1)
0 (01)
0 (0.05.4)
0 (0.06.0)
1.9 (4.3)
0 (7.0 to 10.6)
2.0 (5.7 to 6.5)
2.1 (4.9 to 4.0)
1.4 (7.7 to 4.0)
<0.001
<0.001
<0.001
<0.001
0.93
0.08
0.051
0.020
0.017
Sensitivity
1.0
100
0.8
80
0.6
60
Se
Sp
40
0.4
DSVV100
DPPV100
DCCI100
Reference Line
0.2
20
0.0
0.0
0.2
0.4
0.6
0.8
1.0
Test scale
1-Specificity
DPPV100 (%)
DCCI100 (%)
100
100
Se
Sp
80
80
60
60
40
40
20
20
0
7
3
1
Test scale
0
20 15 10 5
Se
Sp
5 10 15 20 25 30 35 40
Test scale
Fig 1 () Receiver operating characteristic (ROC) curves for SVV100 (%), PPV100 (%), and CCI100 (%) after infusion of 100 ml uid during 1 min. Two-graph ROC curves:
sensitivity (Se) and specicity (Sp) of mini-uid challenge-induced changes in stroke volume variation (SVV; ), pulse pressure variation (PPV; ), and continuous
cardiac index (CCI; ) according to the value of the cut-off for the detection of more than 15% increase in cardiac index after volume expansion. The inconclusive
zone, which is >10% of diagnosis tolerance, is represented as a shaded rectangle. SVV100 is the changes in stroke volume variation after 100 ml of uid challenge.
PPV100 is the changes in pulse pressure variation after 100 ml of uid challenge. CCI100 is the changes in continuous cardiac index variation after 100 ml of uid
challenge.
DSVV100 (%)
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| Mallat et al.
Table 4 Predictive values of 100 ml of uid challenge-induced changes in haemodynamic parameters to detect a more than 15% increase in
cardiac index. AUC, area under the curve; CCI, continuous cardiac index; DAP, diastolic arterial pressure; MAP, mean arterial pressure; PP,
pulse pressure; PPV, pulse pressure variation; SAP, systolic arterial pressure; SVV, stroke volume variation
Parameter
AUC
95% Condence
interval
P-value
Cut-off
(%)
Sensibility
(%)
Specicity
(%)
Grey zone
Patients in the
grey zone (%)
0.91
0.92
0.78
0.66
0.70
0.70
0.65
0.800.97
0.810.98
0.640.88
0.520.82
0.550.82
0.550.82
0.480.76
<0.001
<0.001
<0.001
0.038
0.013
0.001
0.12
2
2
5.2
2.4
4.7
1.7
5.2
86
86
77
86
62
81
95
89
85
74
44
81
55
40
2.5 to 1.4
2.6 to 1.3
1.56 to 12.6
5.6 to 12.2
6.2 to 10.0
4.6 to 11.6
4.8 to 11.3
4 (8%)
6 (12%)
33 (67%)
32 (65%)
29 (60%)
28 (57)
28 (57)
Changes in pulse pressure variation after a mini-uid challange predict uid responsiveness
Conclusion
In spite of a relatively fair predictive value, CCI100, as measured
with the pulse-contour analysis technique (PiCCO device), may
be inconclusive in two-thirds of patients and should not be
used routinely as a predictor of uid responsiveness in the ICU
in patients with acute circulatory failure. However, SVV100 and
PPV100 are able to detect uid responders in mechanically ventilated patients with low tidal volume with excellent sensitivity
and specicity and grey zones of 10% of the subjects.
Authors contributions
Study conception: J.M., L.T., D.T.
Study design: J.M., M.M., E.D.
Patient recruitment and data collection: J.M., M.M., E.D., M.L., F.P.,
J.T., N.V.
Acquisition, analysis, and interpretation of data: all authors.
Statistical analysis: J.M.
Drafting the manuscript: J.M., B.T.
Revising the draft, reading, and approval of the nal manuscript
for publication: all authors.
Acknowledgements
The authors thank the nursing staff of the intensive care unit.
Without their participation, this work would not have been
possible.
Declaration of interest
None declared.
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3. Tavernier B, Makhotine O, Lebuffe G, Dupont J, Scherpereel P.
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89: 131321
4. Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and uid responsiveness in septic patients with acute circulatory failure. Am J
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Supplementary material
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