Prediction of volume responsiveness in critically ill patients with

spontaneous breathing activity

Jean-Louis Teboul and Xavier Monnet
Medical Intensive Care Unit, Research Unit EA 4046,
Bicetre Teaching Hospital, Paris-11 University,
Le Kremlin-Bicetre, France
Correspondence to Professor Jean-Louis Teboul,
Service de Reanimation medicale, Centre Hospitalier
Universitaire de Bicetre, 78, rue du General Leclerc,
94 270 Le Kremlin-Bicetre, France
Tel: +33 1 45 21 35 47; fax: +33 1 45 21 35 51;
e-mail: jean-louis.teboul@bct.aphp.fr
Current Opinion in Critical Care 2008, 14:334
339
Purpose of review
Predicting volume responsiveness in patients with spontaneous breathing activity is a
difficult challenge in the emergency room as well as in the intensive care unit because
heartlung interactions indices cannot be reliably used as they can be in mechanically
ventilated patients fully adapted to their ventilator. The aim of this review is to summarize
the different tools that have been proposed to predict the hemodynamic response to
fluid infusion in the presence of spontaneous breathing activity.
Recent findings
Clinical studies recently demonstrated that neither indicators of cardiac preload (filling
pressures and end-diastolic ventricular dimensions) nor arterial pulse pressure
respiratory variation was an accurate predictor of volume responsiveness in patients
with spontaneous breathing activity with or without mechanical support. In contrast,
performing a passive leg-raising test has been proved as valuable for this purpose.
Summary
The passive leg-raising test is the only method that has been repeatedly shown to be
reliable for predicting volume responsiveness in patients who experience spontaneous
breathing. The appropriate utilization of this test requires a real-time assessment of its
effects on systemic blood flow.

Keywords
passive leg raising, spontaneous breathing, volume responsiveness

Curr Opin Crit Care 14:334339

2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295

Campaign [2] recently proposed levels of central venous

Introduction
Assessing volume responsiveness in patients with spon-
taneous breathing is of variable difficulty depending on
the clinical context. Three different situations can be
distinguished.
The first situation refers to patients admitted in the
emergency room for acute body fluid losses. The diagnosis
of hypovolemia is almost certain. The degree of hypoten-
sion and tachycardia is important for estimating the degree
of hypovolemia and hence the degree of urgency to initiate
volume resuscitation.
The second situation refers to patients admitted in the
emergency room for high suspicion of severe sepsis or
septic shock. In this context in which hypovolemia
(relative and absolute) is always present, volume resuscita-
tion must be urgently undertaken [1]. There is no need for
searching sophisticated parameters to predict fluid respon-
siveness as a positive hemodynamic response is always
present at this phase. Rather, there is a need for defining
parameters that are able to indicate whether volume
infusion should be either continued or stopped because
of no further expected efficacy. The Surviving Sepsis
pressure (CVP) of 8 mmHg in nonintubated patients and of
12 mmHg in patients receiving positive pressure venti-
lation as volume resuscitation endpoints. These levels
have, however, been arbitrarily defined, and there are
no published proofs of their validity.
The third situation refers to patients hospitalized in the
intensive care unit who experience hemodynamic instabil-
ity that requires urgent therapy. In these patients, volume
responsiveness is not guaranteed as they have already been
volume resuscitated and as continuation of fluid infusion
carries risks of pulmonary edema. In spontaneously breath-
ing patients with or without mechanical support, predict-
ing volume responsiveness is a difficult challenge since
heartlung interactions indices have been suspected to be
no longer reliable [3].
Do static measures of cardiac preload predict
volume responsiveness?
The decision to give fluid to a patient with spontaneous
breathing activity could be based intuitively upon the
assessment of preload by static markers: the more the
marker is low, the more fluid responsiveness is likely to

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exist. The reliability of such markers for predicting fluid
responsiveness is, however, doubtful.
Analysis of the literature
Considering the FrankStarling relationship (ventricular
preload versus stroke volume), the response to volume
infusion is more likely to occur when the ventricular pre-
load is low than when it is high. It is the reason why markers
of ventricular preload have been proposed to predict
fluid responsiveness.
Cardiac filling pressures
Ventricular filling pressures, namely CVP or right atrial
pressure (RAP) for the right ventricle and pulmonary
artery occlusion pressure (PAOP) for the left ventricle,
have been first proposed for the issue of the guidance of
volume resuscitation.
Central venous pressure and right atrial pressure
Although numerous studies [35,6,7] addressed the
question of whether CVP or RAP can predict volume
responsiveness in critically ill patients, a few of them
included only patients with spontaneous breathing activity
[5,7]. In these studies, RAP did not appear as a valuable
predictor of volume responsiveness. Coudray et al. [4], who
reviewed studies that included mixed populations of
patients (mechanically ventilated and spontaneous breath-
ing), also concluded that neither CVP nor RAP could
accurately predict volume responsiveness in any category
of critically ill patients.
Pulmonary artery occlusion pressure
The PAOP is the pressure obtained after inflating the
distal balloon of a pulmonary artery catheter in a large
branch of the pulmonary artery. As a static column is
created between the inflated balloon and the venous site
where the blood flow resumes, PAOP is assumed to reflect
the pressure in a large pulmonary vein and thus the left
atrial pressure [8]. Provided that measurements are
reliable, PAOP is considered as a measure of left ventri-
cular preload. Numerous studies addressed the question of
whether PAOP can predict volume responsiveness in
critically ill patients [35,6]. Nevertheless, few of them
included a great number of patients with spontaneous
breathing activity. In the studies reviewed by Coudray
et al. [4], no relationship between the preinfusion PAOP
and the hemodynamic response to fluid infusion was
found. The same conclusion was derived by Heenen
et al. [5], who investigated fluid responsiveness only in
patients with spontaneous breathing activity.
In summary, cardiac filling pressures are poor predictors
of volume responsiveness in patients with spontaneous
breathing activity [4,5,7] as well as in patients receiving
controlled positive pressure ventilation [3,6].
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Volume responsiveness in critically ill Teboul and Monnet 335
End-diastolic ventricular dimensions
As ventricular end-diastolic dimensions are considered as
better indicators of cardiac preload than filling pressures
[9], measurements of ventricular dimensions have been
also proposed to predict volume responsiveness.
Right ventricular and left ventricular end-diastolic
volumes
From the review by Coudray et al. [4], neither the right
ventricular end-diastolic volume (RVEDV) nor the left
ventricular end-diastolic volumes appear as a good pre-
dictor of volume responsiveness in patients with spon-
taneous breathing activity.
Left ventricular end-diastolic area
The left ventricular end-diastolic area (LVEDA)
measured by echocardiography was shown to be a poor
predictor of fluid responsiveness in the only study [10]
that addressed this issue in patients with spontaneous
breathing activity.
Global end-diastolic volume
The global end-diastolic volume (GEDV) is obtained by
the transpulmonary thermodilution method (PiCCO
monitoring system). To our knowledge, there is no study
investigating the accuracy of GEDV to predict volume
responsiveness in patients with spontaneous breathing
activity. It must be remembered that the GEDV was not
found to be valuable to predict the hemodynamic
response to fluid infusion in cardiac surgery patients
receiving mechanical ventilation [11].
Why do static markers of cardiac preload fail to predict
volume responsiveness?
There are two kinds of reasons explaining failure of
markers of preload to predict volume responsiveness:
the first reason is that the markers commonly used at
the bedside are not always accurate measures of cardiac
preload; the second reason is that an assessment of pre-
load is not an assessment of preload responsiveness.
Markers of preload are not always accurate
measures of cardiac preload
This is particularly the case in the following situations:
(1) In the presence of mitral valvulopathy, PAOP can
be higher than the left ventricular end-diastolic pres-
sure. The value measured just before the v wave
upraise must be taken as an estimate of left ventricular
end-diastolic pressure in case of mitral insufficiency.
(2) In the presence of positive end-expiratory pressure
(PEEP), PAOP differs from the left ventricular filling
pressure, even when measured at end-expiratory
period [12].
 336 Cardiopulmonary monitoring
(3) Even when PAOP reflects the left ventricular filling
pressure, it can still be a poor marker of left ventri-
cular preload, in particular, in the case of reduced left
ventricular compliance.
(4) In the presence of tricuspid regurgitation, thermo-
dilution RVEDV measurements can be erroneous.
Assessment of preload is not assessment of
preload responsiveness
In fact, the slope of the FrankStarling curve depends on
ventricular contractility. Thus, a given value of preload can
be associated with preload responsiveness in the case of a
normal ventricular contractility (steep part of the Frank
Starling curve) or with no preload responsiveness in the
case of a decreased ventricular contractility (flat part of the
FrankStarling curve) [13]. Therefore, even the most
accurate measure of preload cannot be a reliable predictor
of preload responsiveness.
Synthesis
The available studies clearly indicate that markers of
ventricular preload are not accurate predictors of volume
responsiveness in patients with spontaneous breathing
activity. Nevertheless, the following important points
have to be outlined:
(1) Patients were generally studied whereas they had
already been resuscitated such that their preload was
rarely low before they received a fluid challenge. It
cannot be excluded that in nonresuscitated-shocked
patients, low values of markers of cardiac preload can
still be associated with a positive hemodynamic
response to fluid challenge. In this regard, in the
study by Heenen et al. [5] the rate of positive
response to fluid challenge was high in patients with
preinfusion RAP of 5 mmHg or less.
(2) On the contrary, fluid challenges were rarely per-
formed in patients with high filling pressures. Thus, it
cannot be excluded that high values of markers
of preload can predict the absence of volume respon-
siveness.
Dynamic parameters
Dynamic indices like pulse pressure respiratory variations
(PPVs) are valuable to predict volume responsiveness in
patients receiving mechanical ventilation in the absence of
active breathing efforts and/or cardiac arrhythmias [3].
Nonetheless, their predictive value in patients with spon-
taneous breathing activity may be lower.
Arterial pressure respiratory variation
Only three studies examined the value of PPV for pre-
dicting volume responsiveness in spontaneously breath-
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
ing patients. In the study by Monnet et al. [14], PPV had
no predictive value in mechanically ventilated patients
experiencing ventilator triggering. This finding was con-
firmed by Heenen et al. [5] who studied patients with
spontaneous breathing movements receiving mechanical
ventilation with pressure support mode or breathing
through a face mask. In a study [7] that included only
nonintubated patients, PPV was higher in fluid respon-
ders than in nonresponders, but this dynamic index
performed poorly with a sensitivity of PPV more than
12% of only 63%, although specificity was good. Impor-
tantly, a forced expiratory maneuver did not improve the
performance of PPV with a sensitivity decreasing to 21%
but a maintained specificity.
Inspiratory decrease in right atrial pressure
Magder et al. [15,16] made the hypothesis that when the
right ventricle is not preload responsive not only the stroke
volume will not increase with volume infusion but also
the RAP will not decrease during normal inspiration. In
their first study, the authors included a heterogeneous
population of patients; 36% of them experienced total
spontaneous breathing and 64% of them received mech-
anical ventilation but were able to breathe spontaneously
after disconnection from the ventilator [15]. The decrease
of RAP was measured either during a spontaneous inspi-
ration or after a short disconnection from the ventilator. An
inspiratory decrease in RAP (DRAP) by at least 1 mmHg
was found to accurately predict volume responsiveness
[15,16].
One of the major limitations of this test is that the patient
must generate a sufficiently profound decrease in
intrathoracic pressure for a correct interpretation. In
the two studies by Magder et al. [15,16] this was ensured
by an inspiratory decrease in PAOP by at least 2 mmHg.
Therefore, the clinical utilization of DRAP would require
the insertion of a pulmonary artery catheter, which
obviously represents an important limitation. On the
contrary, Heenen et al. [5] found that DRAP was not
predictive of volume responsiveness in patients with
spontaneous breathing activity with or without mechan-
ical support. In contrast to previous investigators [15,16],
they, however, did not disconnect their patients from the
ventilator to avoid de-recruitment, and also because
measurements obtained off ventilatory support may
not reflect the situation during respiratory support.
Nevertheless, the meaning of DRAP is still a matter of
debate [17].
Passive leg raising
Raising the lower limbs from the horizontal position is a
postural maneuver that has been used for years by rescuers.
It has recently emerged as an alternative method for
predicting fluid responsiveness.
 Volume responsiveness in critically ill Teboul and Monnet 337

Hemodynamic effects Clinical use

Passive leg raising (PLR) is a maneuver that induces a The best marker of the hemodynamic response to PLR as a
gravitational transfer of blood from the lower part of the predictor of volume responsiveness would be a significant
body toward the central circulatory compartment. The increase in stroke volume. As this response is expected to
PLR increases the right cardiac preload likely through an be brief and transient [14], real-time measurements of
increase in the mean circulatory pressure that is the blood flow are mandatory.
driving pressure for venous return. If the right ventricle
Changes in aortic blood flow measured by esophageal
is preload-responsive, this results in increased right
Doppler monitoring
cardiac output and left ventricular filling. Clinical studies
Technologic developments allow continuous measure-
reported an increase in PAOP [18] or in the E wave of
ment of both the descending aortic blood velocity (Dop-
the mitral flow [19] or in the left ventricular ejection time
pler method) and the diameter of the descending aorta
[14] during PLR, supporting the evidence that the
(timemotion echographic transducer). Therefore, it is
volume of blood transferred to the heart during PLR
possible to monitor descending aortic blood flow (ABF).
is sufficiently large for increasing the left cardiac preload.
As a resultant of the increase in left ventricular preload,
In a study performed in 71 mechanically ventilated
PLR may finally result in an increase in cardiac output,
patients, Monnet et al. [14] hypothesized that the change
depending on the degree of left ventricular preload
in ABF in response to PLR could predict volume respon-
reserve. If the right and/or the left ventricle are not
siveness as defined by an increase in ABF by more than
preload-responsive, no increase in left ventricular stroke
15% after fluid infusion. A PLR-induced increase in ABF
volume is, however, expected. Thus, PLR has been
of at least 10% accurately predicted volume responsive-
proposed as a test detecting fluid responsiveness in
ness in the group of 31 patients with spontaneous breath-
critically ill patients [20,21]. Interestingly, the PLR-
ing activity and/or arrhythmias as well as in the group of
induced changes in PAOP were shown to be immedi-
40 deeply sedated patients with sinus rhythm [14]
ately and fully reversible when the patients legs were
(Fig. 2). Interestingly, a PLR-induced increase in pulse
laid down [18]. This suggests that PLR can help to
pressure of at least 12% predicted volume responsiveness
predict volume responsiveness while avoiding the
with less accuracy [14]. This study concluded that
hazards of unnecessary fluid loading. As it does not
measuring changes in ABF rather than in pulse pressure
require any analysis of respiratory changes in stroke
during PLR was a more robust indicator of preload
volume or its surrogates, PLR is potentially usable in
responsiveness in patients receiving mechanical venti-
patients experiencing spontaneous breathing activity or
lation including those with spontaneous inspiratory
arrhythmias. The postural changes during PLR are also
efforts and/or arrhythmias.
important to consider. If before the maneuver the trunk
is in a semirecumbent position then PLR consists of Figure 2 Receiver operating curves comparing the ability of
pivoting the entire body, with the legs lifted up and the variations in aortic blood flow (ABF) induced by passive leg-
trunk finally in the horizontal position (Fig. 1). With this raising (PLR) and of pulse pressure variation (PPV) to discrimi-
nate responders and nonresponders to volume expansion in a
method, PLR is expected to mobilize a larger blood population of 31 patients with spontaneous breathing activity
volume than if the trunk is initially lying horizontally and/or arrhythmias (adapted from [14])
as not only the venous blood of the legs but also that
contained into the large splanchnic compartment is
mobilized [20]. Sensitivity 100

80
Figure 1 The passive leg-raising test consists of measuring the
hemodynamic effects of a leg elevation up to 45-
60

40

45 45 20

Semirecumbent position Passive leg raising

0
0 20 40 60 80 100
A simple way to perform the postural maneuver is to transfer the patient
100-specificity
from the semirecumbent posture to the passive leg-raising position by
using the automatic motion of the bed.

Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 338 Cardiopulmonary monitoring
Changes in stroke volume measured by transthoracic
echocardiography
In a recent study, Lamia et al. [10] included 24 patients
with spontaneous breathing. Using transthoracic echo-
cardiography (TTE), they measured the response of
stroke volume to PLR and to saline infusion [10]. Fluid
responsiveness was defined as an increase in stroke
volume by more than 15% after saline infusion [10].
The authors showed that a PLR-induced increase in
stroke volume of at least 12.5% predicted fluid respon-
siveness with a sensitivity of 77% and a specificity of
100% [10]. Neither LVEDA nor the ratio of mitral
inflow E wave velocity to early diastolic mitral annulus
velocity predicted fluid responsiveness [10].
In a series of 34 patients who breathed spontaneously
without any mechanical support, Maizel et al. [22] also
found that the response of TTE stroke volume to PLR
was accurate to predict fluid responsiveness.
Conclusion
In patients with spontaneous breathing activity, the pre-
diction of volume responsiveness is a difficult challenge
[17], in particular, in those who have already been resus-
citated in the preceding hours or days and for whom
continuation of fluid infusion carries risks of pulmonary
edema. In these conditions, the static markers of cardiac
preload are generally in the normal range and are far less
valuable than dynamic tests to assess volume responsive-
ness [3,23]. As of the presence of spontaneous breathing,
indices of volume responsiveness that use heartlung
interactions are no longer reliable. Careful analysis of
the hemodynamic response to PLR using real-time
systemic blood flow measurements is helpful for predicting
volume responsiveness. It is likely that pulse contour
cardiac output monitoring devices could also be used
[20,24]. It must, however, be emphasized that the limits
of precision of the technique used for assessing the hemo-
dynamic response to PLR must be far below the 1015%
increase in the blood flow found as a predicting cut-off [25].
In the most difficult cases, fluid challenge strategy can
still be applied, provided that clinicians carefully follow
the recommended rules in terms of type of fluid, rate of
infusion, clinical end points and safety limits in order to
minimize the risks of fluid overload [26].
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 376).
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