Predicting Fluid Responsiveness in Children:

A Systematic Review
Heng Gan, MBBCh, MRCPCH, FRCA,*† Maxime Cannesson, MD, PhD,‡
John R. Chandler, MBBCh, FCARCSI, FDSRDS,§ and
J. Mark Ansermino, MBBCh, MSc (Inf), FFA (SA), FRCPC*†
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BACKGROUND: Administration of fluid to improve cardiac output is the mainstay of hemody-

namic resuscitation. Not all patients respond to fluid therapy, and excessive fluid administra-
tion is harmful. Predicting fluid responsiveness can be challenging, particularly in children.
Numerous hemodynamic variables have been proposed as predictors of fluid responsiveness.
Dynamic variables based on the heart–lung interaction appear to be excellent predictors of fluid
responsiveness in adults, but there is no consensus on their usefulness in children.
METHODS: We systematically reviewed the current evidence for predictors of fluid respon-
siveness in children. A systematic search was performed using PubMed (1947–2013) and
EMBASE (1974–2013). Search terms included fluid, volume, response, respond, challenge,
bolus, load, predict, and guide. Results were limited to studies involving pediatric subjects
(infant, child, and adolescent). Extraction of data was performed independently by 2 authors
using predefined data fields, including study quality indicators. Any variable with an area under
the receiver operating characteristic curve that was significantly above 0.5 was considered
predictive.
RESULTS: Twelve studies involving 501 fluid boluses in 438 pediatric patients (age range 1
day to 17.8 years) were included. Twenty-four variables were investigated. The only variable
shown in multiple studies to be predictive was respiratory variation in aortic blood flow peak
velocity (5 studies). Stroke volume index, stroke distance variation, and change in cardiac
index (and stroke volume) induced by passive leg raising were found to be predictive in single
studies only. Static variables based on heart rate, systolic arterial blood pressure, preload
(central venous pressure, pulmonary artery occlusion pressure), thermodilution (global end
diastolic volume index), ultrasound dilution (active circulation volume, central blood volume,
total end diastolic volume, total ejection fraction), echocardiography (left ventricular end
diastolic area), and Doppler (stroke volume index, corrected flow time) did not predict fluid
responsiveness in children. Dynamic variables based on arterial blood pressure (systolic
pressure variation, pulse pressure variation and stroke volume variation, difference between
maximal or minimal systolic arterial blood pressure and systolic pressure at end-expiratory
pause) and plethysmography (pulse oximeter plethysmograph amplitude variation) were also
not predictive. There were contradicting results for plethymograph variation index and inferior
vena cava diameter variation.
CONCLUSIONS: Respiratory variation in aortic blood flow peak velocity was the only vari-
able shown to predict fluid responsiveness in children. Static variables did not predict fluid
responsiveness in children, which was consistent with evidence in adults. Dynamic variables
based on arterial blood pressure did not predict fluid responsiveness in children, but the evi-
dence for dynamic variables based on plethysmography was inconclusive.  (Anesth Analg
2013;117:1380–92)

T
he goal of hemodynamic resuscitation is to achieve
adequate oxygen delivery by maintaining ade-
quate cardiac output and perfusion pressure.
This is typically attempted initially with intravascular
From the *Department of Anesthesiology, Pharmacology, and Therapeutics,
University of British Columbia; †Department of Anesthesia, BC Children’s
Hospital, Vancouver, Canada; ‡Department of Anesthesiology and Periop-
erative Care, University of California, Irvine, School of Medicine, Irvine,
California; and §Department of Anaesthesia, University College London
­ underline the need for more reliable predictors of fluid
Trust, London, United Kingdom.
Accepted for publication August 9, 2013.
Funding: Not funded.
Conflict of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Heng Gan, MBBCh, MRCPCH, FRCA, Depart-
ment of Anesthesia, Room V3-317, 950 W. 28th Ave., Vancouver, British
­Columbia V5Z 4H4 Canada. Address e-mail to heng.gan@gmail.com.
Copyright © 2013 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e3182a9557e
volume expansion. However, in pediatric studies exam-
ining fluid responsiveness, only 40% to 69% of chil-
dren responded to intravascular volume expansion.1–9
Appropriate early fluid resuscitation improves sur-
vival,10,11 but excessive fluid therapy increases mortal-
ity.12–14 Clinical assessment of hemodynamic status based
on physical examination and routine monitoring is
inadequate, particularly in children.15–17 These findings
responsiveness.
Numerous hemodynamic variables have been proposed
as predictors of fluid responsiveness. Static variables are
based on a single observation in time. This includes clinical
observations such as heart rate and arterial blood pressure,
preload pressures such as central venous pressure (CVP)
and pulmonary artery occlusion pressure, and preload
volume estimates from thermodilution and ultrasound
dilution.

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 Dynamic variables reflect the variation in preload
induced by mechanical ventilation. With positive pres-
sure ventilation, the vena cava blood flow is impeded
during inspiration, causing a decrease in venous return
and pulmonary artery blood flow. This effect on venous
return can be quantified as inferior vena cava diameter
variation (∆IVCD). Approximately 3 heart beats later
(pulmonary transit time), this decrease in blood flow is
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value of these static and dynamic variables on predicting
fluid responsiveness in children.
METHODS
Selection of Studies
Published studies evaluating the predictive factors of
fluid responsiveness in pediatric patients in the periopera-
tive and critical care settings were included. Studies were

transmitted to the left heart, resulting in a decrease in

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identified by electronic searches of PubMed (from 1947)

left ventricular end diastolic volume and consequently
stroke volume.18 This ventilation-induced variation in
stroke volume is then observed downstream as variation
in aortic blood flow, arterial blood pressure, and plethys-
mographic waveform amplitude. The degree of variation
observed is larger in hypovolemia19,20 when the heart is
functioning at the steep portion of the Frank–Starling
relationship. Dynamic variables quantify this variation
as the percentage difference between the maximal and
the minimal measured value in a single breath, indexed
to either the maximum, mean, or midpoint value. For
example, one of the earliest dynamic variables, systolic
pressure variation (SPV) is calculated as:
SPV (%) = (SAPmax − SPBmin)/[(SAPmax + SAPmin)/2] × 100
and EMBASE (from 1974) databases. The final search was
performed on 2 July, 2013. Results were limited to stud-
ies involving pediatric subjects by using MeSH terms
(PubMed) or by setting search limits (EMBASE). Search
terms included fluid, volume, response, respond, chal-
lenge, bolus, load, predict, and guide. Study selection was
performed independently by HG and JMA. Figure 1 illus-
trates the full search strategy.
Data Extraction
Using a data extraction spreadsheet, 1 review author
(HG) extracted data from included studies, and a second
author (JMA) checked the extracted data. Information was
extracted from each included study on:

where SAP is systolic blood pressure. An average is (1) Characteristics of trial participants (age, weight, rel-
­ sually taken over a period of time or a number of respira-
u evant clinical diagnosis, vasoactive therapy)
tory cycles. (2) Characteristics of study (clinical setting, ventilation,
Many of these hemodynamic variables have been consis- fluid bolus type, volume, and duration)
tently shown to be the best predictors of fluid responsive- (3) Reference standard used (definition of response,
ness in adults. However, in the pediatric population, the method of assessment)
predictive value of these variables remains controversial. (4) Variables tested (method of assessment, area under
We systematically reviewed the current evidence for the receiver operating characteristic [ROC] curve)

PubMed database search EMBASE database search

(fluid or volume) AND (((fluid or volume) ADJ3

(response* or respond* or
challenge or bolus or load) AND
(predict* or guide) AND
(hemodynamics[mh] or fluid
therapy[mh]) AND
(infant[mh] or child[mh] or
adolescent [mh])
(response* or respond* or
challenge or bolus or load)) AND
(predict* or guide)).ti,ab.
Limit: (infant <to one year> or child
<unspecified age> or preschool
child <1 to 6 years> or school child
<7 to 12 years> or adolescent <13
to 17 years>)

Figure 1. Flow diagram of literature search

98 records and study selection.
244 records
identified identified

317 records after 297 of records excluded

duplicates removed by title

20 articles assessed 8 articles excluded:

for eligibility 5 adult studies
2 not fluid bolus study
1 not prediction study
12 studies included

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 Predicting Fluid Responsiveness in Children

Summary Measures ROC]) against precision, using a significance level of 0.1

The areas under the ROC curves and their 95% confidence
intervals (CIs) were the primary measures for comparison.
Standard deviations (SDs) and 95% CI, when not quoted,
were reconstructed from P values if available. Any variable
with an area under the ROC curve that was significantly
above 0.5 (i.e. the lower limit of the 95% CI was above 0.5)
was considered predictive. Any variable with a 95% CI
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because of small sample size.23
RESULTS
Study Characteristics
We included 12 studies, totaling 501 fluid boluses in 438
pediatric patients (age range 1.0 day to 17.8 years). All but 29
patients’ lungs were mechanically ventilated. Six studies (156

overlapping 0.5 is no better than chance and was consid- patients) standardized tidal volume at 10 mL/kg. Positive
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ered not predictive. No meta-analysis was done due to the
limited number of studies and diverse study characteristics.
Risk of Bias
Using an 18-item assessment tool (Appendix), which incor-
porated the recommendations from Quality Assessment
of Diagnostic Accuracy Studies (QUADAS)21 and the
Cochrane Handbook for Systematic Reviews of Diagnostic
Test Accuracy,22 the quality and risk of bias of individual
studies were assessed by consensus based on joint review
by 2 authors (HG and JMA).
To assess for publication bias, we created funnel plots
of the area under the ROC curve against sample size for
each variable that was investigated by 5 or more studies.
The funnel plot is based on the fact that precision increases
with sample size. Results from smaller studies will scatter
widely at the bottom of the graph, with the spread narrow-
ing among larger studies. The funnel plots were assessed
visually for symmetry. In the absence of bias the plot will
resemble a symmetrical inverted funnel.23 To formally test
for asymmetry, we applied Egger regression tests on sec-
ondary funnel plots of log (area under ROC/[1-area under
end-expiratory pressure, where reported, ranged from 0 to
5 cm H2O. Three studies used crystalloid as fluid bolus, 6
studies used colloid, 2 studies used a mixture of fluids, and 1
study did not report type of fluid given. The hemodynamic
response to intravascular volume expansion was defined by
an increase in stroke volume in 10 studies, cardiac output
in 1 study and arterial blood pressure in another. Cardiac
diagnoses were present in 176 patients (40%) from 6 studies.
Vasoactive drugs were administered during study measure-
ments to 92 patients (21%) from 5 studies. All potential pre-
dictors studied and their abbreviations are listed in Table 1.
Study characteristics are detailed in Table 2.
Static Variables
Twelve static variables were included in this review,
although only heart rate and CVP were investigated by >1
study. The area under the ROC curve and its 95% CI for each
static variable is illustrated in Figure 2.
Clinical and Preload Variables
The area under the ROC curve for heart rate was not signifi-
cantly >0.5 in 3 pediatric studies.6,8 Similarly, the area under
ROC for SAP was not significantly >0.5 in 1 study.24

Table 1.  List of Potential Predictors and Their Abbreviations

STATIC
Clinical Heart rate HR
Systolic arterial blood pressure SAP
Preload pressure Central venous pressure CVP
Pulmonary artery occlusion pressure PAOP
Thermodilution Global end diastolic volume index GEDVI
Ultrasound dilution Active circulation volume ACV
Central blood volume CBV
Total end diastolic volume TEDV
Total ejection fraction TEF
Echocardiography and Doppler Left ventricular end diastolic area LVEDA
Stroke volume index SVI
Corrected flow time FTc
Dynamic
Arterial pressure Systolic blood pressure variation SPV
Pulse pressure variation PPV
Stroke volume variation SVV
Difference between minimal SAP and SAP at end-expiratory pause ∆Down
Difference between maximal SAP and SAP at end-expiratory pause ∆Up
Plethysmography Pulse oximeter plethysmograph amplitude variation ∆POP
Plethysmograph variability index PVI
Echocardiography and Doppler Respiratory variation in aortic blood flow peak velocity ∆Vpeak
Stroke distance variation ∆VTI
Inferior vena cava diameter variation ∆IVCD
Passive leg raising (PLR)
Echocardiography and Doppler PLR-induced change in cardiac index ∆CIPLR
PLR-induced change in stroke volume ∆SVPLR

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Table 2. Characteristics of Studies

Age, median Weight, median Fluid Fluid Bolus Ventilation Predictors with
(range), or mean (range) or mean Patients, bolus, volume, time, tidal volume Definition of Method of reported areas under
Publication Population (SD), years (SD), kg n n Fluid type mL/kg min (mL/kg) PEEP, cm H2O CVS status response assessment the ROC curves
Tibby et al.25 Cardiac and 2.1 (0–16) 12 (3–60) 94 94 FFP, 4.5% Alb or 10 30 NR NR 50 had vasoactive ∆SV >10% TD CVP, FTc
General PRBC infusion(s)
PICU
Tran et al.26 Cardiac OR 0.7 (0–17.2) 6.2 (2.2–71.5) 25 44 Blood NR NR NR NR Post-CPB, open chest, ∆MBP ≥80 mm IABP CVP, SPV,
vasoactive drugs not Hg/L/m2 PPV (manual), SVV
controlled (manual)
Durand et al.1 General PICU 2.4 (IQR 1.3–3.7) 13 (IQR 9.8–15) 26 26 Plasmion or 0.9% 20 15–30 7.4 (median) 4 (median) 11 received ∆SV ≥15% TTE SPV, PPV (manual), ∆Vpeak
NaCl norepinephrine
Choi et al.2 Cardiac PICU 2.6 (1.8) 12 (4) 21 21 6% HES 10 20 10 0 10 received milrinone or ∆SV ≥15% TTE CVP, ∆Vpeak, ∆IVCD
dopamine

December 2013 • Volume 117 • Number 6

Raux et al.3 General OR (0–0.5) (2.5–5) 50 50 4% Alb, 6% HES or 10–30 20–40 NR NR Clinically hypovolaemic, ∆SV ≥15% TED HR, MAP, CI, SVI, FTc, mean
0.9% NaCl no vasoactive drugs acceleration
Lukito et al.4 General PICU (1–13) Mean BSA (SD) 40 40 0.9% NaCl 10 NR 29 (spontaneous NR 3 received epinephrine ∆CO >10% TTE Response to PLR: HR, MBP,
0.76 (0.24) breathing) SAP, SV and CI
Pereira de Neurosurgical 2 (0.5–5) and 11 and 32 30 30 0.9% NaCl 20 15 10 0–2 No vasoactive drugs ∆SV ≥15% TTE ∆POP, PVI, PPV (manual),
Souza OR 11 (6–14) PPV (automated),
Neto et al.6 LVEDA, ∆Vpeak
Renner et al.8 Cardiac OR 1.4 (1.3) 10.4 (6.3) 27 27 6% HES 10 NR 10 3–5 Congenital heart disease, ∆SV ≥15% TEE PVI, ∆Vpeak, ∆VTI
pre-CPB, closed chest,
no vasoactive drug
Saxena et al.9 Cardiac and 1 NR 47 65 NR 10 NR 11 (median) NR NR ∆SV >15% US dilution ACV, CBV, TEDV, TEF, SPV,
General PPV, SV
PICU
Renner et al.7 Cardiac OR 1.2 (1) 9.7 (4.3) 26 52 6% HES 10 NR 10 3–5 Pre- and post-CPB, ∆SV >15% TEE CVP, PPV (auto), SVV, GEDVI
closed chest, 18
received enoximone
and epinephrine
post-VSD repair
Chandler et al.5 Cardiac cath lab 6.1 (1.2–17.8) 26.3 (8.9–74) 19 19 Crystalloid 10 NR 10 5 Postcardiac cath, no ∆SV ≥15% TD ∆POP, PVI, PPV (manual),
residual shunt CVP, PAOP
Byon et al.24 Neurosurgical OR 6.2 (0.6–10.0) 24.3 (10.2) 33 33 6% HES 10 10 10 0 No vasoactive drugs ∆SV ≥10% TTE SAP, HR, CVP, ∆IVCD, SPV,
∆Down, ∆Up, PPV,
∆Vpeak, PVI

SD = standard deviation; n = number of subjects; PEEP = positive end-expiratory pressure; CVS = cardiovascular system; ROC = receiver operating characteristic; PICU = pediatric intensive care unit; FFP = fresh frozen
plasma; Alb = human albumin solution; PRBC = packed red blood cells; NR = not reported; ∆SV = change in stroke volume; TD = thermodilution; CVP = central venous pressure; FTc = corrected flow time; OR = operating
room; CPB = cardiopulmonary bypass; ∆MBP = change in mean blood pressure; IABP = invasive arterial blood pressure; SPV = systolic pressure variation; PPV = pulse pressure variation; IQR = inter-quartile range;
NaCl = sodium chloride solution; TTE = transthoracic echocardiography; TED = transesophageal Doppler; ∆Vpeak = respiratory variation in aortic blood flow peak velocity; ∆IVCD = inferior vena cava diameter variation;
HES = hydroxyethyl starch; TEE = transesophageal echocardiography; HR = heart rate; MAP = mean arterial blood pressure; CI = cardiac index; SVI = stroke volume index; BSA = body surface area; ∆CO = change in cardiac
output; PLR = passive leg raising; MBP = mean blood pressure; SAP = systolic blood pressure; SV = stroke volume; ∆POP = pulse oximeter plethysmograph amplitude variation; PVI = plethysmograph variability index;
LVEDA = left ventricular end diastolic area; ∆VTI = stroke distance variation; US = ultrasound; ACV = active circulation volume; CBV = central blood volume; TEDV = total end diastolic area; TEF = total ejection fraction;
VSD = ventricular septal defects; SVV = stroke volume variation; GEDVI = global end diastolic volume index; SAP = systolic arterial blood pressure; ∆Down = difference between minimal SAP and SAP at end-expiratory
pause; ∆Up = difference between maximal SAP and SAP at end-expiratory pause.

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Figure 2. Comparison of the areas under the receiver operating characteristic (ROC) curve for static variables. CI = confidence interval;
̶ · ̶ · ̶ = CI not reported; n  =  number of subjects; HR  =  heart rate; SAP  =  systolic arterial blood pressure; OR  =  operating room;
CVP  =  central venous pressure; PICU  =  pediatric intensive care unit; ASD  =  atrial septal defects; VSD  =  ventricular septal defects;
PAOP = pulmonary artery occlusion pressure; US = ultrasound; GEDVI = global end diastolic volume index; ACV = active circulation vol-
ume; CBV = central blood volume; TEDV = total end diastolic volume; TEF = total ejection fraction; LVEDA = left ventricular end diastolic
area; SVI = stroke volume index; FTc = corrected flow time; TTE = transesophageal echocardiography; TED = transesophageal Doppler.

In eight studies that investigated the predictive value of
CVP and 1 study the predictive value of pulmonary artery
occlusion pressure, none of the areas under the ROC curves
were significantly >0.5.2,5,7–9,24–26
Thermodilution and Ultrasound Dilution
In 1 pediatric study of 26 children with atrial or ventricular
septal defects (ASD/VSD), the area under the ROC curve for
global end diastolic volume index was not significantly >0.5.7
One pediatric intensive care unit (PICU) study, using
ultrasound dilution to measure stroke volume, investigated
using measurements derived from ultrasound dilution (total
end diastolic volume, active circulation volume, central
blood volume, and total ejection fraction) to predict fluid
responsiveness.9 The study found that the 95% CI for areas
under the ROC curve for these variables overlapped 0.5.
Echocardiography and Doppler
The use of left ventricular end diastolic area measured
by transthoracic echocardiography to predict fluid
responsiveness was investigated in 1 pediatric study and
was found not to predict fluid responsiveness.6 Stroke vol-
ume index (SVI) predicted fluid responsiveness (95% CI
lower limit 0.80) in 1 perioperative study involving 50 chil-
dren younger than 6 months.3 One pediatric study found
that corrected flow time (FTc) predicted fluid responsive-
ness in general PICU patients (95% CI lower limit 0.58) but
not in postoperative cardiac patients.25
Dynamic Variables
Ten dynamic variables were included in this review. The
area under the ROC curve and its 95% CI for each dynamic
variable is illustrated as a forest plot in Figure 3.
Arterial Pressure
Four pediatric studies found that SPV did not accurately
predict fluid responsiveness in children.1,9,24,26 Of the 7
studies investigating the use of pulse pressure varia-
tion (PPV) to predict fluid responsiveness in children, 6
had negative results.1,5–7,9,24,26 In contradiction, 1 study,

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Figure 3. Comparison of the areas under the receiver operator curve (ROC) curve for dynamic and passive leg raising (PLR) variables.
CI = confidence interval; ̶ ̶ ̶ = CI reported as not significant; ̶ · ̶ · ̶ = CI not reported; n = number of subjects; PPV = pulse pres-
sure variation; PICU = pediatric intensive care unit; OR = operating room; ASD = atrial septal defects; VSD = ventricular septal defects;
SPV = systolic pressure variation; SVV = stroke volume variation; ∆POP = pulse oximeter plethysmograph amplitude variation; PVI = ple-
thysmograph variability index; ∆Vpeak  =  peak velocity variation; ∆VTI  =  stroke distance variation; ∆IVCD  =  inferior vena cava diameter
variation; ∆CIPLR = PLR-induced change in cardiac index; ∆SVPLR = PLR-induced change in stroke volume; TTE = transesophageal echocar-
diography; TEE = transthoracic echocardiography.

involving 26 children aged 0 to 2 years, found that PPV
predicted fluid responsiveness both before (95% CI lower
limit 0.59) and after (95% CI lower limit 0.58) ASD/VSD
closure.7 Three studies investigating the use of stroke vol-
ume variation (SVV) in children did not find SVV predic-
tive of fluid responsiveness,7,9,26 except in 1 study where
SVV was predictive (95%  CI lower limit 0.56) of fluid
responsiveness in children after surgical repair of ASD/
VSD.7 One study investigated the difference between mini-
mal and maximal SAP and SAP at end-expiratory pause
(∆Down and ∆Up, respectively) and found neither had
areas under the ROC curve that was significantly >0.5.24

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 Predicting Fluid Responsiveness in Children
Plethysmography
Two pediatric studies involving a total of 49 patients
found that pulse oximeter plethysmograph amplitude
variation (∆POP) did not predict fluid responsiveness in
children.5,6
Two pediatric studies found plethysmograph variability
index (PVI) predictive (95% CI lower limit 0.58 and 0.77)
of fluid responsiveness.8,24 Two other pediatric studies,
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in children.5,6
Echocardiography and Doppler
Five studies investigated the use of respiratory variation
in aortic blood flow peak velocity (∆Vpeak) to predict fluid
responsiveness in children in the operating room6,7,24 and the
intensive care unit1,2 and found that ∆Vpeak predicted fluid
responsiveness in children (95% CI lower limits 0.64, 0.61,
0.66, 0.82, 0.73, and 0.73). One study found stroke distance
variation (∆VTI) measured using transesophageal echocar-
diography a predictor of fluid responsiveness (95% CI lower
limit 0.65) in children with congenital heart disease.7 ∆IVCD
was found to predict fluid responsiveness in children in a
study in the PICU (95% CI lower limit 0.69)2 but not in another
study in the operating room (95% CI lower limit 0.16).24
Passive Leg Raising
One study investigated using hemodynamic changes
induced by passive leg raising (PLR) to predict fluid respon-
siveness in 40 PICU patients, the most which were sponta-
neously breathing.4 The study demonstrated that changes
in cardiac index and stroke volume induced by PLR (∆CIPLR
and ∆SVPLR, respectively) predicted fluid responsiveness
(95% CI lower limits 0.55 and 0.59, respectively). However,
after multivariate analysis using logistic regression analy-
sis, the study concluded that only ∆CIPLR significantly cor-
related with fluid responsiveness.
Risk of Bias
Table  3 summarizes the assessment of quality and risk of
bias of individual studies. Twenty-one of 216 items were
initially assessed differently but were resolved by consen-
sus. The quality of the most studies was high with low risk
of bias, except for the 2 included abstracts,5,9 which lacked
detailed description of study methodology. Most studies
could not avoid incorporation bias because the same modal-
ity (e.g., transthoracic echocardiography) was used both as
the reference and as the index variable. None of the studies
established cutoff values prospectively because they were
using area under the ROC curve as effect measure. Five
studies tested for observer variation in echocardiography
and Doppler measurements.
Funnel plots of the area under the ROC curve against sam-
ple size were constructed for CVP, PPV, and ∆Vpeak (Fig. 4),
the only variables investigated by 5 or more studies. The
funnel plot for PPV appeared symmetrical, but the funnel
plot for CVP and ∆Vpeak appeared asymmetrical. However,
Egger regression test for symmetry showed nonsignificant
P values (0.46, 0.33, and 0.17, respectively for CVP, PPV, and
∆Vpeak), suggesting low risk of publication bias.
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DISCUSSION
Static Variables
The studies included in this review failed to demon-
strate any predictive value in heart rate, CVP, pulmo-
nary artery occlusion pressure, left ventricular end
diastolic area, global end diastolic volume index, and
ultrasound dilution measurements (total end diastolic
volume, active circulation volume, central blood vol-
ume, and total ejection fraction). The only static vari-
ables that potentially have predictive values are SVI
and FTc. SVI was found to be predictive of fluid respon-
siveness in 1 study of 50 pediatric patients undergoing
general surgery.3 There are, however, no other pediatric
studies to support this result.
FTc is derived from transesophageal Doppler mea-
surement of blood flow in the descending thoracic aorta.
Flowtime is measured from the beginning to end of the aor-
tic velocity waveform. FTc controls for varying heart rate
using the equation FTc = Flowtime/√cycletime.
FTc is influenced by preload as well as contractil-
ity and systemic vascular resistance.27,28 In individual
patients, FTc may increase with fluid administration and
increased stroke volume and has been used to guide
intraoperative fluid management in adults.29 Studies
in adults using FTc to predict fluid responsiveness are
inconclusive.30,31 The only pediatric study found that FTc
predicted fluid responsiveness in general PICU patients
but not in cardiac patients who had comparatively lower
cardiac index and higher (and more variable) systemic
vascular resistance.25
Dynamic Variables
Dynamic preload variables are those which reflect
the cyclical changes in left ventricular stroke volume
induced by positive pressure ventilation. Several sys-
tematic reviews and meta-analyses suggest that in
adults, dynamic variables based on arterial blood pres-
sure (SPV, PPV, and SVV) and plethysmography (∆POP
and PVI) all have excellent predictive value. 32–36 The
evidence for this in children is disappointingly poor.
Dynamic parameters extracted from the arterial pres-
sure waveform (SPV, PPV, SVV, ∆Down, and ∆Up) on
the whole do not predict fluid responsiveness in chil-
dren. PPV and SVV have only been demonstrated in
single studies to predict fluid responsiveness in chil-
dren with congenital heart disease. 7,8 There were con-
tradicting results for the predictive value of dynamic
parameters based on the plethysmographic waveform.
Studies agreed ∆POP did not predict fluid responsive-
ness in children, but there were conflicting results for
PVI. Only ∆V peak appeared to predict fluid respon-
siveness in children. We explore a number of possible
explanations.
Thoracic/Lung Compliance and Ventilation
Children have higher chest wall and lung compliance.37
The variation in intrathoracic pressure with normal tidal
volume ventilation may not cause significant circulatory
changes in children. In adults, a tidal volume of at least
8 mL/kg is required.38 Most of the pediatric studies in
anesthesia & analgesia
 Table 3.  Methodological Quality Summary
Pereira de
Tibby Tran Durand Choi Raux Lukito Souza Neto Renner Saxena Renner Chandler Byon
et al.25 et al.26 et al.1 et al.2 et al.3 et al.4 et al.6 et al.,20118 et al.9 et al.,20127 et al.5 et al.24
Representative Yes No No No No Yes No No Unclear No No No
spectrum?
Clear selection No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes
criteria?
Acceptable Yes No Yes Yes Yes Yes Yes Yes Unclear Yes Yes Yes
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reference
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standard?
Acceptable Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
delay
between
tests?
Partial Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
verification
avoided?
Differential Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
verification
avoided?
Incorporation Yes No No No No No No No No Yes Yes No
avoided?
Detailed Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes
description
of index
test?
Detailed Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes
description
of reference
standard?
Reference Yes Yes No Yes No No Yes Yes No Yes No No
standard
results
blinded?
Index test Yes Yes No Yes No No Yes Yes No Yes No No
results
blinded?
Same clinical Yes Yes Yes Yes Yes Yes Yes Yes Unclear Yes No Yes
data
available?
Interpretable Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
results
reported?
Withdrawals Unclear Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
explained?
Cutoff No No No No No No No No No No No No
established
before
study?
Clear definition No No No Yes Yes Yes Yes Yes No Yes No Yes
of “positive”
result?
Reported and Yes No Yes Yes No Yes Yes No No No No Yes
acceptable
observer
variation?
No commercial No Yes Yes Yes Yes Yes Yes Yes Unclear Yes Yes Yes
funding?
Yes = high quality; No = low quality.

this review used a tidal volume of 10 mL/kg, although
some either did not report or did not control tidal vol-
umes used. Four studies investigating ∆Vpeak demon-
strated that there is indeed measurable variation in aortic
blood flow in children with ventilation tidal volumes of
10 mL/kg.2,6,7,24
Arterial Blood Pressure, Vascular Compliance,
and Cardiac Compliance
SPV and PPV are dynamic preload indicators based on
arterial blood pressure. They quantify the magnitude of
change induced by positive pressure ventilation in SAP and
pulse pressure (PP), respectively. SPV is calculated using

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 Predicting Fluid Responsiveness in Children

the maximal and minimal SAP values measured in a single

respiratory cycle: CVP
SPV (%) = (SAPmax − SPBmin)/[(SAPmax + SAPmin)/2] × 100 70

PPV is calculated with PP using an analogous formula. 60

An average is taken either over 3 consecutive respiratory
cycles or over 30 seconds.7,39,40 50

Sample size
Respiratory-induced changes in cardiac stroke volume
40
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centrally are measured as changes in the arterial blood pres-

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sure peripherally. Children have a more compliant arterial 30

tree than adults.41,42 The magnitude of the change in arterial
blood pressure induced by ventilation is smaller in a more 20
compliant arterial vascular system because the peripherally
10
measured PP is dependent on arterial compliance.43 This
may explain why dynamic variables based on arterial blood 0
pressure in general do not predict fluid responsiveness in 0 0.5 1
children.1,5,6,9 The picture is less clear in children with intra- Area under ROC curve
cardiac shunts who may have reduced arterial compliance
due to sympathetic upregulation.5,44 Renner et al.7 found
PPV to predict fluid responsiveness in a study of children PPV
before and after ASD or VSD closure. However, when PPV 70
was examined in children after transcatheter closure of
intracardiac shunts, it was not a predictive value of fluid 60
responsiveness.5
Animal studies suggest that immature ventricles are 50
Sample size
less compliant and have less steep Starling curves.45 A
40
recent study demonstrated PPV values that were lower in
immature pigs compared with adult pigs with the same 30
degree of hypovolemia.46 Reduced cardiac compliance
may be a possible explanation why PPV and SPV do not 20
predict fluid responsiveness as well in children compared
with adults. 10

0
Flow Variables 0 0.5 1
The most convincing predictor was ∆Vpeak, a direct ultrasound
measurement of variations in aortic blood flow induced Area under ROC curve
by small reversible changes in preload due to ventilatory-
induced changes in venous return. Unlike variables based on ∆Vpeak
arterial blood pressure or plethysmographic measurements, 40
flow measurements are not affected by arterial compliance or
changes in arterial tone.47 ∆Vpeak is measured using Doppler
echocardiography, which requires a skilled operator. 30
This may limit its utility in routine clinical practice,
Sample size

despite being a reliable predictor of fluid responsiveness.

20
Plethysmographic Variables
The plethysmographic waveform is the quantity of infra-
red light detected by the oximeter photo detector, which
10
varies during the cardiac cycle. The plethysmographic
waveform amplitude is measured beat to beat as the
vertical distance between peak and preceding valley in
the output waveform. ∆POP is then calculated using a 0
0 0.5 1
formula analogous to that of SPV and PPV. The plethys-
mographic gain factor is held constant during record- Area under ROC curve
ing so that the waveform amplitude is not modified by Figure 4. Funnel plots for central venous pressure (CVP), pulse
automatic gain adjustment.39,48 Similar to the calculation pressure variation (PPV) and peak velocity variation (∆Vpeak). Plots of
of PPV, an average is usually taken over 3 consecutive area under the receiver operating characteristic (ROC) curve against
sample size to assess for publication bias. In the absence of bias,
­respiratory cycles.39,48 the plot resembles a symmetrical inverted funnel.
PVI (Masimo Corp., Irvine, CA) is an algorithm for auto-
mated and continuous representation of the respiratory

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www.anesthesia-analgesia.org anesthesia & analgesia
 variations in the plethysmographic waveform amplitude,
using the perfusion index (PI) as a surrogate. PVI is the
maximum change in PI over a time interval that includes at
least 1 complete respiratory cycle:
PVI = [(PImax − PImin)/PImax] × 100
The plethysmographic waveform reflects the amount of
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infrared light detected by the pulse oximeter sensor, which
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is dependent on the blood volume in the tissue where the
oximeter sensor is placed. The blood volume depends on
vascular distensibility and stroke volume.49 Since vascular
distensibility is considered unchanged during the course
of 1 mechanical breath, respiratory-induced changes in the
arterial pulse pressure become the main determinants of
PVI and ∆POP. Indeed, ∆POP has been shown to be corre-
lated to SPV50 and PPV39 in adults, and to PPV in children.51
Furthermore, the increased impedance to venous return
during a positive pressure inspiration may increase the
volume of venous blood, thus exaggerating the decrease in
plethysmographic wave amplitude.49 PVI and ∆POP should
therefore be expected to be more sensitive to ventilator-
induced changes than SPV or PPV. In adult studies, PVI and
∆POP predicted fluid responsiveness, both in the periopera-
tive32,48,52–54 and critical care settings.55,56 Disappointingly, in
children, ∆POP did not predict fluid responsiveness. PVI
was found to predict fluid responsiveness in 2 pediatric
studies8,24 but not in 2 other pediatric studies.5,6 This contra-
dicting result is difficult to explain. The studies all involved
patients of similar ages, and their lungs were ventilated at
tidal volumes of 10 mL/kg. The 2 positive studies used col-
loid fluid boluses, and the 2 negative studies used crystal-
loid, but this should not influence the results, particularly
since all 4 studies similarly defined fluid responsiveness as
an increase in stroke volume measured using echocardiog-
raphy. One of the positive studies was in children with con-
genital heart disease,8 which may be explained by reduced
vascular compliance due to sympathetic upregulation.5,44
However, this does not explain the other positive study in
children undergoing neurosurgery.24
Passive Leg Raising
∆CIPLR appeared to be an excellent predictor of fluid respon-
siveness in children, which is consistent with findings in
adult studies.57 In adults, PLR induces an “autotransfu-
sion” of approximately 150 mL.58 Children have a lower
leg-length to body-length ratio than adults,59 so the effect
of PLR may be smaller. A major advantage of PLR-induced
changes in cardiac output as a predictor of fluid respon-
siveness is that its accuracy seemed unaffected by venti-
lation mode, underlying cardiac rhythm, and technique of
measurements.57 ∆CIPLR is also completely reversible,4,60,61
and therefore, any detrimental effects of unnecessary fluid
administration are only minimal and temporary.
Limitations
A number of different thresholds were used for fluid respon-
siveness. The most common definition of fluid responsive-
ness was change in stroke volume of >15% as measured by
transesophageal or transthoracic echocardiography. This
­ way with the editorial process or decision.
December 2013 • Volume 117 • Number 6 www.anesthesia-analgesia.org 1389
seemed reasonable, as 15% is more than the expected error
of echocardiographic measurements and is generally consid-
ered clinically relevant. Other studies used a 10% increase
as threshold, or measured stroke volume differently, using
transesophageal Doppler, thermodilution or ultrasound
dilution. An increase in mean arterial blood pressure or car-
diac output was also used to define fluid responsiveness,
which in our opinion was inappropriate. An increase in arte-
rial blood pressure or cardiac output would not necessarily
reflect increased stroke volume. All studies measured fluid
responsiveness within 10 minutes of a fluid bolus, except for
2 studies which did not report a time interval.
There was no uniformity in the type, volume, and rate
of fluid bolus across the studies. A slow small volume bolus
of crystalloid would have a different impact on intravascu-
lar volume expansion compared with a rapid large-volume
bolus of colloid. However, the proportion of subjects with a
positive fluid response was consistently approximately 50%
across the studies.
Most of the studies had subjects with a median age
younger than 3 years, but the ranges did vary, and some
included subjects in their late teens. It is difficult to inter-
pret the validity of pooled results from subjects of diverse
weights and physiology (e.g., vascular compliance, stroke
volume). One study included 2 separate age groups,
but their results did not differ significantly between the
age groups.6
All except 1 study involved fewer than 50 fluid boluses.
Most variables were only included in single studies. Only
CVP, PPV, SPV, PVI, and ∆Vpeak were investigated by 4 or
more studies.
Seven studies included patients receiving vasoactive
infusions, which would have affected vascular compliance.
Eighteen of 26 subjects in the Renner et al.7 study received
enoximone and epinephrine after VSD closure. Two of the 5
studies supporting ∆Vpeak as a predictor of fluid responsive-
ness included patients receiving norepinephrine, milrinone,
or dopamine.1,2
Conclusions
ΔVpeak was the only variable to reliably predict fluid respon-
siveness in children. Most static variables did not predict
fluid responsiveness in children, which was consistent with
findings in adults. However, in contrast to adults, dynamic
variables based on arterial blood pressure also did not
predict fluid responsiveness in children. The evidence for
dynamic variables based on plethysmography was incon-
clusive. Children have different lung, vascular, and cardiac
compliances compared with adults. Research is needed to
explain how these affect the ability of dynamic variables to
predict fluid responsiveness in children.
RECUSE NOTE
Maxime Cannesson is the Section Editor for Technology,
Computing, and Simulation for the Journal. This manuscript
was handled by Peter Davis, Section Editor for Pediatric
Anesthesiology, and Dr. Cannesson was not involved in any
 Predicting Fluid Responsiveness in Children

APPENDIX
Representative spectrum?
Clear selection criteria?
Acceptable reference standard?
Acceptable delay between tests?
Partial verification avoided?
Differential verification avoided?
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Was the spectrum of patients representative of the patients who will receive the test in practice?
Were selection criteria clearly described?
Is the reference standard likely to classify the target condition correctly?
Is the time period between reference standard and index test short enough to be reasonably sure
that the target condition did not change between the 2 tests?
Did the whole sample or a random selection of the sample, receive verification using the intended
reference standard?
Did patients receive the same reference standard irrespective of the index test result?

Incorporation avoided? Was the reference standard independent of the index test (i.e. the index test did not form part of the
reference standard)?
Detailed description of index test? Was the execution of the index test described in sufficient detail to permit its replication?
Detailed description of reference standard? Was the execution of the reference standard described in sufficient detail to permit its replication?
Reference standard results blinded? Were the index test results interpreted without knowledge of the results of the reference standard?
Index test results blinded? Were the reference standard results interpreted without knowledge of the results of the index test?
Same clinical data available? Were the same clinical data available when test results were interpreted as would be available when
the test is used in practice?
Interpretable results reported? Were uninterpretable/ intermediate test results reported?
Withdrawals explained? Were withdrawals from the study explained?
Cutoff established before study? Were cutoff values established before the study was started?
Clear definition of “positive” result? Did the study provide a clear definition of what was considered to be a ‘positive’ result?
Reported and acceptable observer variation? Were data on observer variation reported and within an acceptable range?
No commercial funding? Was the study free of commercial funding?

DISCLOSURES
Name: Heng Gan, MBBCh, MRCPCH, FRCA.
Contribution: This author helped design the study, collect and
analyze the data, and prepare this manuscript.
Attestation: This author approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to
declare.
Name: Maxime Cannesson, MD, PhD.
Contribution: This author helped design the study and prepare
this manuscript.
Attestation: This author approved the final manuscript.
Conflicts of Interest: Sironis is a biomedical company I
cofounded in 2010 to develop closed-loop fluid manage-
ment systems and noninvasive hemodynamic monitoring
tools. I hold 37% equity interest in Sironis. During the past 5
years, I have consulted and/or have prepared CME materi-
als for Covidien, Draeger, Philips Medical System, Edwards
Lifesciences, Fresenius Kabi, Masimo Corp., and ConMed.
My department has received research fundings from Edwards
Lifesciences and Masimo Corp. to support clinical studies for
which I act as principal investigator.
Name: John R. Chandler, MBBCh, FCARCSI, FDSRDS.
Contribution: This author helped prepare this manuscript.
Attestation: This author approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to
declare.
Name: J. Mark Ansermino, MBBCh, MSc (Inf), FFA (SA),
FRCPC.
Contribution: This author helped design the study, analyze the
data, and prepare this manuscript.
Attestation: This author approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to
declare.
ACKNOWLEDGMENTS
Partial salary support for HG was received from a Canadian
Institutes of Health Research Grant to JMA. The authors wish
to thank Dorothy Myers (manuscript presentation) and Guohai
Zhou (statistical analysis) for their contributions.
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