Open Journal of Anesthesiology, 2013, 3, 413-420
Published Online November 2013 (http://www.scirp.org/journal/ojanes)
http://dx.doi.org/10.4236/ojanes.2013.39087
Open Access OJAnes
413
Extracellular Fluid Accumulation Predicts Fluid
Responsiveness after Hydroxyethyl Starch 70/0.5 Bolus
Infusion during Major Abdominal Surgery
Takeshi Ide1, Tsuneo Tatara2, Takahiko Kaneko2, Shinichi Nishi1
1Department of Intensive Care Medicine, Hyogo College of Medicine, Nishinomiya, Japan; 2Department of Anesthesiology, Hyogo
College of Medicine, Nishinomiya, Japan.
Received September 15th, 2013; revised October 16th, 2013; accepted October 30th, 2013
Copyright © 2013 Takeshi Ide et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Obje ctive: The purpose of this study was to test the hypothesis that extracellular fluid accumulation predicts fluid re-
sponsiveness after hydroxyethyl starch (HES) solution bolus infusion during major abdominal surgery. Methods:
Twenty patients who underwent elective pancreaticoduodenectomy under general anesthesia were studied. Patients re-
ceived 4 mL/kg boluses of Ringer’s acetate or 6% HES 70/0.5 solution over 15 min in random order when urine output
decreased below 1.0 mL/kg/h. Stroke volume variation (SVV) and stroke volume index (SVI) were measured using the
FloTracTM/VigileoTM system at pre-bolus, 15, 30, and 60 min after initiating bolus infusion. The percent change in
pre-bolus extracellular fluid volume relative to that at the skin incision for arm (ΔVECF) was measured by bioelectrical
impedance. Prediction of fluid responsiveness (an increase in SVI of ≥5%) by pre-bolus SVV or pre-bolus ΔVECF was
tested by calculating the area under the receiver operating characteristic curve (AUC). Results: Fluid bolus infusions in
this study consisted of 61 Ringer’s acetate infusions and 62 HES infusions. The best AUCs for identifying fluid respon-
siveness were seen with pre-bolus ΔVECF for HES at 30 min and 60 min (AUC = 0.74, P = 0.022; AUC = 0.74, P =
0.0054, respectively). Optimal threshold values of pre-bolus ΔVECF for predicting fluid responsiveness were 6.5% for 30
min (sensitivity: 78%, specificity: 58%) and 7.7% for 60 min (sensitivity: 56%, specificity: 76%). Conclusion: Ex-
tracellular fluid volume predicts fluid responsiveness after HES solution bolus infusion during major abdominal surgery.
Substantial fluid responsiveness is observed upon increased accumulation of extracellular fluids.
Keywords: Plasma Expanders; Blood Volume; Fluid Therapy; Abdominal Surgery
1. Introduction
Volume replacement with hydroxyethyl starch (HES)
solution according to goal-directed fluid therapy has been
recommended in major abdominal surgery [1-3]. How-
ever, fluid therapy aimed at maximizing cardiac output
by fluid challenge can lead to frequent HES bolus infu-
sions, which should be avoided due to potential adverse
effects on renal and coagulation functions [4,5]. More-
over, HES solution may leak into the interstitial space
with time due to capillary leakage arising from surgical
injury [6], thereby leading to interstitial edema and de-
laying postoperative recovery [7].
While stroke volume variation (SVV) predicts fluid
responsiveness for surgical patients [8], little is known
about the effect of extracellular fluid volume on fluid res-
ponsiveness. Continuous infusion of crystalloid solu-
tion during surgery monotonously increases interstitial
fluid accumulation with time [9], leading to a fall in col-
loid osmotic pressure in the interstitium [10]. Given that
HES induces volume expansion via a colloid osmotic ef-
fect, it is possible that, with increased extracellular fluid
accumulation, HES extracts more fluid from the intersti-
tial space to the intravascular space due to a larger gra-
dient of colloid osmotic pressure across the capillary wall,
thereby increasing fluid responsiveness. This information
may help explore the most effective timing of HES infu-
sion and thus prevent overdose of HES solution during
major abdominal surgery.
Given the inherent difficulties of controlling extracel-
lular fluid volume for patients undergoing surgery, we

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
414
performed a longitudinal analysis of fluid responsiveness
as assessed by stroke volume index (SVI) during long-
duration major abdominal surgery. We [11] and other
groups [12,13] have demonstrated that localized perio-
perative fluid accumulation in the extracellular fluid
space can be quantitatively analyzed by segmental bio-
electrical impedance analysis. The aim of this study was
to test the hypothesis that extracellular fluid accumula-
tion, as measured by bioelectrical impedance, can predict
fluid responsiveness after HES solution bolus infusion
during major abdominal surgery.
2. Materials and Methods
2.1. Patients
This study was approved by the Ethics Review Board of
Hyogo College of Medicine and written informed con-
sent was obtained from each patient after explaining the
study. As data on the effect of extracellular fluid volume
on fluid responsiveness were not available in the litera-
ture, this study was planned as a pilot study. We enrolled
21 consecutive American Society of Anesthesiologists
(ASA) physical status 1 - 3 patients (age range, 20 - 80
years) who were scheduled for elective pancreaticoduo-
denectomy for cancer from February 2010 to July 2011.
Exclusion criteria included cardiac arrhythmia, severe
pulmonary disease, severe renal dysfunction, chronic use
of diuretics, and an expected duration of surgery <6 h.
2.2. Procedure
All patients fasted from midnight on the night before sur-
gery. On arrival to the operating room, Ringer’s acetate
solution (RA) was intravenously infused into a peripheral
vein on the left hand at a rate of 2 mL/kg/h using an in-
travenous catheter. Anesthesia was induced by fentanyl,
propofol and rocuronium. After tracheal intubation, an-
esthesia was maintained with sevoflurane and oxygen in
air, together with a continuous infusion of remifentanil.
Mechanical ventilation was performed with PEEP 5 cm
H2O and tidal volume 8 mL/kg. Diuretics were not used
during surgery.
Hypotension (i.e., systolic arterial blood pressure <80
mmHg) was treated by intravenous administration of
ephedrine in 4 mg increments if heart rate (HR) was <90
beats/minute and phenylephrine in 0.1 mg increments if
HR was >90 beats/minute. Packed red blood cells were
transfused when blood hemoglobin concentration was <8
- 9 g/dL. When massive bleeding (e.g., 30 mL/kg) oc-
curred, fresh frozen plasma was provided.
2.3. Fluid Therapy
At the time of skin incision, the rate of RA infusion was
increased to 4 mL/kg/h (i.e., basal fluid infusion). Urine
output was monitored every hour from the time of skin
incision. If urine output over a 1-hour period decreased
below 1.0 mL/kg, 4 mL/kg fluid boluses of RA solution
or 6% HES solution (HES 70/0.5, average molecular
weight 70,000, molar substitution 0.5, Salinhes®, Fre-
senius-Kabi Japan, Tokyo, Japan) were provided over 15
min instead of basal fluid infusion (Figure 1). After fin-
ishing bolus infusion, RA infusion was restarted at basal
infusion rates (i.e., 4 mL/kg/h). For each bolus infusion,
the choice of RA or HES solution was randomized by a
computerized random number generator. No vasopres-
sors were administered during bolus infusion.
2.4. Hemodynamic Monitoring
A catheter was inserted into the right radial artery and
connected to the FloTracTM/VigileoTM system (ver. 3.02,
Edwards Lifesciences, Irvine, CA, USA) to obtain SVV
and SVI. Hemodynamic variables including mean arterial
blood pressure (MAP), HR, SVV, and SVI were re-
corded.
2.5. Bioelectrical Impedance Analysis
Multifrequency segmental bioelectrical impedance analy-
sis was conducted for the right arm every hour after skin
incision. Body resistance and reactance were measured
using a multifrequency bioimpedance analyzer (4200
Hydra, Xitron Technologies, San Diego, CA, USA). The
resistance at zero frequency (corresponding to resistance
for extracellular fluid, Re) was determined by performing
Figure 1. Study protocol. Patients received 4 mL/kg boluses
of Ringer’s acetate (RA) or hydroxyethyl starch (HES) solu-
tion over 15 min in random order when urine output de-
creased below 1.0 mL/kg/h. Time 0 denotes the time of skin
incision. ΔVECF: percent change of extracellular fluid volu-
me relative to that at skin incision; SVV: stroke volume va-
riation; SVI: stroke volume index; ΔSVV: change of SVV
after start of bolus infusion relative to pre-bolus; ΔSVI:
change of SVI after start of bolus infusion relative to pre-
bolus.
Open Access OJAnes

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
415
non-linear curve-fitting and subsequent extrapolation of
impedance values at 50 frequencies from 5 kHz to 1
MHz. Current-injecting electrodes were placed at the
dorsal surface of the third metacarpal bone of the right
hand and the center of the anterior face of the right hu-
meral head.
The detector electrodes were placed at the anterior part
of the right wrist and 5 cm distal to the center of the an-
terior face of the right humeral head. While high-fre-
quency current passes through cell membranes and thus
reflects total body fluid volume, low-frequency current
passes only through extracellular fluid space due to cell
membrane capacitance [14]. Based on the assumption
that the electrical properties of body tissues are similar to
those of a concentrated suspension of spherical particles
(cells) in the outer conducting medium (extracellular
fluid), the extracellular fluid volume for the arm (VECF,
mL/kg) is related to the resistivity of the arm at zero fre-
quency (ρ, ohm·cm) [11,14]:
23
ECF
ECF
V
VW





(1)
where V is the volume of the arm (cm3), W is body
weight (kg), and ρECF is the resistivity of extracellular
fluid (= 50 ohm·cm). Given that the value of ρ is propor-
tional to Re in the same patient, percent changes of VECF
relative to baseline (i.e., at the skin incision) (ΔVECF) is
calculated as ([Re value relative to baseline]−2/3−1) multi-
plied by 100.
2.6. Data Analysis
Pre-bolus (i.e., immediately before infusion) values for
MAP, HR, and volume of urine produced during a 1-hour
period from the start of infusion (mL/kg) were obtained.
Pre-bolus ΔVECF and changes in SVV (i.e., ΔSVV in %)
and SVI (i.e., ΔSVI in %) at 15 min, 30 min, and 60 min
after the start of infusion relative to pre-bolus were cal-
culated.
2.7. Statistical Analysis
Data are expressed as mean (SD) or median (interquartile
range) depending on the distribution. Time to bolus infu-
sion (defined as hours from the time of skin incision to
the time when the fluid bolus was started); pre-bolus
values including MAP, HR, SVV, SVI, and ΔVECF; urine
volume during a 1-hour period from the start of infusion;
ΔSVV; and ΔSVI were compared between RA and HES
boluses using the Student’s t-test or Mann-Whitney
rank-sum test. Data for pre-bolus ΔVECF for all fluid bo-
luses were analyzed using linear regression, with pre-
bolus SVV set as an independent variable. One-way re-
peated measures analysis of variance with the Student-
Newman-Keuls post hoc test was used to compare ΔSVI
between 15 min, 30 min, and 60 min after the start of in-
fusion for RA and HES boluses.
Fluid responsiveness was defined as an increase in
SVI of ≥5%. Pre-bolus values of SVV and ΔVECF were
compared between non-responding boluses and respond-
ing boluses for RA and HES. The prediction of fluid re-
sponsiveness by pre-bolus SVV or pre-bolus ΔVECF was
tested by calculating the area under the receiver operat-
ing characteristic curves (AUCs) with 95% confidence
intervals (CIs). Threshold values for pre-bolus SVV and
pre-bolus ΔVECF were determined to maximize both sen-
sitivity and specificity. GraphPad Prism 5 (GraphPad
Software Inc., San Diego, CA, USA) and SigmaPlot 12
(Systat Software Inc., Chicago, IL, USA) were used for
statistical analysis. P < 0.05 was considered statistically
significant.
3. Results
3.1. Patient Characteristics
One patient was excluded from the analysis because the
surgical procedure was changed to a palliative surgery
that lasted <6 h. Patient characteristics and intraoperative
parameters are shown in Table 1. Fresh frozen plasma
was provided to two patients (7.3 mL/kg and 14.8
mL/kg).
3.2. Comparison of RA and HES Bolus Infusion
Parameters
We performed a total of 123 fluid bolus infusions (RA: n
Table 1. Patient characteristics and intraoperative parame-
ters.
Variable N = 20
Gender (male/female) 13/7
Age (yr) 67 (11)
Weight (kg) 56 (10)
Body mass index (kg/m2) 21.7 (3.1)
Duration of surgery (h) 10.4 (2.3)
ASA status (1/2/3) 0/12/8
RA solution (mL/kg) 58.0 (12.4)
HES solution (mL/kg) 15.6 (9.3 - 18.7)
PRBC (mL/kg) 5.9 (0 - 10.4)
Urine output (mL/kg) 9.8 (3.7)
Blood loss (mL/kg) 15.4 (12.0 - 26.6)
Data are presented as mean (SD) or median (interquartile range) depending
on distribution. RA: Ringer’s acetate; HES: hydroxyethyl starch; PRBC:
packed red blood cells.
Open Access OJAnes

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
Open Access OJAnes
416
= 61, 3.1 [1.1] times per patient; HES: n = 62, 3.1 [1.0]
times per patient). There were no significant differences
between RA and HES boluses with respect to time to
bolus infusion, urine volume during a 1-hour period, and
pre-bolus values of MAP, HR, SVV, SVI, and ΔVECF
(Table 2). ΔSVV between RA and HES boluses was
significantly different at 15 min (0.08% vs. −0.21%, P =
0.0075) and 30 min (0.19% vs. −0.21%, P = 0.048).
ΔSVI between RA and HES boluses was also signifi-
cantly different at 15 min (−0.33% vs. 0.59%, P = 0.010).
There was no correlation between pre-bolus SVV and
pre-bolus ΔVECF (r2 = 0.017, P = 0.15).
The HES bolus showed a larger ΔSVI value at 60 min
compared to values at 15 min (P = 0.034) and 30 min (P
= 0.047), while there was no difference in ΔSVI for the
RA bolus (P = 0.78).
3.3. Comparison of Pre-Bolus SVV and ΔVECF
between Non-Responding and Responding
Fluid Boluses
There were no differences in pre-bolus SVV between
non-responding and responding fluid boluses for RA and
HES at 15, 30, and 60 min after initiating bolus infusion
(Figure 2). While the RA bolus did not show significant
differences in pre-bolus ΔVECF between non-responding
and responding fluid boluses, pre-bolus ΔVECF for the
responding HES bolus was larger compared to that of the
non-responding HES bolus at 30 min (P = 0.0072) and 60
min (P = 0.0019) after initiating bolus infusion (Figure
3).
3.4. Prediction of Fluid Responsiveness
Receiver operating characteristic curves for predicting
fluid responsiveness for RA and HES boluses by pre-
bolus SVV and pre-bolus ΔVECF are shown in Figures 4
and 5, respectively.
The best AUCs for identifying fluid responsiveness
were seen with pre-bolus ΔVECF for HES at 30 min and
60 min (AUC = 0.74 [0.08], P = 0.022; AUC = 0.74
[0.07], P = 0.0054, respectively). Optimal threshold val-
ues of pre-bolus ΔVECF for predicting fluid responsive-
ness were 6.5% for 30 min with a sensitivity of 78%
Table 2. Comparison of hemodynamic parameters between bolus infusions of Ringer’s acetate (RA) and hydroxyethyl starch
(HES) solutions.
Variable RA bolus (N = 61) HES bolus (N = 62) Mean Difference* P-value
Time to bolus infusion (h) 4.9 (2.9) 5.0 (2.9) −1.0 to 1.0 0.97
Urine volume (mL/kg)† 0.87 (0.64) 0.86 (0.51) −0.19 to 0.22 0.91
Blood loss (mL/kg) 2.2 (1.9) 2.4 (2.4) −0.89 to 0.66 0.78
PRBC (mL/kg)† 0.79 (1.59) 0.79 (1.58) −0.56 to 0.56 0.99
Vasopressor use (times)# 0.8 (1.4) 0.7 (1.1) −0.4 to 0.5 0.79
Pre-bolus values
MAP (mmHg) 72 (15) 71 (14) −3 to 7 0.48
HR (beats/minute) 77 (16) 81 (16) −9 to 2 0.20
SVV (%) 13.2 (5.3) 13.0 (5.1) −1.6 to 2.0 0.82
SVI (mL/m2) 37.4 (7.2) 37.0 (6.9) −2.1 to 2.9 0.77
ΔVECF (%) 6.5 (4.8) 6.2 (4.4) −1.3 to 1.9 0.72
ΔSVV at 15 min (%) 0.08 (0.55) −0.21 (0.62) 0.08 to 0.49 0.0075
at 30 min (%) 0.19 (1.10) −0.21 (1.11) 0.00 to 0.79 0.048
at 60 min (%) 0.01 (2.08) −0.39 (2.02) −0.32 to 1.12 0.28
ΔSVI at 15 min (%) −0.33 (1.92) 0.59 (1.96)$ −1.60 to −0.23 0.010
at 30 min (%) −0.41 (3.59) 0.86 (4.05)$ −2.63 to 0.08 0.067
at 60 min (%) −0.06 (7.08) 1.95 (7.55) −4.60 to 0.57 0.13
Data are presented as mean (SD) or median (interquartile range). MAP: mean arterial blood pressure; HR: heart rate; SVV: stroke volume variation; SVI: stroke
volume index; ΔVECF: percent change of extracellular fluid volume relative to that at skin incision; ΔSVV: change of SVV after start of bolus infusion relative to
pre-bolus; ΔSVI: change of SVI after start of bolus infusion relative to pre-bolus. *95% confidence interval; †during a 1-hour period from the start of bolus
infusion; #intravenous administration of ephedrine or phenylephrine during a 15 - 60 min period after the start of bolus infusion; $difference compared to 60 min
(P < 0.05). No vasopressor was used during the 0 - 15 min period after the start of bolus infusion according to the protocol. Time to bolus infusion denotes
ours from the time of skin incision to the time when the fluid bolus was initiated. h

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
417
Figure 2. Comparison of pre-bolus stroke volume variation
(SVV) between non-responding (NR) and responding (R)
fluid boluses for Ringer’s acetate (RA, n = 61) or hydro-
xyethyl starch (HES, n = 62) at 15, 30, and 60 min after
initiating bolus infusion. Data are presented as mean (SD).
Figure 3. Comparison of pre-bolus percent changes of ex-
tracellular fluid volume relative to that at skin incision
(ΔVECF) between non-responding (NR) and responding (R)
fluid boluses for Ringer’s acetate (RA, n = 61) or hydro-
xyethyl starch (HES, n = 62) at 15, 30, and 60 min after ini-
tiating bolus infusion. Data are presented as mean (SD).
(95% CI, 40% to 97%) and a specificity of 58% (95% CI,
44% to 72%), and 7.7% for 60 min with a sensitivity of
Figure 4. Receiver operating characteristic curve showing
the ability of pre-bolus stroke volume variation to predict
fluid responsiveness for Ringer’s acetate (RA, n = 61) or hy-
droxyethyl starch (HES, n = 62). AUC: area under the re-
ceiver operating characteristic curve.
Figure 5. Receiver operating characteristic curve showing
the ability of pre-bolus percent changes of extracellular
fluid volume relative to that at skin incision to predict fluid
responsiveness for Ringer’s acetate (RA, n = 61) or hydro-
xyethyl starch (HES, n = 62). AUC: area under the receiver
operating characteristic curve.
Open Access OJAnes

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
418
56% (95% CI, 30% to 80%) and a specificity of 76%
(95% CI, 61% to 87%).
4. Discussion
The major finding of the present study was that the re-
sponding fluid bolus for HES showed a larger pre-bolus
ΔVECF compared to the non-responding fluid bolus. The
optimal threshold value of pre-bolus ΔVECF for predicting
fluid responsiveness after HES bolus infusion was 6% -
8%.
A comparison of cardiac preload change (i.e., ΔSVV)
and fluid responsiveness (i.e., ΔSVI) between RA and
HES boluses was not the primary aim of this study. The
RA bolus served as a control for the HES bolus given
that values of ΔSVV and ΔSVI are affected by not only
the type of fluid solution but also various factors such as
surgical stress and blood loss. Fluid bolus loading was
conducted based on urine output. While urine output is
not a validated criterion for fluid bolus during surgery,
urine output is a routinely used clinical parameter for
deciding on fluid bolus loading [15]. Moreover, a SVV-
guided fluid bolus (e.g., SVV > 13%) may be inappro-
priate for this study because it would result in a narrow
range of pre-bolus SVV.
Contrary to our expectations, pre-bolus SVV did not
predict fluid responsiveness after HES bolus infusion.
The threshold of SVV for fluid responsiveness defined as
an increase in cardiac output (e.g., 12%) was reported to
range from 9.5% to 12.5% [16]. Despite that the mean
value of pre-bolus SVV for HES bolus infusions in the
present study (13%) falls within this range, HES bolus
infusion on average caused only a minimal SVV de-
crease (0.2%) and SVI increase (0.6%) at the end of fluid
infusion. This SVV decrease was much smaller com-
pared to the 3% SVV decrease after a 250 mL bolus in-
fusion of HES 130/0.4 solution during major abdominal
surgery in another study [17]. Based on this, we defined
fluid responsiveness as an increase in SVI of ≥5%, which
is smaller than values usually used (e.g., 10%) [18]. In-
deed, ongoing blood loss (2.4 mL/kg on average) may be
responsible for the small increase in cardiac preload after
HES bolus infusion and substantial fluid unresponsive-
ness in our study. However, capillary leakage due to sur-
gical injury may also be involved in that it can lead to
poor plasma volume expansion [19]. This possibility is
supported by the finding that HES was infused at 5.7 h
on average after skin incision and the peak of microvas-
cular permeability at the surgical site begins at 3 or 4
hours after surgical injury [20].
No correlation was found between pre-bolus SVV and
pre-bolus ΔVECF ranging from 0.1% to 16% (r2 = 0.017),
suggesting that fluid accumulates in the extracellular
fluid space independently of intravascular volume status.
For HES, we found a larger pre-bolus ΔVEC F in respond-
ing boluses compared to non-responding boluses at 30
min and 60 min after initiating bolus infusion (Figure 3).
Given that bioelectrical resistance at zero frequency re-
flects extracellular fluid volume changes mainly in the
interstitium [11-13,21], this finding suggests that HES
enhances intravascular volume expansion by extracting
accumulated fluid from the interstitium to the intravas-
cular space due to a colloid osmotic effect. This increases
in intravascular volume by HES may have increased car-
diac preload, thereby increasing stroke volume in the
steep portion of the Frank-Starling curve. This scenario is
consistent with a previous study in healthy volunteers
showing that gelatin infusion increased blood volume,
while it decreased extracellular fluid volume as assessed
by the conductivity technique [22]. This scenario is also
supported by the significantly large ΔSVI at 60 min
compared to those at 15 min and 30 min after initiating
HES bolus infusion (Table 2), suggesting that this fluid
shift takes up to an hour to complete.
The validity of uncalibrated cardiac output measure-
ment using Vigileo-FloTrac system has not yet been fully
established. However, two recent studies showed that the
third-generation Vigileo-FloTrac device, which was also
used in this study, demonstrated improved precision of
cardiac output measurement compared to the previous
version, and could accurately track changes in cardiac
output in anesthetized patients [23,24]. Longitudinal
analysis of fluid bolus infusion is another problem in our
study because the effects of each infusion on SVV and
SVI changes were not completely independent. Moreover,
SVI values are affected by the balance of surgical stress
and depth of anesthesia, which may differ depending on
the surgical procedure. However, given that these prob-
lems are common to RA and HES boluses, a significantly
large pre-bolus ΔVECF for responding boluses compared
to non-responding boluses for HES suggests that fluid
responsiveness after HES bolus infusion depends on ex-
tracellular fluid volume. Finally, we used bioelectrical
impedance to assess extracellular fluid volume. Given
that bioelectrical impedance electrically measures ex-
tracellular fluid volume, absolute value of extracellular
fluid volume predicted by this method is not identical
with anatomical value of extracellular fluid volume [11].
However, as relative change of bioelectrical impedance
in the same patient could detect time-course of extracel-
lular fluid accumulation in surgical patients [11-13], this
problem is unlikely to affect our conclusion.
Goals for fluid optimization, such as cardiac output
and stroke volume, mainly relate to intravascular volume
but provide no information on extracellular fluid volume.
Our study showed that increased cardiac preload (i.e.,
decrease in SVV) at the end of HES bolus infusion may
Open Access OJAnes

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
419
be reduced due to capillary leakage arising from surgical
injury. Yet, upon enhanced accumulation of extracellular
fluid, HES bolus infusion can recover cardiac preload
and fluid responsiveness 30 - 60 min after bolus infusion
by extracting more fluid from the interstitial space. The
threshold of pre-bolus ΔVECF for exerting this effect was
6% - 8%, corresponding to 12 - 16 mL/kg of extracellular
fluid accumulation in the entire body. The dependence of
fluid responsiveness after HES bolus infusion on ex-
tracellular fluid volume should be taken into account
when determining the optimal timing and right volume of
HES infusion for intra- and postoperative use in patients
undergoing major abdominal surgery. Our findings sug-
gest that HES use is preferable during the later stages of
surgery when interstitial fluid accumulates, thereby pre-
venting HES overdose.
In conclusion, our finding suggests that extracellular
fluid volume can predict fluid responsiveness after HES
bolus infusion during major abdominal surgery, which
becomes larger with interstitial fluid accumulation.
5. Acknowledgements
We thank Dr. Maxime Cannesson for critical comments
and valuable suggestions. This work was supported by
Grants-in-Aid for Scientific Research (C) [No. 20591846]
and [No. 24592365] from the Ministry of Education,
Science and Culture of Japan. Tsuneo Tatara received
speaking fees from Edwards Lifesciences and Fresenius
Kabi Japan.
REFERENCES
[1] T. J. Gan, A. Soppitt, M. Maroof, et al., “Goal-Directed
Intraoperative Fluid Administration Reduces Length of
Hospital Stay after Major Surgery,” Anesthesiology, Vol.
97, No. 4, 2002, pp. 820-826.
http://dx.doi.org/10.1097/00000542-200210000-00012
[2] A. Donati, S. Loggi, J.-C. Preiser, et al., “Goal-Directed
Intraoperative Therapy Reduces Morbidity and Length of
Hospital Stay in High-Risk Surgical Patients,” Chest, Vol.
132, No. 6, 2007, pp. 1817-1824.
http://dx.doi.org/10.1378/chest.07-0621
[3] M. Bundgaard-Nielsen, K. Holte, N. H. Secher and H.
Kehlet, “Monitoring of Peri-Operative Fluid Administra-
tion by Individualized Goal-Directed Therapy,” Acta An-
aesthesiologica Scandinavica, Vol. 51, No. 3, 2007, pp.
331-340.
http://dx.doi.org/10.1111/j.1399-6576.2006.01221.x
[4] C. S. Hartog, M. Bauer and K. Reinhart, “The Efficacy
and Safety of Colloid Resuscitation in the Critically Ill,”
Anesthesia & Analgesia, Vol. 112, No. 1, 2011, pp. 156-
164. http://dx.doi.org/10.1213/ANE.0b013e3181eaff91
[5] C. S. Hartog, M. Kohl and K. Reinhart, “A Systematic
Review of Third-Generation Hydroxyethyl Starch (HES130/
0.4) in Resuscitation: Safety Not Adequately Addressed,”
Anesthesia & Analgesia, Vol. 112, No. 3, 2011, pp. 635-
645. http://dx.doi.org/10.1213/ANE.0b013e31820ad607
[6] D. Chappell, M. Jacob, K. Hofmann-Kiefer, et al., “A
Rational Approach to Perioperative Fluid Management,”
Anesthesiology, Vol. 109, No. 4, 2008, pp. 723-740.
http://dx.doi.org/10.1097/ALN.0b013e3181863117
[7] J.-L. Vincent, “Let’s Give Some Fluid and See What
Happens” versus the “Mini-Fluid Challenge,” Anesthesi-
ology, Vol. 115, No. 3, 2011, pp. 455-456.
http://dx.doi.org/10.1097/ALN.0b013e318229a521
[8] M. Cannesson, “Non-Invasive Guidance of Fluid Ther-
apy,” In: R. G. Hahn, Ed., Clinical Fluid Therapy in the
Perioperative Setting, Cambridge University Press, Cam-
bridge, 2011, pp. 103-111.
http://dx.doi.org/10.1017/CBO9780511733253
[9] T. Tatara, Y. Nagao and C. Tashiro, “Effect of Duration
of Surgery on Fluid Balance during Abdominal Surgery:
A Mathematical Model,” Anesthesia & Analgesia, Vol.
109, No. 1, 2009, pp. 211-216.
http://dx.doi.org/10.1213/ane.0b013e3181a3d3dc
[10] K. Aukland and R. K. Reed, “Interstitial-Lymphatic Me-
chanisms in the Control of Extracellular Fluid Volume,”
Physiological Reviews, Vol. 73, No. 1, 1993, pp. 1-78.
[11] T. Tatara and K. Tsuzaki, “Segmental Bioelectrical Im-
pedance Analysis Improves the Prediction for Extracellu-
lar Water Volume Changes during Abdominal Surgery,”
Critical Care Medicine, Vol. 26, No. 3, 1998, pp. 470-
476.
http://dx.doi.org/10.1097/00003246-199803000-00017
[12] D. Bracco, J.-P. Revelly, M. M. Berger and R. Chioléro,
“Bedside Determination of Fluid Accumulation after Car-
diac Surgery Using Segmental Bioelectrical Impedance,”
Critical Care Medicine, Vol. 26, No. 6, 1998, pp. 1065-
1070.
http://dx.doi.org/10.1097/00003246-199806000-00029
[13] D. Bracco, M. M. Berger, J.-P. Revelly, et al., “Segmen-
tal Bioelectrical Impedance Analysis to Assess Periopera-
tive Fluid Changes,” Critical Care Medicine, Vol. 28, No.
7, 2000, pp. 2390-2396.
http://dx.doi.org/10.1097/00003246-200007000-00034
[14] A. De Lorenzo, A. Andreoli, J. Matthie and P. Withers,
“Predicting Body Cell Mass with Bioimpedance by Using
Theoretical Methods: A Technological Review,” Journal
of Applied Physiology, Vol. 82, No. 5, 1997, pp. 1542-
1558.
[15] V. Nisanevich, I. Felsenstein, G. Almogy, et al., “Effect
of Intraoperative Fluid Management on Outcome after In-
traabdominal Surgery,” Anesthesiology, Vol. 103, No. 1,
2005, pp. 25-32.
http://dx.doi.org/10.1097/00000542-200507000-00008
[16] J. Renner, J. Scholz and B. Bein, “Monitoring Fluid Ther-
apy,” Best Practice & Research Clinical Anaesthesiology,
Vol. 23, No. 2, 2009, pp. 159-171.
http://dx.doi.org/10.1016/j.bpa.2008.12.001
[17] D. Lahner, B. Kabon, C. Marschalek, et al., “Evaluation
of Stroke Volume Variation Obtained by Arterial Pulse
Contour Analysis to Predict Fluid Responsiveness Intra-
operatively,” British Journal of Anaesthesia, Vol. 103,
Open Access OJAnes

Extracellular Fluid Accumulation Predicts Fluid Responsiveness after Hydroxyethyl Starch 70/0.5
Bolus Infusion during Major Abdominal Surgery
Open Access OJAnes
420
No. 3, 2009, pp. 346-351.
http://dx.doi.org/10.1093/bja/aep200
[18] T. E. Miller and T. J. Gan, “Goal-Directed Fluid Ther-
apy,” In: R. G. Hahn, Ed., Clinical Fluid Therapy in the
Perioperative Setting, Cambridge University Press, Cam-
bridge, 2011, pp. 91-102.
http://dx.doi.org/10.1017/CBO9780511733253.012
[19] J. Persson and P.-O. Grände, “Plasma Volume Expansion
and Transcapillary Fluid Exchange in Skeletal Muscle of
Albumin, Dextran, Gelatin, Hydroxyethyl Starch, and Sa-
line after Trauma in the Cat,” Critical Care Medicine,
Vol. 34, No. 9, 2006, pp. 2456-2462.
http://dx.doi.org/10.1097/01.CCM.0000233876.87978.A
B
[20] J. C. Fantone and P. A. Ward, “Inflammation,” In: E.
Rubin and J. L. Farber, Eds., Pathology, Lippincott-Ra-
ven Publishers, Philadelphia, 1999, pp. 37-75.
[21] B. T. Tedner, H. S. Jacobson, D. Linnarsson and L. E.
Lins, “Impedance Fluid Volume Monitoring during In-
travenous Infusion in Healthy Subjects,” Acute Care, Vol.
10, No. 3-4, 1983, pp. 200-206.
[22] C. G. Olthof, J. P. P. M. de Vries, P. M. J. M. de Vries, et
al., “The Influence of Ringer’s Lactate and Gelatin Infu-
sion on the Internal Fluid Balance of Healthy Volunteers
Measured by a Non-Invasive Conductivity Technique,”
European Journal of Anaesthesiology, Vol. 10, No. 6,
1993, pp. 397-402.
[23] G. Biancofiore, L. A. H. Critchley, A. Lee, et al., “Eva-
luation of a New Software Version of the Flotrac/Vigileo
(Version 3.02) and a Comparison with Previous Data in
Cirrhotic Patients Undergoing Liver Transplant Surgery,”
Anesthesia & Analgesia, Vol. 113, No. 3, 2011, pp. 515-
522.
[24] L. Meng, N. P. Tran, B. S. Alexander, et al., “The Impact
of Phenylephrine, Ephedrine, and Increased Preload on
Third-Generation Vigileo-FloTrac and Esophageal Dop-
pler Cardiac Output Measurements,” Anesthesia & Anal-
gesia, Vol. 113, No. 4, 2011, pp. 751-757.