Gynecologic Oncology 151 (2018) 299–305

Contents lists available at ScienceDirect

Gynecologic Oncology

journal homepage: www.elsevier.com/locate/ygyno

Goal-directed hemodynamic management in patients undergoing

primary debulking gynaecological surgery: A matched-controlled
precision medicine study
Andrea Russo a ,b , Paola Aceto a ,b ,⁎, Domenico Luca Grieco a ,b , Gian Marco Anzellotti a ,b , Valter Perilli a ,b ,
Barbara Costantini c ,d , Bruno Romanò a ,b , Giovanni Scambia c ,d , Liliana Sollazzi a ,b , Massimo Antonelli a ,b
a
Department of Anesthesia, Emergency and Intensive Care Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
b
Institute of Anesthesiology and Intensive Care Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
c
Department of Women's and Children's health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
d
Institute of Obstetrical and Gynecological clinic, Università Cattolica del Sacro Cuore, Rome, Italy

H I G H L I G H T S

• GDHM may help limit intraoperative fluids amount without generating hyperlactatemia in patients with advanced ovarian cancer.
• GDHM may enhance bowel function recovery after primary debulking gynaecological surgery.
• GDHM may shorten length of postoperative hospital stay in high tumor-load patients without comorbidities.

a r t i c l e i n f o a b s t r a c t

Article history: Background. Usefulness of intraoperative goal-directed hemodynamic management (GDHM) for patients
Received 18 July 2018 without comorbidities is debated. After clinical implementation of a pulse contour analysis-guided GDHM proto-
Received in revised form 23 August 2018 col, which foresees early vasopressor use for recruiting unstressed volume, we conducted a matched-controlled
Accepted 26 August 2018
analysis to explore its impact on the amount of fluids intraoperatively administered to patients without comor-
Available online 7 September 2018
bidities who underwent extended abdominal surgery for ovarian cancer.
Keywords:
Methods. After 1:1 matching accounting for body mass index, oncologic disease severity and intraoperative
Fluid-therapy blood losses, 22 patients treated according to this GDHM protocol were compared to a control group of 22 pa-
Hemodynamic monitoring tients who had been managed according to the clinical decision of attending physicians, taken without advanced
Perioperative management monitoring. Results are displayed as median[interquartile range].
Patient-centered care Results. All analyzed patients underwent radical hysterectomy, bilateral adnexectomy, bowel resection,
Personalized medicine peritonectomy and extended pelvic/periaortic lymphadenectomy; median length of surgery was 517
[480–605] min in patients receiving GDHM and 507[480–600] min in control group. Intraoperatively, patients
undergoing GDHM received less fluids (crystalloids 2950[2700–3300] vs. 5150[4700–6000] mL, p b 0.001; col-
loids 100[50–200] vs. 750[500–1000] mL, p b 0.001) and showed a trend to more frequent vasopressor admin-
istration (32 vs 9%, p = 0.13). Greater intraoperative diuresis (540[480–620] mL vs. 450[400–500] mL, p =
0.007), lower blood lactates at surgery end (1.5[1.1–2] vs. 4.1[3.3–5] mmol/L, p b 0.001), shorter time to bowel
function recovery (1 [1, 2] vs. 4 [3–5] days, p b 0.001) and hospital discharge (7 [6–8] vs 12 [9–16] days, p b
0.0001) were detected in patients receiving GDHM.
Conclusions. In high-tumor load gynaecological patients without comorbidities who receive radical and
prolonged surgery, intraoperative use of this novel GDHM protocol helped limit fluids administration with safety.
© 2018 Elsevier Inc. All rights reserved.

1. Introduction

Primary debulking surgery appears as the optimal first-line ap-

⁎ Corresponding author at: Department of Anesthesiology and Intensive Care,
Fondazione Policlinico Universitario A. Gemelli IRCCS, “A.Gemelli” Hospital, Largo A.
Gemelli, 8, 00168 Rome, Italy.
E-mail address: pa.aceto@gmail.com (P. Aceto).
proach in patients with advanced ovarian cancer [1,2], but carries the
risk of high postoperative morbidity (up to 50%) [3]. Preoperative clini-
cal conditions and the extension of surgical procedure are the most

https://doi.org/10.1016/j.ygyno.2018.08.034
0090-8258/© 2018 Elsevier Inc. All rights reserved.
300 A. Russo et al. / Gynecologic Oncology 151 (2018) 299–305
relevant factors affecting short-term clinical outcome; indeed, postop-
erative complications can also occur in otherwise healthy patients re-
quiring radical and prolonged surgery [4]. Raising evidence suggests
that intraoperative hemodynamic management affects clinical outcome
in the setting of major abdominal surgery [5,6]. In particular, it is well
acknowledged that both fluid overload and hypovolemia with hypoper-
fusion contribute to the development of postoperative complications
[7,8]: thus, clinicians must often search for the optimal balance between
the need for hemodynamic support and the commitment of restricting
intravenous fluids administration [9].
Pulse-contour analysis allows continuous monitoring of cardiac out-
put/index (CO/CI) and stroke volume variation (SVV) with a minimally
invasive technique and may help tailor hemodynamic interventions on
patient's individual needs. In high-risk patients, systematic protocols
providing goal-directed hemodynamic support have been shown to re-
duce the risk of both hypovolemia and fluid overload, finally reducing
the rate of postoperative complications and shortening the length of
postoperative hospital stay [6,10–15]. Differently, goal directed therapy
may not benefit aerobically fit patients receiving short and low-risk sur-
gery [16]. Nevertheless, whether such approach may be feasible and
useful in patients without relevant comorbidities but receiving large,
radical and prolonged surgery has not been specifically investigated
and remains debated [9,17].
We conducted a pilot matched-controlled study to determine the ef-
fects of a hemodynamic protocol guided by continuous CO and SVV
monitoring by pulse contour analysis and providing goal-directed man-
agement (GDHM), as compared to standard care by expert
anaesthesiologists, on the amount of crystalloids intraoperatively ad-
ministered to ASA (American Society of Anesthesiologists) physical sta-
tus II patients (without comorbidities nor functional limitations)
undergoing primary debulking gynaecological surgery due to high
tumor load.
2. Methods
The GDHM protocol was based on the measurements provided by
pulse contour analysis with Vigileo™ monitor (Edwards, Lifesciences,
Irvine, CA, USA), which was introduced in our tertiary care university
hospital for clinical purposes in 2014 as a part of the hemodynamic
monitoring in patients expected to undergo radical and prolonged sur-
gery for ovarian cancer, irrespectively of the ASA physical status. We ret-
rospectively compared in a matched-controlled analysis the patients
who had received this GDHM with a control group of patients that
had undergone similar surgical and anesthesia procedures in the same
time period but whose hemodynamic management was carried out ac-
cording to the clinical decision of the attending anesthesiologist. The
study was approved by local Ethics Committee and written informed
consent to data analysis was obtained by all studied patients.
2.1. Patients
Between January 1st, 2014 and December 31st, 2015, all patients
with no comorbidities nor functional limitations (ASA physical status
2 due to high tumor load) who were diagnosed with ovarian cancer
with a laparoscopic predictive index value (PIV) N 6 and received pri-
mary cytoreductive open abdominal surgery in our dedicated surgical
division were considered eligible for being included in the analysis
[18]. Age b 18 and N65 years, body mass index b20 and N30 kg/m2
and duration of surgery b 300 min were the main non-inclusion criteria.
PIV was assessed during a first-look laparoscopic staging by an ex-
pert and trained surgeon according to a standardized approach de-
scribed elsewhere [19]; essentially, PIV rates cancer extension and
takes into account the presence of omental cake, peritoneal extensive
carcinomatosis, diaphragmatic confluent carcinomatosis, bowel infiltra-
tion, stomach and/or spleen and/or less omentum infiltration, superfi-
cial liver metastases and mesenteric retraction [20,21].
All patients who underwent a standard anesthesia protocol and sim-
ilar surgical procedures were considered for the analysis. For this pur-
pose, we only included patients who underwent all of the following
interventions: radical hysterectomy, bilateral adnexectomy, one or
more bowel resection, peritonectomy, pelvic lymphadenectomy and
extended periaortic lymphadenectomy. Surgeons were not aware of
the hemodynamic management administered to the patient.
The anesthesia protocol required for inclusion in the analysis is the
one that was established by internal guidelines in 2012 and was used
in clinical practice by attending anesthesiologists at the time of the
study, and includes: anesthesia induction with propofol 2–3 mg kg−1 ,
fentanyl 1.5–2.5 μg kg−1 and rocuronium bromide 0.9 mg kg−1 ; main-
tenance provided by sevoflurane titrated to keep bi-spectral index
values between 40 and 60%, continuous infusion remifentanil 0.05–0.4
μg kg−1 /min, repeated boluses of rocuronium bromide 0.02 mg kg−1
to maintain a train of four of 1–3 by neuromuscular monitoring; postop-
erative analgesia provided by an elastomeric pump containing trama-
dol, in addition to the ultrasound-guided block of the abdomen
transverse plane, which is obtained with 40 mL Ropivacaine 0.2%. Ac-
cording to our standard monitoring for gynaecological surgery, all pa-
tients were monitored with pulse oximetry, five‑lead
electrocardiogram, invasive blood pressure (20-G cannula in the radial
artery), train of four by neuromuscular twitch, bi-spectral index. In pa-
tients treated with GDHM, SVV and CI were also continuously assessed
by uncalibrated pulse contour analysis (20-G cannula in the radial ar-
tery connected to Vigileo™ monitor, Edwards, Lifesciences, Irvine, CA,
USA). Patients that had received epidural analgesia were excluded be-
cause of possible interferences with GDHM protocol [22].
All patients received tracheal intubation and mechanical ventilation
in the volume-control mode. Because ventilator settings may affect the
efficacy of dynamic variables to predict fluid responsiveness, a stan-
dardized tidal volume of 8 mL/kg of predicted body weight with PEEP
5 cmH2O was delivered to all patients in GDHM group [23]. In control
group, only patients that had received tidal volume within 6–8 mL/kg
and PEEP within 2–7 cmH2O for the whole surgical procedure were con-
sidered eligible for the analysis. In both groups respiratory rate was ti-
trated to maintain end-tidal CO2 within the physiological range and
FiO2 was set at 0.4.
In addition, as a standard of care in our institution, hemoglobin was
kept ≥8 g/dL throughout surgical procedure and a forced-air warming
system (Bair Hugger Model 505, Arizant Healthcare Inc., MN, USA)
and a fluid warming device (enFlowR, BD, USA) were used to maintain
patients' temperature within the normal range.
2.2. Treatments
In patients receiving GDHM, hemodynamics were managed accord-
ing to the protocol described in Fig. 1; if CI was N2.5 L/min/m2 but mean
arterial pressure (MAP) ≤ 60 mmHg, continuous infusion of norepi-
nephrine was started at a dose 0.1 μg/kg/min and titrated to achieve a
MAP N 60 mmHg, irrespectively of SVV and before any fluid administra-
tion [24,25]: after the achievement of this MAP target, patients were re-
assessed. If cardiac index N2.5 L/min/m2 with MAP N 60 mmHg but SVV
N 10%, a 250-ml crystalloid bolus was administered; afterwards, the pa-
tient was re-assessed. A similar fluid bolus was also administered in case
of CI ≤ 2.5 L/min/m2 and SVV N 10%. Continuous dobutamine infusion
was considered the first-line intervention when CI b 2.5 L/min/m2 and
SVV ≤ 10%. The use of colloids (human albumin 20 g/L) was allowed
only to treat clinically documented hypoalbuminemia.
The control group, matched 1:1 for BMI, severity of oncologic disease
(rated by PIV) and intraoperative blood loss, included patients who met
the aforementioned enrolment criteria but received fluid administra-
tion and inotropic drugs according to the judgement of the attending
anesthesiologist on the basis of conventional hemodynamic parameters
(five‑lead electrocardiogram, invasive blood pressure, SpO2 and
capnography). All anesthesiologists who provided standard care in the
 A. Russo et al. / Gynecologic Oncology 151 (2018) 299–305
Fig. 1. Hemodynamic algorithm used in GDHM group. SVV: stroke volume variation MAP: mean arterial pressure CI: cardiac index.
control group were experts in the management of gynaecological sur-
gery and were unaware of study design and aims, which were defined
a posteriori, as already stated. Although any decision was left to the cli-
nician in charge, as a general rule, fluids were infused in order to main-
tain MAP and heart rate (HR) within ±20% of the baseline value, while
norepinephrine (0.01–0.05 μg/kg/min) was the suggested first-line va-
soactive agent in case of nonfluid-responsive hypotension (MAP
b 60 mmHg). In this group, the choice between using balanced crystal-
loids or colloids (albumin 5–20 g/L) was left to the attending
anesthesiologist.
At the time of the study, in our surgical division, synthetic colloids
were not used for fluid resuscitation in patients with hemodynamic in-
stability, as they were considered at risk for acute kidney injury [26]:
thus, none of the patients included in the analysis had received intraop-
erative synthetic colloids.
2.3. Endpoints
The primary endpoint of this study was the amount of crystalloids
intraoperatively administered in the two groups.
The main safety endpoint was blood lactate levels at the end of
surgery.
Prespecified secondary endpoints were: intraoperative intravenous
colloids administration, the proportion of patients receiving continuous
infusion of vasoactive/inotropic drugs, intraoperative diuresis, surgery
duration, blood lactate levels 24 h after surgery, postoperative compli-
cations, time to recovery of bowel function (i.e. time to flatus and nor-
mal bowel sounds), intensive care unit (ICU) and hospital length of stay.
Relevant postoperative complications were classified and defined as
follows:
- Postoperative cardiopulmonary edema, defined as clinical signs of
congestion, including dyspnea, rales, and jugular venous distension
with chest X–ray demonstrating increase in vascular markings and
301
diffuse alveolar interstitial infiltrates, diagnosed by a radiologist
blinded to the design of the study within 2 days after surgery;
- Anastomotic leak requiring re-intervention;
- Acute kidney injury (AKI), defined according to the RIFLE criteria
[27].
2.4. Statistical analysis
The minimum number of patients needed to be included in the anal-
ysis to have sufficient statistical power to the study was established by
an a-priori power analysis using G*Power 3.0.10. Assuming that patients
treated according to the decision of the attending anesthesiologists had
received 2680 ± 1154 mL of crystalloids [14], we estimated that 19 pa-
tients per group could provide 80% power to detect an hypothesized re-
duction of 40% in the amount of crystalloids intraoperatively
administered in patients treated with GDHM, with a α level set at 0.05.
Patients in the intervention group matched in a 1:1 ratio to patients
in the control group based on BMI ± 2 kg/m2 , PIV ± 2 and intraopera-
tive blood losses ± 100 mL.
Data are expressed as number of events (%) or median [interquartile
range]. Inter-group difference concerning continuous data (including
primary outcome measure) were assessed with Mann-Whitney U test.
Distribution of categorical variables in the two study groups was ana-
lyzed with the Chi-square or Fisher's exact test, as appropriate.
Pearson's or point biserial correlations were performed in order to
explore the univariate association between all investigated intraopera-
tive variables and blood lactate values at the end of surgery: rbp
(biserial point correlation coefficient) or Pearson's r are reported along
with the p-value for significant results. To establish the safety of the
treatment, multiple regression analysis was performed to determine
the factors individually associated to higher blood lactate values at
end of surgery: all variables with a p value b 0.2 at the univariate anal-
ysis were included in the multivariate model.
302 A. Russo et al. / Gynecologic Oncology 151 (2018) 299–305

Fig. 2. Study flow diagram.

Statistical analysis was performed with the Stata 14 software 0.0001, respectively); blood lactates were negatively correlated with in-
(StataCorp. 2015. Stata Statistical Software: Release 14. College Station, traoperative diuresis (Pearson's r = −0.42; p = 0.004) (Table 3).
TX: StataCorp LP). A two-tailed p value ≤ 0.05 was considered statisti- The multiple regression model showed that belonging to GDHM
cally significant. group (β = 1.348, C.I. 0.067–2.630); p = 0.04), receiving a smaller
amount of colloids (β = 0.002, C.I. 0.0006–0.003; p = 0.003) and
3. Results lower intraoperative blood losses (β = 0.002, C.I. 0.0005–0.003); p =
0.01) were independently associated to lower blood lactate levels at
Seventy-seven patients have been considered eligible for being in- the end of surgery (model significance: R2 = 0.71; F (6,37) = 14.86;
cluded in the study. After 1:1 matching, 44 patients were analyzed p b 0.0001) (Table 4).
(Fig. 2). Demographics, predictive index and duration of surgery were Lactate values 24 h after surgery, postoperative pulmonary edema,
similar between the two groups (Table 1). acute kidney injury and need for ICU admission were not different be-
The main results of the study are reported in Table 2. The amount of tween study groups.
fluids infused in the intraoperative period was lower in patients receiv-
ing the GDHM protocol (crystalloids: 2950 [2700–3300] mL vs. 5150 Table 1
[4700–6000] mL, p b 0.001; colloids 100 [50–200] mL vs. 750 Patients' demographics and clinical characteristics. Values are shown as median (inter-
[500–1000] mL, p b 0.001); conversely, a trend to a higher use of norepi- quartile range, IQR) or number of events (%).
nephrine was identified in patients treated with GDHM (32% vs. 9%, p =
GDHM Control p value
0.13). None of the patients needed red blood cells transfusion nor dobu- (n = 22) (n = 22)
tamine. Median intraoperative diuresis was greater in GDHM compared
Age (years) 49 (42–58) 55 (43–58) 0.55
to standard fluid-therapy group (540 [480–620] mL vs. 450 [400–500] BMI (Kg/m2 ) 24 (23–26) 24 (23–26) 0.59
mL; p = 0.007). Median blood lactate levels at the end of surgery ASA physical status, no. (%) II 22 (100) 22 (100) 1
were lower in patients treated with GDHM (1.5 [1.1–2] mmol/L vs. 4.1 Patients with comorbidities, no (%) 0 (0) 0 (0) 1
[3.3–5] mmol/L; b0.001). Time to bowel function recovery and hospital Patients with Functional limitations, 0 (0) 0 (0) 1
no. (%)
discharge was shorter in GDHM group: 1 [1-2] days vs 4 [3-5] days, p b
Predictive index, no. of patients 0.57
0.001; 7 [6-8] vs. 12 [9-10] days, p b 0.001. All patients received large 6 0 1
bowel resections, while small bowel resections were not observed: 8 19 19
one patient in GDHM group vs. 5 in control group were jeopardized 10 2 2
12 1 0
by anastomotic leak requiring re-intervention in the postoperative pe-
Surgery duration (min) 517 (480–605) 507 (480–600) 0.90
riod (4% vs 23%, p = 0.19). Ascites (Yes/No) 21/1 22/0 1.0
Univariate analysis showed that lactate values at the end of surgery Ascites (mL) 850 (350–1500) 750 (450–1400) 0.30
were positively correlated with belonging to the control group (rbp = Data are displayed as median (interquartile range), if not otherwise specified.
0.75; p b 0.001) and with the amount of crystalloids and colloids intra- Acronyms: GDHM, goal-directed hemodynamic management; BMI, body mass index; PIV,
operatively administered (rpb = 0.58, p = 0.0001 and rpb = 0.74; p = predictive index value.
 A. Russo et al. / Gynecologic Oncology 151 (2018) 299–305 303

Table 2
Intraoperative variables and postoperative outcome data in patients receiving the GDHM protocol compared to those of the control group.

GDHM Control p value

(n = 22) (n = 22)

Crystalloids (mL) 2950 (2700–3300) 5150 (4700–6000) b0.001

Colloids (mL) 100 (50–200) 750 (500–1000) b0.001
Intraoperative diuresis (mL) 540 (480–620) 450 (400–500) 0.007
Blood loss (mL) 650 (600–900) 750 (650–900) 0.39
Norepinephrine use, no. (%) 7 (32) 2 (9) 0.13
Serum lactate at the end of surgery (mmol/L) 1.5 (1.1–2) 4.1 (3.3–5) b0.001
Serum lactate 24 h after surgery (mmol/L) 1.2 (1–1.4) 1.9 (0.9–2.1) 0.14
Postoperative pulmonary edema, no. (%) 1 (5) 4 (18) 0.34
Need for postoperative ICU, no. (%) 3 (14) 8 (36) 0.16
Patients with postoperative AKI, no. (%) 1 (5) 2 (9) 1.0
Patients with anastomotic leak, no. (%) 1 (4) 5 (23) 0.19
Time to recovery of bowel function (days) 1 (1–2) 4 (3–5) b0.001
Length of hospital stay (days) 7 (6–8) 12 (9–16) b0.001

Data are displayed as median (interquartile range), if not otherwise specified.

Acronyms: GDHM, goal-directed hemodynamic management, BMI, body mass index; AKI, acute kidney injury; ICU, intensive care unit.

Table 3
Univariate Correlation between lactate value at the end of surgery and intraoperative variables.

Group (GDHM) Cristalloids Colloids Norepinephrine use Diuresis Blood loss Surgery duration

Lactate r or rpb 0.75 0.58 0.74 −0.21 −0.42 0.27 0.02

p 0.0001 0.0001 0.0001 0.18 0.004 0.07 0.92

4. Discussion no changes in intraoperatively infused fluids and no benefit on clinical

outcome [16,28]. Nevertheless, median length of surgery in our study
Consistently with previous findings [11,28], in this matched- was far higher than those reported in previous investigations [16,28]:
controlled cohort study, the use of an intraoperative pulse contour it is reasonable to suggest that an increase in the size effect due to the
analysis-guided hemodynamic management protocol yielded reduction extended time of exposure to the treatment was observed in our series.
in the amount of intraoperatively administered fluids, without increas- In our study, an increased use of norepinephrine was registered in
ing blood lactates at the end of surgery. To our knowledge, this is the the GDHM group compared to standard fluid-therapy group (7 versus
first study that elucidates the feasibility, safety and possible effective- 2 patients), even if this finding did not reach statistical significance.
ness of this new GDHM protocol in patients with no comorbidities nor Our GDHM protocol foresees the use of norepinephrine as first-line in-
functional limitations but who are threatened by high tumor load and tervention to treat hypotension, independently from SVV; importantly,
undergo major abdominal surgery. norepinephrine can normalize this dynamic index and can hence be ad-
Many post-surgical complications can occur when excessive fluids ministered before fluid challenge [25,34]. This could have helped recruit
are administered in the perioperative period [11]. However, also un- the unstressed volume before fluid resuscitation, which was instead re-
guided restrictive fluid regimens yielding hypovolemia have been served to patients with SVV N 10% and no hypotension or those with a
proven to jeopardize high-risk surgical patients [29]; therefore any in- fluid-responsive reduction in cardiac output [24,25,32]. Consistently,
tervention capable to limit and individualize fluid administration with we show that, in the absence of a systematic protocol relying on flow-
safety can be deemed highly desirable at the bedside [30]. based hemodynamic monitoring to assess fluid responsiveness [31],
Dynamic variables (i.e. Stroke Volume Variation, Systolic Pressure during radical and prolonged surgery expert anesthesiologists can in-
Variation and Pulse Pressure Variation), based on ventilation-induced fuse an uncontrolled and possibly harmful amount of fluids, which,
changes in cardiac output, help objectifying fluid responsiveness, plausibly, do not always raise cardiac output but rather yield increased
allowing to promptly counteract hypotension and hemodynamic insta- venous capacitance.
bility, tailoring interventions on patient's individual needs [31,32]. Blood lactate reflects anaerobic cellular metabolism due to global tis-
The benefits by goal-directed fluid management are magnified in sue hypoxia: when oxygen supply is insufficient, pyruvate cannot enter
high-risk patients [7,33]: accordingly, previous investigations testing the Krebs cycle and it is shunted to lactate [35]. Whenever oxygen deliv-
this approach on aerobically fit and low-risk patients showed trivial or ery is inadequate to fulfill tissue metabolism requirements, blood lactate
levels rise: because even occult hypoperfusion with no clinically evident
signs of shock generate elevated blood lactate levels [36], these can be
Table 4 considered a robust physiological endpoint to rate non-adequate oxy-
Results of multiple regression analysis on factors associated with lactate values at end of gen delivery. We ruled out any increase in blood lactates in the inter-
surgery.
Model significance: r2 = 0.71; F (6,37) = 14.86; p b 0.0001.
vention group: thus, our protocol, by restricting fluid administration,
unlikely provided an undertreatment of hypotensive statuses and can
Beta 95% CI t p be considered safe. Importantly, previous authors showed that a goal-
value
oriented protocol targeting normal blood lactate can shorten the length
Group (GDHM) 1.348 0.067–2.630 2.13 0.04 of stay in cardiac surgical patients [37].
Intraoperative administered 0.002 0.0006–0.003 3.19 0.003
In our study, we observed both lower postoperative lactate levels
colloids
Intraoperative Blood losses 0.002 0.0005–0.003 2.73 0.01 and shorter length of stay in patients treated with GDHM protocol.
Intraoperative administered −0.00009 −0.0005–0.0003 −0.52 0.60 However, a mechanistic relationship between length of stay and lactate
crystalloids levels cannot be established from our data. It has been previously shown
Intraoperative diuresis −0.002 −0.005–0.001 −1.36 0.18 that lactate impacts on postoperative complications, with high blood
Norepinephrine use −0.105 −0.908–0.697 −0.27 0.79
lactates after intensive care admission being an independent risk factor
304 A. Russo et al. / Gynecologic Oncology 151 (2018) 299–305
for the development of renal failure after cardiac surgery [38]. During
prolonged hypoperfusion with inadequate oxygen delivery, kidneys
suffer from an imbalance between oxygen supply and needs. A recent
study showed that patients treated with an unguided restrictive proto-
col for fluid administration are burdened by higher risk of acute kidney
injury in the postoperative period, and this is associated to lower intra-
operative urine output [28]. Differently, our protocol provides prompt
interventions tailored on patients' individual requirements and intraop-
erative diuresis was greater in GDHM group. This contributes to high-
light the safety of our approach.
With the aim of an exploratory analysis, we report faster bowel func-
tion recovery in patients treated with GDHM. This appears consistent
with other studies showing that GDHM enhances recovery of bowel
function by avoiding fluid overload [39]. It has been shown that bowel
anastomotic leakage, occurring in 10–20% of all patients undergoing
colon resection, is independently associated with survival [40]. This
complication seems to depend not only on patient- and surgery-
related factors, but also on imbalanced fluid therapy altering mucosal
perfusion [8,41–43]. It is possible that our GDHM protocol, by promptly
counteracting hemodynamic instability, limited tissue exposure to hy-
poperfusion, as also showed by the lower lactate levels reported. How-
ever, in our study, regional gastrointestinal perfusion was not analyzed
and the difference in anastomotic leak rate did not reach statistical sig-
nificance, possibly because of the limited sample that does not allow to
draw any conclusion on this specific endpoint.
The present study has limitation.
First, the non-randomized and retrospective design: to mitigate this
aspect, we accurately selected a homogeneous cohort of patients, we
thoroughly excluded those in whom possible confounders could have
biased the interventions (i.e. epidural anesthesia/analgesia) and we se-
lected a control group on the basis of a 1:1 matching. Second, we ac-
knowledge that the extension and duration of surgical procedures
limit the generalizability of the results, confining their reproducibility
to environments where these treatments are common. This should
not alter, and could even strengthen, the message of the study: indeed,
GDHM may be beneficial also in patients who have no comorbidities but
receive extended surgery due to the severity of oncological disease. Fi-
nally, we do not show results from continuous recording of hemody-
namic variables, which unfortunately were not available nor reliable a
posteriori, and this hampers any speculation on the relationship be-
tween outcome measures and hemodynamic derangement duration.
Nevertheless, we took into account robust, clinically relevant and
objectifiable indices as endpoints to assess treatments efficacy and
safety, as already discussed.
5. Conclusions
Among patients with no comorbidities nor functional limitations
who undergo radical, prolonged debulking abdominal surgery for ad-
vanced ovarian cancer, clinical use of this GDHM protocol helped limit
the amount of crystalloids intraoperatively administered without gen-
erating hyperlactatemia; this was associated to faster recovery of
bowel function and shorter hospitalization. An adequately powered
prospective study appears warranted to confirm these findings and ex-
plore potential effects on clinical outcome.
Conflict of interests
The authors declare that there are no conflicts of interest.
Authors' contribution
AR and PA contributed equally to the manuscript. AR, PA, DLG and
MA designed the study and interpreted the results. AR, GMA, BR, VP
conducted the study on enrolled patients. PA and BC analyzed the
data; AR, PA and LS interpreted the results and wrote the first draft of
the manuscript. MA and DLG revised the first draft of the manuscript.
MA organized the study as an overall supervisor. All the authors
reviewed the final draft.
References
[1] J.A. Ledermann, F.A. Raja, C. Fotopoulou, A. Gonzalez-Martin, N. Colombo, C. Sessa,
ESMO Guidelines Working Group, Newly diagnosed and relapsed epithelial ovarian
carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-
up, Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 24 (Suppl. 6) (2013) vi24–32, https://
doi.org/10.1093/annonc/mdt333.
[2] R.J. Morgan, D.K. Armstrong, R.D. Alvarez, J.N. Bakkum-Gamez, K. Behbakht, L.-M.
Chen, L. Copeland, M.A. Crispens, M. DeRosa, O. Dorigo, D.M. Gershenson, H.J.
Gray, A. Hakam, L.J. Havrilesky, C. Johnston, S. Lele, L. Martin, U.A. Matulonis, D.M.
O'Malley, R.T. Penson, S. Percac-Lima, M. Pineda, S.C. Plaxe, M.A. Powell, E. Ratner,
S.W. Remmenga, P.G. Rose, P. Sabbatini, J.T. Santoso, T.L. Werner, J. Burns, M.
Hughes, Ovarian Cancer, version 1.2016, NCCN clinical practice guidelines in oncol-
ogy, J. Natl. Compr. Cancer Netw. 14 (2016) 1134–1163.
[3] A. Fagotti, G. Ferrandina, G. Vizzielli, F. Fanfani, V. Gallotta, V. Chiantera, B.
Costantini, P.A. Margariti, S. Gueli Alletti, F. Cosentino, L. Tortorella, G. Scambia,
Phase III randomised clinical trial comparing primary surgery versus neoadjuvant
chemotherapy in advanced epithelial ovarian cancer with high tumour load (SCOR-
PION trial): final analysis of peri-operative outcome, Eur. J. Cancer 59 (2016) 22–33,
https://doi.org/10.1016/j.ejca.2016.01.017.
[4] G. Vizzielli, B. Costantini, L. Tortorella, I. Pitruzzella, V. Gallotta, F. Fanfani, S. Gueli
Alletti, F. Cosentino, C. Nero, G. Scambia, A. Fagotti, A laparoscopic risk-adjusted
model to predict major complications after primary debulking surgery in ovarian
cancer: a single-institution assessment, Gynecol. Oncol. 142 (2016) 19–24, https://
doi.org/10.1016/j.ygyno.2016.04.020.
[5] E. Futier, J.-Y. Lefrant, P.-G. Guinot, T. Godet, E. Lorne, P. Cuvillon, S. Bertran, M.
Leone, B. Pastene, V. Piriou, S. Molliex, J. Albanese, J.-M. Julia, B. Tavernier, E.
Imhoff, J.-E. Bazin, J.-M. Constantin, B. Pereira, S. Jaber, INPRESS Study Group, Effect
of individualized vs standard blood pressure management strategies on postopera-
tive organ dysfunction among high-risk patients undergoing major surgery: a ran-
domized clinical trial, JAMA 318 (2017) 1346–1357, https://doi.org/10.1001/jama.
2017.14172.
[6] R.M. Pearse, D. a Harrison, N. MacDonald, M. a Gillies, M. Blunt, G. Ackland, M.P.W.
Grocott, A. Ahern, K. Griggs, R. Scott, C. Hinds, K. Rowan, OPTIMISE Study Group, Ef-
fect of a perioperative, cardiac output-guided hemodynamic therapy algorithm on
outcomes following major gastrointestinal surgery: a randomized clinical trial and
systematic review, JAMA 311 (2014) 2181–2190, https://doi.org/10.1001/jama.
2014.5305.
[7] E. Futier, J.-M. Constantin, A. Petit, G. Chanques, F. Kwiatkowski, R. Flamein, K. Slim,
V. Sapin, S. Jaber, J.-E. Bazin, Conservative vs restrictive individualized goal-directed
fluid replacement strategy in major abdominal surgery: a prospective randomized
trial, Arch. Surg. 145 (2010) 1193–1200, https://doi.org/10.1001/archsurg.2010.275.
[8] M.G. Mythen, A.R. Webb, Intra-operative gut mucosal hypoperfusion is associated
with increased post-operative complications and cost, Intensive Care Med. 20
(1994) 99–104.
[9] B. Brandstrup, P.E. Svendsen, M. Rasmussen, B. Belhage, S.Å. Rodt, B. Hansen, D.R.
Møller, L.B. Lundbech, N. Andersen, V. Berg, N. Thomassen, S.T. Andersen, L.
Simonsen, Which goal for fluid therapy during colorectal surgery is followed by
the best outcome: near-maximal stroke volume or zero fluid balance? Br. J. Anaesth.
109 (2012) 191–199, https://doi.org/10.1093/bja/aes163.
[10] J. Benes, I. Chytra, P. Altmann, M. Hluchy, E. Kasal, R. Svitak, R. Pradl, M. Stepan, In-
traoperative fluid optimization using stroke volume variation in high risk surgical
patients: results of prospective randomized study, Crit. Care 14 (2010) R118,
https://doi.org/10.1186/cc9070.
[11] J. Mayer, J. Boldt, A.M. Mengistu, K.D. Röhm, S. Suttner, Goal-directed intraoperative
therapy based on autocalibrated arterial pressure waveform analysis reduces hospi-
tal stay in high-risk surgical patients: a randomized, controlled trial, Crit. Care 14
(2010) R18, https://doi.org/10.1186/cc8875.
[12] C. Kusano, M. Baba, S. Takao, S. Sane, M. Shimada, K. Shirao, S. Natsugoe, T.
Fukumoto, T. Aikou, Oxygen delivery as a factor in the development of fatal postop-
erative complications after oesophagectomy, Br. J. Surg. 84 (1997) 252–257.
[13] M.T. Giglio, M. Marucci, M. Testini, N. Brienza, Goal-directed haemodynamic therapy
and gastrointestinal complications in major surgery: a meta-analysis of randomized
controlled trials, Br. J. Anaesth. 103 (2009) 637–646, https://doi.org/10.1093/bja/
aep279.
[14] C. Salzwedel, J. Puig, A. Carstens, B. Bein, Z. Molnar, K. Kiss, A. Hussain, J. Belda, M.Y.
Kirov, S.G. Sakka, D.A. Reuter, Perioperative goal-directed hemodynamic therapy
based on radial arterial pulse pressure variation and continuous cardiac index
trending reduces postoperative complications after major abdominal surgery: a
multi-center, prospective, randomized study, Crit. Care 17 (2013) R191, https://
doi.org/10.1186/cc12885.
[15] T.J. Gan, A. Soppitt, M. Maroof, H. El-Moalem, K.M. Robertson, E. Moretti, P. Dwane,
P.S.A. Glass, Goal-directed intraoperative fluid administration reduces length of hos-
pital stay after major surgery, Anesthesiology 97 (2002) 820–826.
[16] C. Challand, R. Struthers, J.R. Sneyd, P.D. Erasmus, N. Mellor, K.B. Hosie, G. Minto,
Randomized controlled trial of intraoperative goal-directed fluid therapy in aerobi-
cally fit and unfit patients having major colorectal surgery, Br. J. Anaesth. 108
(2012) 53–62, https://doi.org/10.1093/bja/aer273.
[17] H. Vermeulen, J. Hofland, D.A. Legemate, D.T. Ubbink, Intravenous fluid restriction
after major abdominal surgery: a randomized blinded clinical trial, Trials 10
(2009), 50. https://doi.org/10.1186/1745-6215-10-50.
 A. Russo et al. / Gynecologic Oncology 151 (2018) 299–305
[18] G. Vizzielli, B. Costantini, L. Tortorella, M. Petrillo, F. Fanfani, V. Chiantera, A. Ercoli, R.
Iodice, G. Scambia, A. Fagotti, Influence of intraperitoneal dissemination assessed by
laparoscopy on prognosis of advanced ovarian cancer: an exploratory analysis of a
single-institution experience, Ann. Surg. Oncol. 21 (2014) 3970–3977, https://doi.
org/10.1245/s10434-014-3783-6.
[19] A. Fagotti, G. Ferrandina, F. Fanfani, G. Garganese, G. Vizzielli, V. Carone, M.G.
Salerno, G. Scambia, Prospective validation of a laparoscopic predictive model for
optimal cytoreduction in advanced ovarian carcinoma, Am. J. Obstet. Gynecol. 199
(2008)https://doi.org/10.1016/j.ajog.2008.06.052 642.e1-6.
[20] M. Petrillo, G. Vizzielli, F. Fanfani, V. Gallotta, F. Cosentino, V. Chiantera, F. Legge, V.
Carbone, G. Scambia, A. Fagotti, Definition of a dynamic laparoscopic model for the
prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof
of a concept, Gynecol. Oncol. 139 (2015) 5–9, https://doi.org/10.1016/j.ygyno.2015.
07.095.
[21] A. Fagotti, G. Vizzielli, B. Costantini, A. Lecca, V. Gallotta, M.L. Gagliardi, G. Scambia, F.
Fanfani, Learning curve and pitfalls of a laparoscopic score to describe peritoneal
carcinosis in advanced ovarian cancer, Acta Obstet. Gynecol. Scand. 90 (2011)
1126–1131, https://doi.org/10.1111/j.1600-0412.2011.01227.x.
[22] K. Holte, N.B. Foss, C. Svensén, C. Lund, J.L. Madsen, H. Kehlet, Epidural anesthesia,
hypotension, and changes in intravascular volume, Anesthesiology 100 (2004)
281–286.
[23] D. De Backer, S. Heenen, M. Piagnerelli, M. Koch, J.-L. Vincent, Pulse pressure varia-
tions to predict fluid responsiveness: influence of tidal volume, Intensive Care Med.
31 (2005) 517–523, https://doi.org/10.1007/s00134-005-2586-4.
[24] P.Y. Wuethrich, F.C. Burkhard, G.N. Thalmann, F. Stueber, U.E. Studer, Restrictive de-
ferred hydration combined with preemptive norepinephrine infusion during radical
cystectomy reduces postoperative complications and hospitalization time: a ran-
domized clinical trial, Anesthesiology 120 (2014) 365–377, https://doi.org/10.
1097/ALN.0b013e3182a44440.
[25] X. Monnet, J. Jabot, J. Maizel, C. Richard, J.-L. Teboul, Norepinephrine increases car-
diac preload and reduces preload dependency assessed by passive leg raising in sep-
tic shock patients, Crit. Care Med. 39 (2011) 689–694, https://doi.org/10.1097/CCM.
0b013e318206d2a3.
[26] K. Reinhart, A. Perner, C.L. Sprung, R. Jaeschke, F. Schortgen, A.B. Johan Groeneveld,
R. Beale, C.S. Hartog, European Society of Intensive Care Medicine, Consensus state-
ment of the ESICM task force on colloid volume therapy in critically ill patients, In-
tensive Care Med. 38 (2012) 368–383, https://doi.org/10.1007/s00134-012-2472-9.
[27] R. Bellomo, C. Ronco, J.A. Kellum, R.L. Mehta, P. Palevsky, Acute Dialysis Quality
Initiative workgroup, Acute renal failure - definition, outcome measures, animal
models, fluid therapy and information technology needs: the second international
consensus conference of the acute dialysis quality initiative (ADQI) group, Crit.
Care 8 (2004) R204–R212, https://doi.org/10.1186/cc2872.
[28] J.C. Gómez-Izquierdo, A. Trainito, D. Mirzakandov, B.L. Stein, S. Liberman, P.
Charlebois, N. Pecorelli, L.S. Feldman, F. Carli, G. Baldini, Goal-directed fluid therapy
does not reduce primary postoperative ileus after elective laparoscopic colorectal
surgery: a randomized controlled trial, Anesthesiology 127 (2017) 36–49, https://
doi.org/10.1097/ALN.0000000000001663.
[29] P.S. Myles, R. Bellomo, T. Corcoran, A. Forbes, P. Peyton, D. Story, C. Christophi, K.
Leslie, S. McGuinness, R. Parke, J. Serpell, M.T.V. Chan, T. Painter, S. McCluskey, G.
Minto, S. Wallace, Australian and New Zealand College of Anaesthetists Clinical Tri-
als Network and the Australian and New Zealand Intensive Care Society Clinical Tri-
als Group, Restrictive versus liberal fluid therapy for major abdominal surgery, N.
Engl. J. Med. 378 (2018) 2263–2274, https://doi.org/10.1056/NEJMoa1801601.
305
[30] A. Feldheiser, O. Aziz, G. Baldini, B.P.B.W. Cox, K.C.H. Fearon, L.S. Feldman, T.J. Gan,
R.H. Kennedy, O. Ljungqvist, D.N. Lobo, T. Miller, F.F. Radtke, T. Ruiz Garces, T.
Schricker, M.J. Scott, J.K. Thacker, L.M. Ytrebø, F. Carli, Enhanced recovery after sur-
gery (ERAS) for gastrointestinal surgery, part 2: consensus statement for anaesthe-
sia practice, Acta Anaesthesiol. Scand. 60 (2016) 289–334, https://doi.org/10.1111/
aas.12651.
[31] P.E. Marik, X. Monnet, J.-L. Teboul, Hemodynamic parameters to guide fluid therapy,
Ann. Intensive Care 1 (1) (2011)https://doi.org/10.1186/2110-5820-1-1.
[32] A.M. Dell'Anna, D.L. Grieco, A. Russo, E. Marana, M. Antonelli, Case scenario: periop-
erative management of a young woman with Fontan repair for major gynecologic
surgery, Anesthesiology 124 (2016) 464–470, https://doi.org/10.1097/ALN.
0000000000000966.
[33] M. Cecconi, C. Corredor, N. Arulkumaran, G. Abuella, J. Ball, R.M. Grounds, M.
Hamilton, A. Rhodes, Clinical review: goal-directed therapy-what is the evidence
in surgical patients? The effect on different risk groups, Crit. Care 17 (2013) 209,
https://doi.org/10.1186/cc11823.
[34] J. Renner, P. Meybohm, R. Hanss, M. Gruenewald, J. Scholz, B. Bein, Effects of norepi-
nephrine on dynamic variables of fluid responsiveness during hemorrhage and after
resuscitation in a pediatric porcine model, Paediatr. Anaesth. 19 (2009) 688–694,
https://doi.org/10.1111/j.1460-9592.2009.03017.x.
[35] T.C. Jansen, J. van Bommel, J. Bakker, Blood lactate monitoring in critically ill pa-
tients: a systematic health technology assessment, Crit. Care Med. 37 (2009)
2827–2839, https://doi.org/10.1097/CCM.0b013e3181a98899.
[36] G. Friedman, G. Berlot, R.J. Kahn, J.L. Vincent, Combined measurements of blood lac-
tate concentrations and gastric intramucosal pH in patients with severe sepsis, Crit.
Care Med. 23 (1995) 1184–1193.
[37] P. Pölönen, E. Ruokonen, M. Hippeläinen, M. Pöyhönen, J. Takala, A prospective, ran-
domized study of goal-oriented hemodynamic therapy in cardiac surgical patients,
Anesth. Analg. 90 (2000) 1052–1059.
[38] J.C. Lopez-Delgado, F. Esteve, H. Torrado, D. Rodríguez-Castro, M.L. Carrio, E. Farrero,
C. Javierre, J.L. Ventura, R. Manez, Influence of acute kidney injury on short- and
long-term outcomes in patients undergoing cardiac surgery: risk factors and prog-
nostic value of a modified RIFLE classification, Crit. Care 17 (2013) R293, https://
doi.org/10.1186/cc13159.
[39] J.C. Gómez-Izquierdo, L.S. Feldman, F. Carli, G. Baldini, Meta-analysis of the effect of
goal-directed therapy on bowel function after abdominal surgery, Br. J. Surg. 102
(2015) 577–589, https://doi.org/10.1002/bjs.9747.
[40] K.G. Walker, S.W. Bell, M.J.F.X. Rickard, D. Mehanna, O.F. Dent, P.H. Chapuis, E.L.
Bokey, Anastomotic leakage is predictive of diminished survival after potentially cu-
rative resection for colorectal cancer, Ann. Surg. 240 (2004) 255–259.
[41] N.C. Buchs, P. Gervaz, M. Secic, P. Bucher, B. Mugnier-Konrad, P. Morel, Incidence,
consequences, and risk factors for anastomotic dehiscence after colorectal surgery:
a prospective monocentric study, Int. J. Color. Dis. 23 (2008) 265–270, https://doi.
org/10.1007/s00384-007-0399-3.
[42] M.E. Foster, J.R. Laycock, I.A. Silver, D.J. Leaper, Hypovolaemia and healing in colonic
anastomoses, Br. J. Surg. 72 (1985) 831–834.
[43] O. Kimberger, M. Arnberger, S. Brandt, J. Plock, G.H. Sigurdsson, A. Kurz, L.
Hiltebrand, Goal-directed colloid administration improves the microcirculation of
healthy and perianastomotic colon, Anesthesiology 110 (2009) 496–504, https://
doi.org/10.1097/ALN.0b013e31819841f6.