A Prospective Randomized Controlled Clinical Trial of Standard Compared to Goal-directed Perioperative Fluid Management (GDT) for Patients Undergoing Liver Resection
Phase: PHASE3
Conditions: Liver Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

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A Prospective Randomized Controlled Clinical Trial of Standard versus Goal-
Directed Perioperative Fluid Management (GDT) for Patients Undergoing Liver 
Resection 
 
PROTOCOL FACE PAGE FOR  
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal 
Investigator/Department: 
Mary Fischer, MD 
Department of Anesthesiology 
Co-Principal 
Investigator(s)/Department: 
William R. Jarnagin, MD 
Michael D’Angelica, MD 
Vittoria Arslan-Carlon, MD 
Department of Surgery 
Department of Surgery 
Department of Anesthesiology 
Investigator(s)/Department: 
Ronald DeMatteo, MD 
Peter J Allen, MD 
Yuman Fong, MD 
T. Peter Kingham, MD 
Camilo Correa, MD 
Florence Grant, MD 
Jennifer Mascarenhas, MD 
Mithat Gönen, PhD 
 
Department of Surgery 
Department of Surgery 
Department of Surgery 
Department of Surgery 
Department of Surgery 
Department of Anesthesiology 
Department of Anesthesiology 
Department of Epidemiology and Biostatistics 
 
Consenting 
Professional(s)/Department: 
William R. Jarnagin, MD
Michael D’Angelica, MD 
Ronald DeMatteo, MD 
Peter J Allen, MD 
Yuman Fong, MD 
T. Peter Kingham, MD 
Mary Fischer, MD 
Vittoria Arslan-Carlon, MD 
Florence Grant, MD 
Jennifer Mascarenhas, MD
Department of Surgery
Department of Surgery 
Department of Surgery 
Department of Surgery 
Department of Surgery 
Department of Surgery 
Department of Anesthesiology 
Department of Anesthesiology 
Department of Anesthesiology 
Department of Anesthesiology
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065

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Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ..................................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS .............................................................................. 5 
3.0 
BACKGROUND AND RATIONALE ................................................................................... 5 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................ 9 
4.1 
Design ............................................................................................................................. 9 
4.2 
Intervention ................................................................................................................... 11 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ......................................................................... 13 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ......................................................................... 13 
6.1 
Subject Inclusion Criteria ............................................................................................... 13 
6.2 
Subject Exclusion Criteria.............................................................................................. 13 
7.0 
RECRUITMENT PLAN ..................................................................................................... 14 
8.0 
PRETREATMENT EVALUATION .................................................................................... 15 
9.0 
TREATMENT/INTERVENTION PLAN .............................................................................. 15 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ................................................. 19 
11.0 TOXICITIES/SIDE EFFECTS ........................................................................................... 21 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ..................... 22 
13.0 CRITERIA FOR REMOVAL FROM STUDY ..................................................................... 23 
14.0 BIOSTATISTICS .............................................................................................................. 23 
15.0  RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES24 
15.1 Research Participant Registration ................................................................................. 24 
15.2 Randomization .............................................................................................................. 24 
16.0 DATA MANAGEMENT ISSUES ....................................................................................... 24 
16.1 Quality Assurance ......................................................................................................... 25 
16.2 Data and Safety Monitoring ........................................................................................... 25 
17.0 PROTECTION OF HUMAN SUBJECTS .......................................................................... 26 
17.1 Privacy .......................................................................................................................... 26 
17.2 Serious Adverse Event (SAE) Reporting ....................................................................... 27 
17.2.1 ................................................................................................................................... 27 
18.0 INFORMED CONSENT PROCEDURES .......................................................................... 27 
19.0 REFERENCES ................................................................................................................. 28 
20.0 APPENDICES .................................................................................................................. 30 
 

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1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
Title: A Prospective Randomized Controlled Clinical Trial of Standard versus Goal-Directed 
Perioperative Fluid Management (GDT) for Patients Undergoing Liver Resection.   
Null Hypothesis: Goal-directed fluid management does not impact the incidence of 
postoperative complications in patients undergoing liver resection.   
Objectives:  Determine the impact of goal-directed fluid therapy on the incidence of 30-day 
overall postoperative morbidity. 
 Patient Population: 270 Patients undergoing elective liver resection.  135 patients on each 
arm. 
Design: Single-blinded, prospective randomized trial.  
Agents: Standard volume replacement solutions (crystalloid and colloid) and vasoactive  
agents will be administered to reach the goals of resuscitation according to pre-established 
protocols.   
Time to completion: 2 years   
 
 
 
 
Chart 1. Flow of management through different phases of the protocol
Pts Undergoing 
liver resection
Eligible patients 
consented in clinic
Randomization 
after resection 
phase  (OR)
Standard fluid 
management:  
Group 1
Goal directed 
fluid therapy:  
Group 2

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. 
 
 
 
 
 
 
 
Pre-
induction 
•Arterial line placement.
•Hemodynamic measures, PLR. (preoperative baseline)
Induction
•Intraoperative hemodynamic measures (intraoperative 
baseline).
•Biochemical measurements.
•Low CVP anesthetic technique. Resection phase.
Post liver 
resection
•RANDOMIZATION
•Resuscitation (Post Resection) phase.
•Hemodynamic measures.
•Biochemical measurements.
•Fluid replacement end-points according to randomization arm.
Post-Op 
(PACU)
•Hemodynamic measures.
•Biochemical measurements.
•Fluid replacement end-points as per algorithm B
Ward
•All patients will receive:
•Maintenance IV crystalloid at 1.2 ml/kg/hr with a maximum 
rate of 130 ml/hr.
•500 ml crystalloid boluses for UOP < 80ml/4 hours
•D/C fluids when oral intake ≥ 400ml/24h

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2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
Primary objective:  
• 
Evaluate the impact of goal-directed fluid management on the incidence of overall 
postoperative morbidity in patients undergoing liver resection.  
Secondary Objective: 
• 
Assess the impact of GDT compared to standard fluid therapy on the total time 
patients experience low cardiac output perioperatively (i.e. intraoperative and in the 
first 24 postoperative hours). 
• 
Assess the impact of GDT compared to standard fluid therapy on the total volume of 
fluid given intraoperatively and during the first 72 hrs postoperatively.  
• 
Assess the impact of GDT compared to standard fluid therapy on the requirement for 
blood transfusion.  
• 
Compare the total dose (mcg/kg) of vasoactive agents used in the first 24 hrs 
between the standard management and GDT groups. 
• 
Measure the difference in end-organ perfusion markers between GDT and standard 
therapy for fluid management. 
• 
Assess the impact of GDT compared to standard fluid therapy on net fluid balance for 
the total admission time.  
• 
Assess the impact of GDT compared to standard fluid therapy on the systemic 
inflammatory response.  
3.0 
BACKGROUND AND RATIONALE 
An association between early postoperative complications (particularly infectious) and 
decreased long-term survival after liver resection for malignant disease has been previously 
documented.1-6 In the last two decades, improved surgical technique and management of 
complications have been responsible for a significant reduction in perioperative mortality 
rates, which now range between 0.1%-3%. However, grade 3 and 4 complications (most 
clinically relevant – see appendix 2) have been reported to range between 28 – 30%;7-9 
moreover, overall postoperative morbidity reaches 45% in single-institution reports.10-12 
Furthermore, in a recent paper derived from the Patient Safety in Surgery (PSS) Study, 
Virani et. al presented 30-day morbidity and mortality rates after liver resections in 14 private-
institutions in the US. They found morbidity and mortality rates of 22.6% and 2.6%, 
respectively; this large population-based study, however, did not capture bile collections 

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(bilomas) among their complications, thus underestimating the morbidity rate. Somewhat 
intuitively, this retrospective analysis also showed that patients who developed complications 
had an increased 30-day mortality rate when compared to patients that had an uneventful 
recovery (0.7% compared to 9%; p <0.0001)13. These findings underscore the significant 
impact of postoperative morbidity and justify further attempts at reducing it.  
 
The optimal peri-operative fluid management strategy is yet to be determined. For years, the 
debate has centered (perhaps erroneously) around the comparison of colloid vs crystalloid 
solutions, each of which have their own advantages and shortcomings in specific clinical 
scenarios. In the past, trials have failed to recognize the fact that different resuscitation fluids 
belong to different drug classes and have individual pharmacologic profiles and indications.14 
In a large multicenter randomized trial, published in New England Journal of Medicine, Finfer 
et al. found no significant outcome differences in patients admitted to general intensive care 
units and randomized to receive normal saline compared to 4% albumin; this large trial 
however was underpowered for subgroup analyses and estimation of differential mortality 
among different patient populations.15 A meta-analysis recently published by Delaney16 
suggested that the use of albumin for resuscitation in patients with sepsis was associated 
with a marginal, yet signicant reduction in mortality (pooled OR: 0.82 [95% CI 0.67-1.0]; p = 
.047). Conversely, The Cochrane collaboration has reported three reviews analyzing 
available data on the debate of colloid compared to crystalloids for critically ill patients,17-19 
these reviews have failed to find a survival benefit for any of the two and recommends that 
the use of colloids be abandoned outside of randomized studies given their higher cost.18  
 
Results from these studies have prompted a shift away from the use of colloids as 
resuscitation fluids (particularly in the critical care community). Perhaps more concerning, 
some reports have pointed out significant risks associated with the use of colloids 
(specifically increased incidence of renal dysfunction and need for renal replacement 
therapies).20 These studies however, still fail to address the individual patient’s homeostasis 
in the selection of a resuscitation solution, failing to recognize both colloids and crystalloids 
as very different drugs with specific therapeutic indications.  
 
In the last several years, there has been increasing evidence demonstrating the existence of 
two different types of fluid shifts that likely occur simultaneously in the perioperative period; 
these are physiologically distinct and their management should be appropriately tailored to 
meet the requirements of the specific patient.  The existence of the commonly regarded “third 

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space” has been questioned14, 21 and the classical Starling principle that gave physiologic 
support to the use of colloids for maintenance of intravascular volume has been 
complemented to account for the volume status of each individual and the role of the 
glycocalix.21, 22  The concept of a fluid-consuming third space often results in a very liberal 
resuscitation approach after intraabdominal surgery, according to which more is better, 
frequently leading to significant fluid overload and its ensuing consequences. In a well 
conducted prospective study Lowell et al. evaluated the outcomes of 48 consecutive patients 
admitted to a surgical ICU.23 They found a striking increase in mortality associated with 
weight gain as a surrogate marker of fluid overload (figure 1). 
 
 
 
 
Fig. 1. Perioperative weight gain and mortality of patients. No patient survived if perioperative 
weight gain was more than 20%. * P < 0.008 compared to weight gain less than 10%.23 
 
A rational approach to perioperative fluid management should be patient and procedure 
specific and driven by objective data that could, at least theoretically, decrease the 
deleterious effects of perioperative hyper or hypovolemia.24, 25 We seek to evaluate this 
hypothesis in patients undergoing liver resection guiding fluid therapy with the use of 
continuous minimally-invasive hemodynamic monitoring. 
  

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Respiratory arterial pulse pressure variations (PPV) are the best predictors of fluid 
responsiveness in mechanically ventilated patients during general anesthesia and pulse 
wave contour analysis has been previously validated as a reliable dynamic method to assess 
the fluid status and predict fluid responsiveness.26-29 Other devices used clinically to guide 
fluid optimization such as the pulmonary artery catheter or central venous lines, are more 
invasive and associated with potential complications. Trans-esophageal Doppler which has 
been shown to have adequate correlation with PPV as a predictor of fluid responsiveness, 
has multiple shortcomings including the practical impossibility to use this technique in the 
awake patient, thus curtailing the global hemodynamic information that we obtain from it and 
limiting it to the intraoperative period. In consequence, this technique doesn’t provide 
baseline preoperative data or postoperative hemodynamic information to guide 
management.14 Noblett et al. reported on their trial in patients undergoing colorectal surgery 
who were randomized  to liberal management vs Doppler-directed fluid resuscitation.30 They 
found a shortened hospital stay, fewer complications and earlier return of intestinal fuction in 
the intervention group. However, they found no difference in the total amount of fluids 
administered between the groups. The conclusion from their paper insinuates that it is likely 
that the timing of fluid administration and the prevention of early gut ischemia are the drivers 
of the improved outcomes in patients receiving goal-directed therapy.  
 
This report by Noblett, as well as others, has also shown differential alterations in intra and 
post-operative levels of various acute phase reactants (IL-6, IL-10, TNF-α, C-reactive protein, 
procalcitonin, among others) in response to surgical stress during elective procedures.30-33 
Furthermore, higher levels of some of these cytokines have been associated with the degree 
of tissue injury, hypoperfusion states34, 35 and increased postoperative complications.36  
 
These data indicate a possible link between the adequacy of intraoperative fluid 
management and intensity of the inflammatory response to surgical trauma. There is 
however no data to our notice evaluating this relationship in patients undergoing liver 
resection in the context of tightly measured fluid management. The present study proposal 
provides an excellent opportunity to gain insight both into the potential impact of different 
fluid strategies on the inflammatory response as well as the relation between the later and 
the development of postoperative complications. 
 
 
 

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4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
Prospective single-blinded randomized trial. Eligible patients will be consented for the trial 
prior to surgery. However randomization will not occur until the operating room. After the liver 
has been resected, intraoperative randomization will be done by envelopes. Preoperative 
preparation and induction will be standard for all patients. In the OR all patients will have an 
arterial line placed preinduction and baseline hemodynamic data recorded from the Edwards 
EV1000 system.  In the study, all intraoperative fluid therapy will be managed with the 
standard LCVP anesthetic technique for hepatic resection, and then at the completion of the 
resection all fluid therapy will be managed according to randomization arm (Goal-directed 
fluid therapy-appendix 1 compared to standard fluid management- see detail below) for 
reconstruction and closure. In the postoperative phase, management will be standardized for 
both arms as outlines below.   
During low central venous pressure (LCVP) anesthetic technique for partial hepatectomy, 
intraoperative fluid balance is divided in to two phases (as previously published)8:  
• 
Prehepatic resection (the first phase), starts at anesthesia induction and ends 
at the completion of parenchymal transection and hemostasis. This phase 
takes advantage of fluid restriction and the vasodilatory effects of anesthetic 
drugs to provide  LCVP anesthetic management.  Fluid boluses and/or 
vasoactive drugs are administered at the discretion of the anesthesia provider 
to maintain systolic blood pressure > 90 mm Hg and urine output > 25 ml/hr 
while keeping the cvp <5 mmHg (currently, the vast majority of our patients do 
not require central line placement for the performance of liver resections. Low 
central venous pressure is assessed by the surgeon’s direct assessment of 
the distention of the vena cava at the time of surgery). Maintenance fluid is 
1cc/kg/hr.  
Prior to proceeding to the second phase the intraoperative fluid 
management after the hepatic resection, patients will be randomized to 
either 
Goal-directed fluid therapy (see appendix 1) 
Standard fluid management (see appendix 1).  
 

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• 
Posthepatic resection (the second phase), begins once the specimen has 
been delivered and hemostasis secured. During this phase, an attempt is 
made to return the patient to normovolemia. For our standard fluid 
management, blood loss is replaced  volume to volume with albumin and  
crystalloid (6 cc/kg/hr x total operative time) will be infused to achieve the 
assumed fluid requirement (third space). After this fluid therapy, if 
BP<90mmHg or urine output< 25ml/hr, additional fluid boluses either colloid or 
crystalloid are given.  Packed red-blood cells (PRBC) are included in 
resuscitation if the hemoglobin <7 g/dL.  Fresh-frozen plasma (FFP) or 
platelets may be given at the request of the surgeon if surgical hemostasis is 
inadequate, international normalized ration (INR) >1.8 or platelets < 80,000 
mcL. 
 
The GDT arm will have fluid therapy guided by the Edwards EV1000 system. First, blood 
loss will be replaced 1:1 volume with albumin.  After this infusion, additional fluid will be given 
based on the patient’s SVV.  If this value is greater than 2 standard deviations of the baseline 
value more albumin will be given until SVV is less than or equal to no greater than 2 standard 
deviations above the baseline SVV.  If the SVV is at baseline or not greater than 2 standard 
deviations from the baseline value, no additional bolus fluid will be given  (Appendix 1). The 
maintenance crystalloid fluid will continue at 1cc/kg/hr that was begun in the LCVP phase.  
Group and protocol assignment will be maintained from the beginning of the reconstruction 
phase during the index operation, until after the patients are transferred to the PACU and 
receive standardized postoperative management at the discretion of the treating physicians.  
During the intervention period, continuous non-invasive pulse wave analysis will be 
performed (Edwards EV1000) and the information stored in the  monitor. Download is 
enabled to a USB port and memory stick. In the group assigned to standard management the 
monitor will be covered and the data derived from it will not be available to the anesthesia 
care team; this blinding will only be removed for the involved researchers at the completion 
of the study for retrospective analysis and comparison.  At this time only research staff and 
anesthesia staff will have knowledge of patients randomization assignment. 
Adequacy of postoperative resuscitation will be determined by comparing end-tissue 
perfusion variables as well as inflammatory markers (a multiplex cytokine panel that includes 
IL-2, IL-4, IL-6, IL-10, IL-17, TNFα, and INFγ) before skin incision (as baseline), at the 
beginning of resuscitation phase, at time of completion of the case and the morning of the 2 

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first postoperative days. See Table 2  – section 10.0 Evaluation during 
treatment/Intervention. After evaluation of inflammatory response in the initial set of 20 
randomized patients, it was determined that no statistically significant difference was likely to 
be found between the 2 randomization arms and the protocol was amended to discontinue 
the blood collections and cytokine analysis.  
Continuous assessment of cardiac output as determined by the arterial waveform analysis, 
total fluid therapy, (crystalloid and colloid), units of pRBCs, total dose (mcg/kg) of each 
vasoactive agent, cumulative fluid balance and the incidence of overall 30-day postoperative 
complications will be recorded. These are defined in the MSKCC Adverse Events Program 
and organized by categories reflecting organ systems (listed below) and further subdivided 
into specific complications within those and graded as reflected in appendix 2. A detailed 
listing of complications and grading can be found at: http://vssurpweb1/AdverseEvents. 
Categories 
*None at 30 days post-op 
Cardiovascular System 
Endocrine System 
Gastrointestinal System 
General 
Genitourinary System 
Head and Neck 
Hematologic or Vascular System 
Infection 
Metabolic 
Musculoskeletal System 
Nervous System 
Pain 
Pulmonary System 
Wound or Skin 
 
4.2 
Intervention 
Goal-directed fluid therapy (GDT): See details in section 9.0 Treatment/Intervention plan 
and Appendix 1. 

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Preresection Phase: 
Standard low CVP anesthetic technique is initiated. Hemodynamic monitoring is 
performed as usual. Fluid boluses and/or vasoactive drugs are administered at the 
discretion of the anesthesia provider to maintan SBP ≥ 90mmHg and urine output ≥ 
25ml/hr while maintaining the cvp <5mmHg, as determined by the surgeon’s 
intraoperative assessment of the vena cava. Maintenance crystalloid fluid is kept at a 
minimal rate (1cc/kg/hr) during this phase.  
Postresection Phase:  
During this phase, which starts after the specimen is delivered, the goal is to restore 
normovolemia. Fluid replacement will occur in two stages: first, blood loss is replaced 
with a 1:1 albumin volume. Next, albumin will be infused to restore SVV to a value 
that is less than or equal to two standard deviations over the intraoperative baseline 
(immediately after induction). Crystalloid infusion is continued at 1cc/kg/hr. (algorithm 
A)   
 
PACU: 
 
 
Standardized management (algorithm B): 
 
Patients requiring continued mechanical ventilation will receive a tidal 
volume of 8 ml/kg body weight at a frequency of 6 to 12 breaths per 
minute to keep the end-tidal carbon dioxide between 35 to 40 mm Hg. 
Most patients will be extubated in the operating room and not require 
mechanical ventilation. 
 
Maintenance IV crystalloid at 1.2 ml/kg/hr with a maximum rate of 130 
ml/hr. 
 
Strict Inputs and Outputs measured hourly in PACU.  
 
Boluses of 250 ml of albumin solution (given over 20 minutes) will be 
administered for SBP < 90mmHg and/or urine output < 40ml/2hr.  
 
Medications mixed as per pharmacy protocol, to be included in daily 
input.  
 
The use of vasoactive agents will be left to the discretion of the 
treating practitioner. 
 
 

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5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS
Device description: 
The EV1000 monitor continuously measures key parameters of arterial pressure, cardiac output 
(CO), cardiac index (CI),  stroke volume (SV), stroke volume variation (SVV), stroke volume index 
(SVI), systemic vascular resistance (SVR) and systemic vascular resistance index (SVRI).  
This device has been used previously in the surgical and intensive care unit settings elsewhere and 
at MSKCC. Results from their use vary in terms of the outcomes reported, however its use provides 
significant hemodynamic information with minimal invasion.27, 37-39  
 
This monitor has successfully undergone functional and performance testing, including software 
verification and validation, mechanical and electrical testing, bench studies, pre-clinical animal 
studies, comparison testing of clinical cases, and clinical usability. It has been shown to be safe and 
effective and substantially equivalent to the cited predicate devices for their intended use in the OR 
and ICU environments and has obtained FDA approval for these uses.40
The FloTrac sensor is a 501k device. An IDE is not required for this device which is already in use at 
Memorial Sloan-Kettering Cancer Center with appropriate SOPs in place. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY
Describe the characteristics of the patient/subject population. 
6.1 
Subject Inclusion Criteria 
• 
Adults (18 years old or greater) who are able to provide informed consent. 
• 
Patients who undergo an open, elective liver resection. Including those initially 
approached laparoscopically but converted to an open resection and those 
undergoing additional procedures. 
.      
6.2 
Subject Exclusion Criteria 
• 
Active coronary disease. 
o Patients with active coronary disease will be eligible if they have had a cardiac 
stress study showing no reversible ischemia and normal LV function within 3 
months of operation. 
• 
Active symptomatic cerebrovascular disease. 
• 
Active congestive heart failure and ejection fraction <35%.  
• 
Active severe restrictive or obstructive pulmonary disease and resting SpO2 <90%. 

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• 
Active renal dysfunction (Cr >1.8) 
• 
Abnormal coagulation parameters (INR > 1.8 not on Coumadin, or platelet count < 
100,000 per mcL) 
• 
Presence of active infection including HIV 
• 
Patients with active atrial fibrillation or flutter. 
• 
Preoperative hypoalbuminemia (Albumin < 2g/dl). 
• 
Female patients who are pregnant (female patients of child-bearing potential must 
have a negative serum pregnancy test ≤ 14 days prior to surgery or 15 to 30 days 
prior to surgery with a  negative urine pregnancy test the morning of surgery). 
• 
Presence of ascites.  
• 
BMI > 45 or <17 
 
 
7.0 
RECRUITMENT PLAN 
7.1 Number:  
Based on sample size calculations estimating an 80% power for detecting a 15% decrease in 
the proportion of postoperative complications, assuming the standard arm will have a 30% 
overall complication rate (Type I error of 5%), 270 patients will be randomized 1:1 to the two 
arms.  
7.2. Recruitment: 
All patients scheduled to undergo liver resection who meet the established criteria will be 
approached for participation in this study during their preoperative visit. The trial itself, the 
expected outcomes as well as the risks and potential complications associated with it will be 
thoroughly discussed before enrollment. Informed consent will be obtained and documented 
in the patient’s chart at this point. Study subjects will not receive any compensation for 
participation in the study. There will not be any additional costs for the patients derived from 
participation. In most cases, the initial contact with the prospective subject will be conducted 
either by the treatment team, investigator or the research staff working in consultation with 
the treatment team. Patients will be recruited into the study during their preoperative clinic 
visit to the Hepatopancreaticobiliary Service and consent will be obtained by the attending 
surgeon. 

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The recruitment process outlined presents no more than minimal risk to the privacy of the 
patients who are screened and minimal PHI will be maintained as part of a screening log.  
For these reasons, we seek a waiver of authorization for the purposes of (1) reviewing 
medical records to identify potential research subjects and obtain information relevant to the 
enrollment process; (2) conversing with patients regarding possible enrollment; (3) handling 
of PHI contained within those records and provided by the potential subjects; and (4) 
maintaining information in a screening log of patients approached (if applicable).      
7.3 Women and minorities: 
All patients regardless of gender, race or ethnicity will be recruited to this study.  
 
 
8.0 
PRETREATMENT EVALUATION 
Once the patient has been evaluated by an attending surgeon in the Department of Surgery 
and considered a candidate for a liver resection, eligibility will be assessed. All patients will 
undergo the following preoperative work-up for liver resection: 
• 
Complete history including demographics and physical exam. 
• 
Preoperative testing will include electrocardiogram, chest imaging, comprehensive 
metabolic panel (including liver function tests), complete blood count and coagulation 
parameters.  
• 
Negative serum pregnancy test within 14 days prior to surgery or 15 to 30 days prior 
to surgery with a negative urine test the morning of surgery. Medical clearance will be 
considered for every patient and obtained selectively on those patients who require it 
based on symptoms or past medical history. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
• 
In the operating room patients will receive intravenous sedation  and infiltration of 
local anesthetic prior to  placement of an arterial line. The arterial line will be 
connected to the Flo-Trac System and a Square Wave Test will be performed to 
assess for dynamic performance. The Square Wave Test is a pull and release snap-
tab of the arterial flush to observe the the number of oscillations before returning to 
baseline. Optimally damped would be 1.5-2 oscillations before returning to baseline. 

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Before induction, baseline preoperative hemodynamic measures will be obtained (SV, 
CO). As baseline stroke volume (SV), we will use the mean ± 2 x SD of the measures 
obtained for 6 minutes while the patient is at rest, see table 1 below.    
 
• 
Passive leg-raising (PLR) test.  
The standard definition of volume responsiveness is a >15% increase in stroke 
volume in response to volume expansion. PLR consists of passive elevation of the 
lower extremities with the patient in the  semirecumbent (30-45%) position. This 
maneuver rapidly mobilizes 300-500 ml of blood from the lower extremites to the 
intrathoracic compartment and reproduces the effects of similar volume fluid bolus. 
The increase in the preload will give an indication of the patient’s preoperative fluid 
responsiveness and baseline location on the Starling curve. While measuring stroke 
volume (SV) and cardiac output (CO) before and immediately after PLR (1-3 
minutes), an increase of 12.5 % or more  in PLR – induced increase of stroke volume 
will predict an increase of stroke volume of 15% or more after volume expansion and 
the patient is considered volume responsive. Importantly this fluid challenge is 
reversible and therefore compatible with our low central venous anesthetic technique 
for liver resection.41, 42  Figure 2. 
 
Figure 2. The best way to perform a PLR maneuver to predict volume responsiveness is to 
elevate the lower limbs to 45° (automatic bed elevation or wedge pillow) while at the same 
time placing the patient in the supine from a 45° semirecumbent position.42  
 

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• 
Induction and intubation will be carried out routinely and the patient will be placed on 
positive pressure ventilation. Baseline intraoperative hemodynamic parameters and 
biochemical markers will be obtained. For the patients in the standard management 
group, the EV1000 monitor will be covered and the surgeons and anesthesiologists 
will be blinded to the measured parameters. 
 
Baseline hemodynamic data: 
To obtain baseline hemodynamic measures, we will obtain six successive measures 
60 seconds apart and calculate the mean and standard deviation: 
 
 
 
 
 
 
 
 Table 1.  
Actual values from a sample patient to illustrate measured baseline ± standard deviation 
hemodynamic parameters. CO: Cardiac output; SV: stroke volume; SVI: stroke volume index; 
SVV: stroke volume variation (stroke volume variation will only be interpretable in the 
intubated patient).  
 
These measurements will be obtained preoperatively at rest, after a passive leg raise 
maneuver to evaluate fluid responsiveness  and after intubation to obtain baseline 
SVV.  
The mean value ± two-times the standard deviation will be considered the baseline 
and will be the hemodynamic goal during the resuscitation and PACU phases.  These 
numbers will be used for algorithm A. (appendix 1). 
• 
Central venous lines will only be placed when clinically indicated by the anesthesia or 
Time 
CO 
SV 
SVI 
SVV 
 
L/min 
mL/b 
mL/b/m² 
% 
9:00 am 
6.1 
82 
45 
5 
9 01 am 
5.9 
81 
45 
6 
9:02 am 
6.1 
82 
46 
8 
9:03 am 
6.1 
84 
47 
7 
9:04 am 
6.2 
85 
47 
5 
9:05 am 
6 
82 
46 
7 
 
6 
83 
46 
6 
Mean  
0.1 
1.5 
0.9 
1.2 
Std Dev.  

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surgery practitioner. Central venous access is NOT required for participation in this 
protocol.  
 
• 
All patients will undergo mechanical ventilation with a tidal volume of 8 ml/kg body 
weight at a frequency of 6 to 12 breaths per minute to keep the end-tidal carbon 
dioxide between 35 to 40 mm Hg. Patients will have continuous measurement of 
heart rate, blood pressure, ECG tracing, end-tidal CO2, oxygen saturation, 
temperature, urine output and BIS monitoring.  
 
• 
Standard low central venous anesthetic technique will be applied to all patients. 
 
• 
During the pre-resection phase, all patients will undergo LCVP anesthesia as we 
have previously reported.8 This management strategy is detailed in section 4.1.  
 
• 
During the resuscitation (post-resection) phase, patients in the standard fluid 
management group will receive replacement fluids as detailed in section 4.1. 
 
• 
 Replacement fluid for the patients in the GDT group will follow algorithm A. 
(appendix 1)  
 
• 
Postoperatively, all patients will be kept in the PACU until the following morning. 
Management at this stage will be standardized and equal for both arms: 
 
o PACU standardized management (algorithm B):  
 
Patients requiring continued mechanical ventilation will will receive a 
tidal volume of 8 ml/kg body weight at a frequency of 6 to 12 breaths 
per minute to keep the end-tidal carbon dioxide between 35 to 40 mm 
Hg. Most patients will be extubated in the operating room and not 
require mechanical ventilation. 
 
Maintenance IV crystalloid at 1.2 ml/kg/hr with a maximum rate of 130 
ml/hr. 
 
Strict Inputs and Outputs measured hourly in PACU.  
 
Boluses of 250 ml of albumin solution (given over 20 minutes) will be 
administered for SBP < 90mmHg and/or urine output < 40ml/2hr.  

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 
Medications mixed as per pharmacy protocol, to be included in daily 
input.  
 
The use of vasoactive agents will be left to the discretion of the 
treating practitioner.  
 
   
 
• 
When patients leave PACU, the arterial line will be removed upon transfer to the floor 
and fluid management will be as follows:  
o Maintenance IV crystalloid at 1.2 ml/kg/hr (maximum rate of 130 ml/hr) until 
taking > 400ml/24 hrs po, then d/c.  
o Urine output (UOP) to be maintained at 80ml/4 hours (20ml/hr averaged over 
4 hour periods) with boluses of 500 ml crystalloid solution. 
o Lasix 10mg IV starting POD 2 for weight gain greater than 2kg pre operative 
weight if approved by treating practitioner.  
o If UOP is greater than 60ml/hr over 8 hours, IV rate may be decreased at the 
discretion of the treating practitioner.  
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
• 
Preoperative data will be collected and recorded: date of birth, weight, height, 
complete metabolic panel, complete blood count, coagulation profile. 
• 
Standard intraoperative monitoring will be carried out for all patients. 
• 
GDT patients will also be monitored by CO, SV and SVV. These data will similarly be 
obtained and recorded for the patients in the standard management group but it will 
not be available for the treating practitioners. 
• 
Further measures of end-tissue perfusion will be assessed with arterial lactate levels 
and DO2  (oxygen delivery) at baseline (before incision), at completion of the 
resection phase (intraoperatively), upon arrival to PACU (0 hours postoperatively), 
and on the morning of POD #1.  
• 
Assessment and recording of all intraoperative and postoperative complications; the 
latter being considered as those occurring on or after postoperative day 1 until 
postoperative day 30. Complications occurring intraoperatively and after surgery on 

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the same day, are most likely technical in nature and will be considered perioperative 
complications in the analysis.  
• 
Estimated operative blood loss. 
• 
Cumulative volume used for resuscitation will be recorded (stratified by colloids and 
crystalloids) 
• 
Total dose (mcg/kg) of pressors, inotropes or vasodilators used will be recorded and 
stratified by specific drugs.  
• 
Volume and type of blood products transfused.  
• 
Daily comprehensive metabolic panel, complete blood count (these will be recorded 
for seven days or until discharged if discharged earlier). 
• 
Daily coagulation panel, discontinued by POD 3 if normal.  
• 
Volume and type of fluid intake and output until POD 7 or patient tolerates oral intake 
of fluids > 400 ml/24 hrs 
• 
Daily nasogastric tube drainage volume (if used) and length of NG drainage 
• 
Daily weight until POD 7 or until patient tolerates oral intake of fluids > 400 ml/24 hrs.  
• 
Day of tolerating oral intake of fluids > 400ml/24hrs  
• 
Day of IV ≤ KVO  
• 
Day of tolerating oral intake of solids  
• 
Day of passage of flatus  
• 
Day of foley removal. 
• 
Day of passage of feces  
• 
Day of discharge  
 
Table 2. Details hemodynamic and laboratory values obtained at different stages. For laboratory 
values a 30 minute variation will be allowed to account for early or delayed sample collection in the 
PACU and/or surgical ward. 
 
Baseline 
Preop (pre 
intubation) 
Baseline 
intraop 
(after 
intubation) 
Resuscitation 
Phase 
PACU  
(0 hrs 
postOp) 
4 hrs 
postOp 
8 hrs 
postOp 
12 hrs 
postOp 
Morning of 
POD 1 
Morning of 
POD 2 
Stroke Volume 
(μ ± SD) 
x 
 
 
x 
x 
x 
 
x 
 
*Stroke 
Volume (μ ± 
SD) 
x 
 
 
 
 
 
 
  
 
% change in SV 
x 
 
 
 
 
 
 
  
 
Stroke Volume 
Variation- SVV 
(μ ± SD) 
  
x 
x 
 
 
 
 
  
 

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Stroke Volume 
- SV (μ ± SD) 
  
 
x 
x 
x 
x 
x 
  
 
Stroke volume  
index (μ ± SD) 
  
 
x 
 x 
x  
 x 
x 
  
 
LABS 
 
 
 
 
 
 
 
 
 
Na 
 
 
 
x 
 
 
 
 
 
K 
 
 
 
x 
 
 
 
 
 
Cl 
 
 
 
x 
 
 
 
 
 
Arterial Lactate 
X 
 
x 
x 
 
 
 
x 
 
HCO3 
X 
 
x 
x 
 
 
 
X 
 
Creatinine 
 
 
 
x 
 
 
 
 
 
BUN
x 
 
Glucose 
 
 
 
x 
 
 
 
 
 
Glomerular 
filtration rate- 
GFR 
(calculated) 
 
 
 
x 
 
 
 
 
 
WBC 
 
 
 
x 
 
 
 
 
 
Hemoglobin 
X 
 
X 
x 
 
 
 
X 
 
Hematocrit 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Post passive leg raising test values. 
11.0 TOXICITIES/SIDE EFFECTS 
Goal-directed fluid therapy in major abdominal surgery has been reported before with no significant 
adverse events reported.14, 24 The FloTrac system for minimally-invasive hemodynamic monitoring 
has also been tested in clinical trials with no adverse events reported.37 An Adverse Event (AE) is 
defined as any new, untoward or unexpected medical occurrence or worsening of a pre-existing 

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medical condition in a research participant, that does not necessarily have a causal relationship with 
protocol treatment. All adverse events for this protocol will be defined as those listed in the MSKCC 
Surgical Secondary Event Program. Any grade 3 or higher as determined by this database will be 
reported to the IRB. 
A serious adverse event (SAE) is an undesirable sign, symptom or medical condition that is fatal or 
life-threatening 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
requires prolongation of existing hospitalization, unless hospitalization is for: 
o elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of 
a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
o  is medically significant, i.e., defined as an event that jeopardizes the patient or may 
 
require medical or surgical intervention to prevent one of the outcomes listed above 
NOTE: 
The following hospitalizations are not considered to be SAEs: 
• 
Admission for a planned medical/surgical procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status (e.g. 
routine colonoscopy) 
• 
Medical/surgical admission for purpose other than remedying ill health state which was 
planned prior to entry into the study; appropriate documentation is required in such a case 
• 
Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition  
 
All complications will be prospectively recorded.The hepatobiliary surgery service runs a 
biweekly meeting in which all complications are discussed and prospectively recorded into 
the Memorial Sloan-Kettering Surgical Secondary Events Program Database. At this meeting 
attendings discuss individual patients and assess the outcomes in order to record 
complications according to predefined criteria. appendix 2 and 3. Research personnel 
directly involved in the protocol will not influence this process. 
A Hepatopancreaticobiliary research study assistant will query the Surgical Secondary 
Events Program Database at 30 days after each patient’s operation and prospectively collect 
morbidity data for patients enrolled in the study.   
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
The null hypothesis is that GDT in patients undergoing liver resection does not alter the 
incidence of postoperative complications. A 15% decrease (from 30% to 15%) in the 

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incidence of 30-day complications will be considered clinically significant and will represent 
the primary outcome measure. The incidence of these will be assessed after each patient’s 
postoperative visits. 
Secondary outcomes include the impact of GDT on low cardiac output time, total volume of 
fluid used perioperatively, the requirement for blood transfusion, the total dose of vasoactive 
drugs, end-organ perfusion markers and the net fluid balance 48 hrs postoperatively. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
At any point during the study, the attending surgeon or anesthesiologist may decide to go off 
protocol in their resuscitation strategy if they deem it necessary for patient safety. 
Randomized patients will not be replaced for any reason. If a patient is transferred to the 
Intensive Care Unit, they will have that recorded as a complication and will be removed from 
the study. Management will continue in the patient’s best interests and according to ICU 
guidelines.  
14.0 
BIOSTATISTICS 
This is a randomized comparison of goal-directed compared to standard fluid management in 
patients undergoing liver resection. Primary endpoint is overall postoperative morbidity.  
270 patients will be randomized 1:1 to the two arms. This sample size provides 80% power 
for detecting a 15% decrease in the proportion of overall postoperative complications (i.e 
regardless of grade of severity), assuming the standard arm will have a 30% complication 
rate (two-sided Type I error of 5%). It also allows for an interim analysis halfway through 
enrollment, using O’Brien-Fleming boundaries both for efficacy and futility. If p<=0.005 at the 
interim analysis enrollment will stop with the conclusion that goal-directed fluid management 
significantly decreases postoperative morbidity. If p>=0.468 at the interim analysis enrollment 
will stop with the conclusion that goal-directed fluid management does not significantly 
decrease postoperative morbidity. If 0.005<p<0.468 then the trial will continue to full 
enrollment. With an approximate enrollment of 11 patients per month, accrual should be 
complete in 2 years. 
Secondary endpoints will be compared between the two arms using the Wilcoxon rank-sum 
test, except for the categorical endpoints of blood transfusion and systemic inflammatory 
response, which will be compared using Fisher’s exact test. 

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Since one of our main goals for this study is to establish what the individual amount of 
resuscitation is for each patient, tailored to their hemodynamic status, we decided to use 
their baseline value ± 2 standard variations as their homestatic  stroke volume variation. An 
elevation above 2 standard deviations would be statistically unlikely to represent a normal 
variation of the measurement and will thus be considered a hemodincamically significant 
deviation from baseline.  
 
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
This is a single-blinded randomized trial.  After eligibility is established and consent is 
obtained, patients will be registered in the Protocol Participant Registration (PPR) system.   
Eligible patients will be consented for the trial prior to surgery.  However randomization will 
not occur until the operating room. After the liver has been resected, intraoperative 
randomization will be done by envelopes. Randomization will be stratified by diagnosis 
(metastatic liver disease compared to primary disease where primary disease will 
encompass liver cancer and extrahepatic biliary cancer). 
16.0 
DATA MANAGEMENT ISSUES 
All collected data that will only be used for the purposes of the study. It will be maintained in 
a confidential clinical research database by research study personnel only and under direct 

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supervision of the principal investigator. The database will be kept in a password protected 
computer and will not be transferred outside of the hospital network. A minimum dataset will 
be kept in CRDB . The data will be linked to the patients by means of unique tracking subject 
numbers the key to which will be also password protected and only to be accessed by 
research personnel. Data will be reported to the IRB as required.  
 
 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team at pre-established intervals.  
The principal investigator will maintain final responsibility for data during the study and during 
the final analysis of data. Breaches of protocol, problems with informed consent, or 
discrepancies in data accuracy will be reported to the IRB as required.  
 
 
16.2 
Data and Safety Monitoring 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines. The DSM Plans at MSKCC 
were established and are monitored by the Office of Clinical Research. The MSKCC Data 
and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf  
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 

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monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
The responsible investigator will ensure that this study is conducted in agreement with the 
Declaration of Helsinki (Tokyo, Venice, Hong Kong, Somerset West and Edinburgh 
amendments). The study will seek in every way to protect the rights of human subjects. The 
potential risks including adverse drug reactions and potential benefits in terms of reducing 
transfusion requirement and postoperative recovery will be discussed in detail with patients. 
Potential side effects as outlined above will be discussed with the patients. No patient will be 
required to participate in the study and participation or lack of participation will not affect the 
patient’s subsequent care or treatment. The patient will not incur any financial cost as a 
result of participation in the study. Participation will be purely voluntary and subjects will not 
be reimbursed for participation in the study. Throughout the study, patient confidentiality will 
be maintained. No results of the study will be presented or discussed in a fashion that will 
allow identification of a particular patient in the study. All adverse events will be fully 
disclosed to the IRB in a timely fashion as required. 
 
17.1 
Privacy 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 

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17.2 
Serious Adverse Event (SAE) Reporting 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
Fields populated from CRDB: 
• 
Subject’s name (generate the report with only initials if it will be sent outside of     
      MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form. 
The PI’s signature and the date it was signed are required on the completed report. 
17.2.1 NA 
18.0 
INFORMED CONSENT PROCEDURES 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following:  
1. The nature and objectives, potential risks and benefits of the intended study.  
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 

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4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time.  
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
1. 
Chauhan A, House MG, Pitt HA, et al. Post-operative morbidity results in decreased long-
term survival after resection for hilar cholangiocarcinoma. HPB (Oxford). Feb 
2011;13(2):139-147. 
2. 
Farid SG, Aldouri A, Morris-Stiff G, et al. Correlation between postoperative infective 
complications and long-term outcomes after hepatic resection for colorectal liver metastasis. 
Ann Surg. Jan 2010;251(1):91-100. 
3. 
Neal CP, Mann CD, Garcea G, Briggs CD, Dennison AR, Berry DP. Preoperative systemic 
inflammation and infectious complications after resection of colorectal liver metastases. Arch 
Surg. Apr 2011;146(4):471-478. 
4. 
Schepers A, Mieog S, van de Burg BB, van Schaik J, Liefers GJ, Marang-van de Mheen PJ. 
Impact of complications after surgery for colorectal liver metastasis on patient survival. J 
Surg Res. Nov 2010;164(1):e91-97. 
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Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ. Determinants 
of long-term survival after major surgery and the adverse effect of postoperative 
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6. 
Ito H, Are C, Gonen M, et al. Effect of postoperative morbidity on long-term survival after 
hepatic resection for metastatic colorectal cancer. Ann Surg. Jun 2008;247(6):994-1002. 
7. 
Cunningham JD, Fong Y, Shriver C, Melendez J, Marx WL, Blumgart LH. One hundred 
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8. 
Melendez J. Perioperative outcomes of major hepatic resections under low central venous 
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9. 
Jarnagin WR, Gonen M, Maithel SK, et al. A prospective randomized trial of acute 
normovolemic hemodilution compared to standard intraoperative management in patients 
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Kamiyama T, Nakanishi K, Yokoo H, et al. Perioperative management of hepatic resection 
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11. 
Fan ST, Mau Lo C, Poon RT, et al. ContinUOPus improvement of survival outcomes of 
resection of hepatocellular carcinoma: a 20-year experience. Ann Surg. Apr 
2011;253(4):745-758. 
12. 
Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic 
resection: analysis of 1,803 consecutive cases over the past decade. Ann Surg. Oct 
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Virani S, Michaelson JS, Hutter MM, et al. Morbidity and mortality after liver resection: results 
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14. 
Chappell D, Jacob M, Hofmann Kiefer K, Conzen P, Rehm M. A rational approach to 
perioperative fluid management. Anesthesiology. 2008;109(4):723-740. 
15. 
Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R. A comparison of albumin and 
saline for fluid resuscitation in the intensive care unit. N Engl J Med. May 27 
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Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a resuscitation fluid for 
patients with sepsis: a systematic review and meta-analysis. Crit Care Med. Feb 
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Perel P, Roberts I. Colloids compared to crystalloids for fluid resuscitation in critically ill 
patients. Cochrane Database Syst Rev. 2007(4):CD000567. 
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Perel P, Roberts I. Colloids compared to crystalloids for fluid resuscitation in critically ill 
patients. Cochrane Database Syst Rev. 2011;3:CD000567. 
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Roberts I, Alderson P, Bunn F, Chinnock P, Ker K, Schierhout G. Colloids compared to 
crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 
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de Saint-Aurin RG, Kloeckner M, Annane D. Crystalloids compared to colloids for fluid 
resuscitation in critically-ill patients. Acta Clin Belg Suppl. 2007(2):412-416. 
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Jacob M, Chappell D, Rehm M. The 'third space'--fact or fiction? Best Pract Res Clin 
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IRB PROTOCOL 
IRB#: 12-056 A(4) 
Amended: 05/28/13 
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20.0 
APPENDICES 
Appendix 1 - Algorithms for goal-directed fluid therapy (GDT). 
 
Appendix 2 - Complication grade classification. 
 
Appendix 3 - Incidence of complications after liver resection at MSKCC in 2010.