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ORIGINAL ARTICLE

Effects of Intraoperative Fluid Management on

Postoperative Outcomes
A Hospital Registry Study
Christina H. Shin, MD,  Dustin R. Long, MD,  Duncan McLean, MBChB,  y
Stephanie D. Grabitz, Cand. Med,  Karim Ladha, MD, MSc,z Fanny P. Timm, Cand. Med, 
Tharusan Thevathasan, Cand. Med,  Alberto Pieretti, MD,§ Cristina Ferrone, MD,§
Andreas Hoeft, MD, PhD,ô Thomas W. L. Scheeren, MD, PhD,jj Boyd Taylor Thompson, MD, 
Tobias Kurth, MD, ScD,yyzz and Matthias Eikermann, MD, PhD 

length of stay and total cost of care. Our models were adjusted for patient-,
Objective: Evaluate the dose-response relationship between intraoperative
procedure-, and anesthesia-related factors.
fluid administration and postoperative outcomes in a large cohort of surgical
Results: A U-shaped association was observed between the volume of fluid
patients.
administered intraoperatively and 30-day mortality, costs, and postoperative
Background: Healthy humans may live in a state of fluid responsiveness
length of stay. Liberal fluid volumes (highest quintile of fluid administration
without the need for fluid supplementation. Goal-directed protocols driven by
practice) were significantly associated with respiratory complications
such measures are limited in their ability to define the optimal fluid state
whereas both liberal and restrictive (lowest quintile) volumes were signifi-
during surgery.
cantly associated with acute kidney injury. Moderately restrictive volumes
Methods: This analysis of data on file included 92,094 adult patients under-
(second quintile) were consistently associated with optimal postoperative
going noncardiac surgery with endotracheal intubation between 2007 and
outcomes and were characterized by volumes approximately 40% less than
2014 at an academic tertiary care hospital and two affiliated community
traditional textbook estimates: infusion rates of approximately 6–7 mL/kg/hr
hospitals. The primary exposure variable was total intraoperative volume of
or 1 L of fluid for a 3-hour case.
crystalloid and colloid administered. The primary outcome was 30-day
Conclusions: Intraoperative fluid dosing at the liberal and restrictive margins
survival. Secondary outcomes were respiratory complications within three
of observed practice is associated with increased morbidity, mortality, cost,
postoperative days (pulmonary edema, reintubation, pneumonia, or respirat-
and length of stay.
ory failure) and acute kidney injury. Exploratory outcomes were postoperative
Keywords: acute kidney injury, cost, healthcare utilization, intraoperative
fluid management, length of stay, mortality, outcomes, postoperative
respiratory complications
From the Department of Anesthesia, Critical Care, and Pain Medicine, Massa-
chusetts General Hospital, Boston, MA; yDepartment of Anesthesiology, (Ann Surg 2017;xx:xxx–xxx)
University of Rochester Medical Center, Rochester, NY; zDepartment of
Anesthesia, Toronto General Hospital and University of Toronto, Toronto,
Canada; §Department of Surgery, Massachusetts General Hospital, Boston,
MA; ôDepartment of Anesthesiology and Intensive Care Medicine, University
Hospital Bonn, Bonn, Germany; jjDepartment of Anesthesiology, University
D uring surgery, maintenance of intravascular volume by intra-
venous fluid is necessary to mitigate hypovolemia caused by
osmotic loss, evaporation, and bleeding. However, excessive intra-
of Groningen, University Medical Center Groningen, Groningen, the Nether-
lands; Department of Medicine, Massachusetts General Hospital, Boston,
operative fluid administration can expose patients to the risks of acid-
MA; yyInstitute of Public Health, Charité Universitätsmedizin, Berlin, base disturbances and edema formation, increasing the distance
Germany; and zzDivision of Preventive Medicine, Brigham and Women’s between capillaries and cells and impairing gas exchange. Although
Hospital, Harvard Medical School, Boston, MA. adverse respiratory outcomes have generally been associated with
Disclosure: This study was funded by Jeff and Judy Buzen in an unrestricted grant
to Dr. Matthias Eikermann. The authors declare no conflicts of interest.
liberal fluid administration, fluid restriction may confer different but
Author Contributions: equally important risks such as organ hypoperfusion with successive
C.H.S., D.R.L., and D.McL. contributed equally in this study. C.H.S., D.R.L., and dysfunction and failure. Renal function is particularly susceptible to
D.McL. contributed to the design and conception of the study, the analysis and changes in volume status1 and hypovolemia may increase risk of
interpretation of data, and drafting of the work. K.L. and T.W.L.S. contributed
to the design and conception of the study. F.P.T. and S.D.G. contributed to the
postoperative kidney injury.2
analysis and the acquisition of data for the work. T.T. and A.P. contributed to The formulaic approach to balancing perioperative fluids
the acquisition of data. C.F., A.H., T.W.L.S., and B.T.T. contributed to the classically described in textbooks (based on fasting, urine output,
critical review and interpretation of the work. T.K. contributed to design and blood loss, evaporative loss, and so on) has since been supplanted by
conception of the study, data analysis and interpretation of data. M.E. is the
guarantor of the paper; he takes responsibility for the integrity of the work as a
a notion that more restrictive approaches may yield improved out-
whole, from inception to published article. M.E. served as clinical research comes.3 –5 However, prospective trials of empiric dosing strategies
mentor to C.H.S., D.R.L., and D.McL. All authors revised the work critically have utilized varying definitions of ‘‘liberal’’ versus ‘‘restrictive,’’
for important intellectual content. been limited by small sample sizes,6 and yielded conflicting results.7
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
‘‘Goal-directed fluid therapy’’ (GDFT) has emerged as an approach
this article on the journal’s Web site (www.annalsofsurgery.com). to monitoring fluid-recruitable cardiac output with the potential
Reprints: Matthias Eikermann, MD, PhD, Department of Anesthesia, Critical Care, advantage of identifying patients who may benefit from additional
and Pain Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, fluid administration.8,9 However, healthy humans have significant
MA, 02114. E-mail: meikermann@partners.org.
Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
preload reserve and may be fluid responsive at baseline, functioning
ISSN: 0003-4932/16/XXXX-0001 on the ascending limb of the Frank-Starling curve without the need
DOI: 10.1097/SLA.0000000000002220 for fluid supplementation10 Therefore, as demonstrated in one recent

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Shin et al
trial,11 fluid administration to all patients who are fluid responsive
may still increase the risks of fluid overload without conferring
additional benefit. Although lack of fluid responsiveness may mark
the absolute upper bound of safe practice, the optimal state, and the
safe lower limit of fluid restriction in this setting remain unclear. For
these reasons, great variability persists in the perioperative dosing of
intravenous fluid,12 which cannot be explained by patient- or case-
specific factors. Such high variance between providers normally
indicates uncertainty and implies a high potential for improvement.
We hypothesized that variation in intraoperative fluid admin-
istration within the range of standard clinical practice would be
associated with differences in 30-day mortality, postoperative respir-
atory complications (PRCs), and acute kidney injury (AKI). We
sought to quantify the dose-response relationship between fluid
volume and each of these outcomes across 5 quintiles of practice
spanning the range of restrictive to liberal.
METHODS
Study Design and Setting
We performed a retrospective analysis of data on file in
surgeries performed at Massachusetts General Hospital and two
affiliates between January 2007 and August 2014. Local treatment
guidelines for intraoperative fluid management were not in place at any
of the study sites during the data acquisition period. The study was
approved by the Partners Institutional Review Board (2013P001704)
and registered at clinicaltrials.gov (NCT02105298). All adult patients
undergoing noncardiac surgery with intraoperative endotracheal intu-
bation and extubation were enrolled (Fig. 1). Demographic, intra-
operative, and outcomes data were extracted from clinical and
administrative databases, as described in the online supplement.
Exposure Variable
Total fluid volume was derived from the anesthesia record and
defined as the volumes of crystalloid plus one-and-a-half times13
colloid administered between initiation of anesthesia care and arrival
in the postanesthesia care unit. Patients were classified into 5 groups
2 | www.annalsofsurgery.com
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Annals of Surgery  Volume XX, Number XX, Month 2017
FIGURE 1. Study flow diagram illustrat-
ing surgical cohort used for data analysis.
ASA indicates American Society of Anes-
thesiologists physical classification score;
BMI, body mass index.
representing incremental quintiles of the exposure variable: restric-
tive (quintile 1, Q1), moderately restrictive (quintile 2, Q2), moderate
(quintile 3, Q3), moderately liberal (quintile 4, Q4), and liberal
(quintile 5, Q5).
Outcome Measures
The primary outcome was mortality within 30 days after
surgery. Secondary outcomes were PRCs and AKI. PRCs were
defined as the occurrence of pneumonia, pulmonary edema, respir-
atory failure, and/or reintubation within three postoperative days.
AKI was defined as an increase in serum creatinine by at least 0.3 mg/
dL or 50% from preoperative levels within 48 postoperative hours14
or the existence of an AKI diagnostic code within seven postoper-
ative days. Exploratory outcomes included postoperative length of
stay (PLOS) and cost. PLOS was defined as the number of hospi-
talized days after surgery. Hospital costs were derived from an
internal financial tracking system and represent the sum of direct
and indirect expenses incurred by the institution. To arrive at general-
izable cost estimates, our cohort was matched to the 2012 National
Inpatient Sample.15
Statistical Analysis
Quintile-based analysis was performed for all outcomes with
the best-performing quintile serving as the reference group. A
survival analysis using a multivariable Cox proportional hazards
model was performed for 30-day mortality. The proportional hazards
assumption was met based on the parallel nature of the –lng[–
ln(survival)] curves for each category of the exposure variable versus
ln(analysis time). PRCs and AKI were analyzed using logistic
regression models whereas PLOS and cost were analyzed using
zero-truncated negative binomial regression models. Confounders
were included based on a priori knowledge of predictors of respir-
atory failure,16 AKI,17 and factors used by clinicians to estimate fluid
requirements.18 The following were treated as categorical variables:
sex, admission type, emergency status, surgical body region, use of
neuromuscular blocking agents, crystalloid type, and medical comor-
bidities.19 Covariates demonstrating linear correlation with the
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Annals of Surgery  Volume XX, Number XX, Month 2017 Intraoperative Fluid Management

primary outcome [age, body mass index (BMI), ASA score, age-
adjusted anesthetic doses20] were included as continuous, whereas
those demonstrating nonlinear associations with the primary out-
come (vasopressor equivalent dose,21 morphine equivalent dose,22
procedure duration, estimated blood loss, urine output, hypotension,
and procedure relative value units23) were categorized into quintiles.
To quantify the distribution of interprovider variation with regard to
the exposure variable, we plotted the probability of each individual
anesthesia practitioner providing intraoperative fluid volumes within
a specified optimal range, based on the results of the main analyses.
For each provider identified in fifty or more cases in the dataset, the
probability of administering fluids in the moderate range (quintiles
2–4) versus restrictive (quintile 1) or liberal (quintile 5) range
was estimated after propensity matching of cases using the same
covariates.
We performed several sensitivity analyses to assess the robust-
ness of the findings to analytic approach, most notably, an alternate
definition of the primary exposure variable using a formula for fluid
balance to account for individual differences in fasting status,
maintenance fluid requirement, blood loss, and urine output. This
formula and a full presentation of sensitivity analyses are described
in the Supplemental Digital Content, http://links.lww.com/SLA/
B202. We also performed a series of analyses examining the potential
impact of fluid type and colloid utilization in the cohort. Individual
subgroup and sensitivity analyses were also performed to assess the
influences of colloid: crystalloid ratio, categorization of exposure,
and covariate variables, imputation of missing data, adjustment of
PLOS for mortality, anatomic surgical site, emergency status, hos-
pital site, and several patient-oriented factors, further described in the
Supplemental Digital Content, http://links.lww.com/SLA/B202.
Variables defined using International Statistical Classification
of Diseases and Related Health Problems, ninth revision codes (ICD-
9) and Current Procedural Terminology (CPT) codes are described in
the Supplemental Digital Content (see Table S1, Supplemental
Digital Content, http://links.lww.com/SLA/B202). Analyses were
conducted using Stata (versions 13 and 14, StataCorp, TX). Results
are presented as hazard ratios (HR), odds ratios (OR), or incidence
rate ratios (IRR) with 95% confidence intervals (95% CI). A 2-tailed
P < 0.05 was considered statistically significant.
RESULTS
Patient Selection
A total of 137,102 noncardiac surgical cases occurred at our
institution between January 2007 and August 2014. Of these, a total
of 92,094 met our inclusion criteria for analysis (Fig. 1). A total of
18,790 (20.4%) patients received intraoperative fluid volumes of
900 mL (Q1), 18,825 (20.4%) received volumes of >900 to 1100
mL (Q2), 19,292 (20.9%) received volumes of >1100 to 1750 mL
(Q3), 16,769 (18.2%) received volumes of >1750 to 2700 mL (Q4)
and 18,418 (20.0%) received volumes of > 2700 mL (Q5). The
clinical characteristics of the cohort including information about
utilization various fluid types are summarized in Table S2 of the
Supplemental Digital Content, http://links.lww.com/SLA/B202.
Descriptive data derived using the alternate exposure definition of
fluid balance, based on an individualized estimate of fluid require-
ment, are presented Table S3.
Primary Outcome
Approximately, 429 (0.5%) patients died within 30 days
(Table 1). Survival analysis demonstrated a U-shaped curve of risk
which was lowest in the moderately restrictive range of quintile 2
(Fig. 2). Compared with this group, the risk for 30-day mortality was
significantly increased at restrictive (Q1: HR 1.41, 95% CI 1.03–
1.93, P ¼ 0.034) and liberal (Q5: HR 1.65, 95% CI 1.04–2.60, P ¼
0.032) practices.
Secondary Outcomes
A total of 3657 (3.9%) patients experienced PRCs. Increasing
fluid volumes were found to increase the risk of PRCs (Q5: OR 1.27,
95% CI 1.08–1.48, P ¼ 0.003) (Fig. 2, Table 1). Within 48 hours of
surgery, 2669 (2.9%) patients met criteria for AKI. The risk for

TABLE 1. Effect of Total Intraoperative Fluid Volume on Postoperative Outcomes

Total Intraoperative Fluid Volume in Quintiles
Quintile 1 Quintile 2 Quintile 3 Quintile 4 Quintile 5
(n ¼ 18,790) (n ¼ 18,825) (n ¼ 19,292) (n ¼ 16,769) (n ¼ 18,418) Total Population
900 mL >900 to 1100 mL >1100 to 1750 mL >1750 to 2700 mL >2700 mL (N ¼ 92,094)
Primary Outcome
Mortality N (%) 154 (0.8) 62 (0.3) 66 (0.3) 65 (0.4) 82 (0.5) 429 (0.5)
HR (95% 1.41 (1.03–1.93), 1 1.17 (0.81–1.68), 1.47 (0.99–2.19), 1.65 (1.04–2.60),
CI), P P ¼ 0.034 P ¼ 0.403 P ¼ 0.056 P ¼ 0.032
Secondary Outcomes
Postoperative N (%) 527 (2.8) 491 (2.6) 685 (3.6) 707 (4.2) 1247 (6.8) 3657 (3.9)
Respiratory OR (95% 1.05 (0.90–1.21), 1 1.08 (0.94–1.23), 1.07 (0.92–1.24), 1.27 (1.08–1.48),
Complication CI), P P ¼ 0.600 P ¼ 0.300 P ¼ 0.38 P ¼ 0.003
Acute Kidney Injury N (%) 348 (1.9) 275 (1.5) 398 (2.1) 438 (2.9) 1165 (6.3) 2669 (2.9)
OR (95% 1.66 (1.37–2.01), 1.18 (0.99–1.41), 1.16 (1.00–1.34), 1 1.29 (1.14–1.46),
CI), P P < 0.001 P ¼ 0.061 P ¼ 0.054 P < 0.001
Exploratory Outcomes
Postoperative Mean (SD) 3.1 (4.7) 3.1 (4.0) 3.7 (4.1) 4.6 (4.9) 6.2 (5.8) 4.1 (4.9)
Length of IRR (95% 1.03 (1.00–1.06), 1 1.00 (0.98–1.02), 1.03 (1.01–1.06), 1.15 (1.12–1.18),
Stay, days CI), P P ¼ 0.076 P ¼ 0.965 P ¼ 0.005 P < 0.001
Total Hospital NIS Matched $12,385.70 $12,230.52 $12,245.16 $12,343.66 $13,140.87 ($9755.53)
Care Costs, Mean (SD) ($9194.90) ($9079.70) ($9090.57) ($9163.70)
dollars IRR (95% 1.01 (1.00–1.03), 1 1.00 (0.99–1.01), 1.01 (0.99–1.02), 1.07 (1.05–1.09),
CI), P P ¼ 0.084 P ¼ 0.842 P ¼ 0.230 P < 0.001
Results of multivariable Cox, logistic regression, and negative binomial regression modeling are presented as adjusted HR, OR or IRR, 95% CI, and P.
CI indicates confidence intervals; HR, hazard ratio; IRR, incidence rate ratios; NIS, national inpatient sample; OR, odds ratio.

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Shin et al Annals of Surgery  Volume XX, Number XX, Month 2017

FIGURE 2. Effect of intraoperative fluid volume on postoperative outcomes. Total volume of intravenous fluids administered from
initiation of anesthesia care to delivery in post-anesthesia care unit was analyzed as quintiles: quintile 1 (Q1) ¼ restrictive (900 mL);
quintile 2 (Q2) ¼ moderately restrictive (>900 to 1100 mL); quintile 3 (Q3) ¼ moderate (>1100 to 1750 mL); quintile 4
(Q4) ¼ moderately liberal (>1750 to 2700 mL); and quintile 5 (Q5) ¼ liberal (>2700 mL). The association between total intra-
operative fluid volume and postoperative outcomes was analyzed using multivariable models adjusted for age, sex, BMI, ASA,
emergency status, admission type, surgical body region, age-adjusted inhalational anesthestic dose, neuromuscular blocking agent
use, morphine equivalent dose, vasopressor equivalent dose, duration of surgery, estimated blood loss, urine output, duration of
hypotension, chloride composition of crystalloid, procedure relative value units, and medical comorbidities. A, Restrictive and
liberal fluid administration are associated with increased 30-day mortality according to multivariable Cox proportional hazard
model (P ¼ 0.034, #P ¼ 0.032). B, Liberal fluid administration is associated with increased risk of postoperative respiratory
complications according to multivariable negative binomial regression model (P ¼ 0.003). C, Restrictive and liberal fluid
administration are associated with increased risk of acute kidney injury according to multivariable negative binomial regression
model (P < 0.001, #P < 0.001). D, Liberal fluid administration is associated with increased postoperative length of stay according to
multivariable negative binomial regression model (P ¼ 0.005, #P < 0.001). E, Liberal fluid administration is associated with
increased hospital costs according to multivariable negative binomial regression model (P < 0.001). ASA indicates American
Society of Anesthesiologists physical classification score; BMI, body mass index.

postoperative AKI was lowest in the moderately liberal group (Q4),
whereas AKI was increased with both restrictive (Q1: OR 1.66, 95%
CI 1.37–2.01, P < 0.001) and liberal (Q5: OR 1.29, 95% CI 1.14–
1.46, P < 0.001) fluid practices (Fig. 2, Table 1).
Exploratory Analyses
The mean PLOS in the cohort was 4.1 days. Increasing fluid
volumes were predictive of longer PLOS (compared with Q2, Q4:
IRR 1.03, 95% CI 1.01–1.06, P ¼ 0.005; Q5: IRR 1.15, 95% CI
1.12–1.18, P < 0.001) (Fig. 2, Table 1). Total hospital costs were also
lowest in the second quintile and highest in the fifth quintile (Q5: IRR
1.07, 95% CI 1.05–1.09, P < 0.001) (Fig. 2). Based on the IRR
derived from our cost data, we estimate an average savings of $910 in
total hospital cost per case (from $13,140 to $12,230) in patients
receiving moderately restrictive versus liberal fluid volumes.
Provider Variability
The practice patterns of individual anesthesia practitioners
varied with respect to fluid administration even after accounting for
patient- and case-specific factors which may influence fluid require-
ments (Fig. 4). In this figure, each anesthesia provider is represented
as a single point on the horizontal axis and the probability of
delivering a fluid volume in the ‘‘desirable’’ moderate range is
shown on the vertical axis. Only a small group (left) consistently
administers fluids within this optimal range, whereas another group
(right) routinelys provide doses which appear excessively restrictive
or liberal with regard to the outcomes considered in this study.
Sensitivity Analyses
Defining the primary exposure variable as fluid balance rather
than total volume had modest effects on confidence intervals but
demonstrated no overall change in patterns of observed association
(Fig. 3; Table 2). Mortality, PLOS, and cost continued to demonstrate
U-shaped curves of association optimized in the moderately restric-
tive fluid group. PRCs climbed with increasing fluid doses whereas
the risk for AKI gradually fell to a nadir in the moderate quintiles
before rising again.
Our subgroup and sensitivity analyses collectively demon-
strated the robust nature of the reported associations. A complete
presentation of the following analyses is reported in the Supple-
mental Digital Content (http://link-s.lww.com/SLA/B202): use of
alternate number of quantiles for fluid exposure (Fig. S1A-C),

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Annals of Surgery  Volume XX, Number XX, Month 2017 Intraoperative Fluid Management

FIGURE 3. The effect of intraoperative fluid balance on postoperative outcomes. The exposure variable represents the net change in
fluid balance from initiation of anesthesia care to delivery in postanesthesia care unit. Fluid balance accounts for fasting status, blood
loss, urine output, maintenance requirement, and insensible losses. The net change in fluid balance additionally is adjusted for
duration of surgery and patient weight, and is analyzed by quintiles: quintile 1 (Q1) ¼ restrictive fluid balance (–6 mL/kg/hr);
quintile 2 (Q2) ¼ moderately restrictive (>–6 to –3.6 mL/kg/hr); quintile 3 (Q3) ¼ moderate (>–3.6 to –1.5 mL/kg/hr); quintile 4
(Q4) ¼ moderately liberal (>–1.5 to þ1.2 mL/kg/hr); quintile 5 (Q5) ¼ liberal (> þ1.2 mL/kg/hr). The association between fluid
balance and postoperative outcomes was analyzed using multivariable models adjusted for age, sex, BMI, ASA, emergency status,
admission type, surgical body region, age-adjusted inhalational anesthestic dose, neuromuscular blocking agent use, morphine
equivalent dose, vasopressor equivalent dose, duration of surgery, estimated blood loss, urine output, duration of hypotension,
chloride composition of crystalloid, procedure relative value units, and medical comorbidities. A, Liberal fluid administration is
associated with the highest risk of mortality according to multivariable Cox proportional hazard model (P ¼ 0.018). B, Moderately
liberal and liberal fluid administration are associated with increased risk of postoperative respiratory complications according to
multivariable logistic regression model (P ¼ 0.014; #P ¼ 0.003). C, Restrictive and liberal fluid administration are associated with
increased risk of acute kidney injury according to multivariable logistic regression model (P < 0.001, #P < 0.001. D, Moderately
liberal and liberal fluid administration are associated with increased postoperative length of stay according to multivariable negative
binomial regression model (P < 0.001, #P < 0.001). E, A moderately restrictive administration is associated with lowest hospital
costs according to multivariable negative binomial regression model (P < 0.001, #P < 0.001, yP < 0.001). ASA indicates American
Society of Anesthesiologists physical classification score; BMI, body mass index.

expanded use of continuous covariates (Fig. S1D-F), abdominal
surgery only (Fig. S2A-C), exclusion of lung and liver resections
(Fig. S2D-F), stratification by admission type (Fig. S3), stratification
by ASA classification (Fig. S4), preoperative risk score for pulmon-
ary complications (Fig. S5), baseline creatinine clearance (Fig. S6A-
B), duration of intraoperative hypotension (Fig. S6C-D), intraoper-
ative vasopressor use (Fig. S6E-F), adjustments for death prior to
discharge (Fig. S7), emergency status (Fig. S8), imputation of
missing data (Fig. S9), exclusion of hydroxyethyl starch (Fig.
S10A-C), exclusion of all colloids (Fig. S10D-F), exclusion of
non-standard crystalloids (Fig. S10G-I), statistical adjustment for
colloid utilization (Fig. S11), alternative colloid: crystalloid ratios
(Fig. S12), hospital site and provider effects (Fig. S13), and changes
in fluid administration practice over time (Fig. S14-S16).
DISCUSSION
In an analysis of 92,094 surgeries performed at the Massa-
chusetts General Hospital and two community hospitals over a 7-year
period, we observed a robust U-shaped association between
intraoperative fluid administration and 30-day mortality. PRC and
AKI, 2 established predictors of surgical morbidity and mortality,24
were also independently associated with fluid dosing. These fluid-
associated outcome differences were further reflected as differences
in the cost and duration of hospitalization.
Mortality
Existing knowledge about the effects of intraoperative fluid on
outcomes has been drawn from trials comparing two distinct fluid
administration strategies (eg, restrictive vs liberal, GDFT vs liberal,
and so on). This binary approach to comparison conflicts with
physiologic predictions of the perioperative risk attributable to fluid
administration, which has repeatedly been theorized to fall and then
rise with increasing fluid volumes, forming a U-shaped curve.7,25
Previous efforts to characterize the influence of fluid admin-
istration on survival have targeted critically ill populations in which
the expected incidence of postoperative mortality is higher. Both
randomized controlled trials and retrospective studies in the intensive
care unit have found significant associations between positive fluid
balance and mortality.26,27 However, the influence of intraoperative

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TABLE 2. Effect of Fluid Balance on Postoperative Outcomes

Fluid Balance in Quintiles
Quintile 2 Quintile 3 Quintile 4
Quintile 1 (n ¼ 18,419) (n ¼ 18,419) (n ¼ 18,419) Quintile 5 Total
(n ¼ 18,419) >6 to 3.6 >3.7 to 1.5 >1.5 to þ1.2 (n ¼ 18,418) Population
 6 mL/kg/hr mL/kg/hr mL/kg/hr mL/kg/hr >þ1.2 mL/kg/hr (N ¼ 92,094)
Primary Outcome
30-day Mortality N (%) 185 (1.0) 77 (0.4) 62 (0.3) 47 (0.3) 56 (0.3) 429 (0.5)
HR (95% CI), P 1.20 (0.90–1.61), 1 1.08 (0.77–1.52), 1.21 (0.82–1.77), 1.59 (1.08–2.34),
P ¼ 0.0.210 P ¼ 0.663 P ¼ 0.335 P ¼ 0.018
Secondary Outcomes
Postoperative N (%) 1017 (5.5) 875 (4.8) 787 (4.3) 617 (3.4) 361 (2.0) 3657 (4.0)
Respiratory OR (95% CI), P 0.98 (0.87–1.09), 1 1.09 (0.97–1.22), 1.17 (1.03–1.32), 1.26 (1.08–1.46),
Complication P ¼ 0.669 P ¼ 0.138 P ¼ 0.014 P ¼ 0.003
Acute Kidney Injury N (%) 674 (3.7) 538 (2.9) 529 (2.9) 522 (2.8) 406 (2.2) 2669 (2.9)
OR (95% CI), P 1.41 (1.21–1.64), 1.13 (0.98–1.30), 0.98 (0.85–1.12), 1 1.48 (1.27–1.71),
P < 0.001 P ¼ 0.105 P ¼ 0.718 P < 0.001
Exploratory Outcomes
Postoperative Mean (SD) 5.6 (6.1) 4.6 (4.8) 4.2 (4.6) 3.5 (4.3) 2.6 (4.0) 4.1 (4.9)
Length of IRR (95% CI), P 0.99 (0.98–1.01), 1 1.01 (0.99–1.03), 1.05 (1.03–1.07), 1.16 (1.13–1.19),
Stay, days P ¼ 0.615 P ¼ 0.345 P < 0.001 P < 0.001
Total Hospital NIS Matched $17,705.38 $16,872.74 $17,028.44 $17,539.62 $17,403.76
Mean (SD) ($13,646.70) ($13,004.93) ($13,124.94) ($13,518.94) ($13,414.22)
Care Costs, IRR (95% CI), P 1.05 (1.03–1.07), 1 1.01 (1.00–1.02), 1.04 (1.03–1.05), 1.03 (1.01–1.05),
dollars P < 0.001 P ¼ 0.165 P < 0.001 P < 0.001
Results of multivariable Cox, logistic regression, and negative binomial regression modeling are presented as adjusted HR, OR or IRR, 95% CI, and P.
CI indicates confidence intervals; HR, hazard ratio; IRR, incidence rate ratios; NIS, national inpatient sample; OR, odds ratio.

fluid management on survival in noncritically ill patients may
be distinct.
The large size of our cohort uniquely enabled us to study this
endpoint in relatively healthier populations and to examine the role of
fluid administered intraoperatively, before the onset of inflammation
and organ dysfunction characteristic of critical illness. Our study is
unique in that it quantifies the impact of incremental variations in
fluid administration on patient outcomes across this spectrum,
includes a range of surgeries, and examines associations with
mortality and on complications known to predict mortality. We
found the risk of 30-day mortality to be increased with both
restrictive and liberal intraoperative fluid strategies. Moderate fluid
restriction, representing the second most restrictive quintile of
practice, was associated with the highest rate of survival.
Respiratory Complications
The harmful effects of fluid excess are frequently manifested
in the lungs. Pulmonary edema can impair gas exchange, placing
patients at heightened risk for infection, respiratory failure, and
reintubation. PRCs are the most common non-surgical compli-
cation24,28,29 and are known to increase PLOS, mortality, and the
financial costs associated with an episode of care.29,30
Small randomized trials of various fluid dosing strategies and
respiratory outcomes have reached differing conclusions, even when
performed by the same group.31,32 It is difficult to determine whether
this heterogeneity is the result of sampling error, differences in
population, study design, or outcome definition. A meta-analysis
of several trials suggested that larger fluid volumes increase the risks
of postoperative pneumonia and pulmonary edema.33 However, these
findings are limited by marked differences in the definitions of
‘‘liberal’’ and ‘‘restrictive,’’ which make the results of individual
studies difficult to harmonize.7 A subsequent study examining fluid
dosing as a continuous variable in patients undergoing lung resection
described an inflection point in the risk for complications at 6 mL/kg/
hr,34 however this population is known to be susceptible to the
pulmonary consequences of fluid overload, which calls into question
the generalizability of the reported trend.
Our findings support the view that liberal fluid volumes have
harmful effects on postoperative lung function and add to the current
understanding in several ways. First, we confirm that the association
between liberal fluid administration and PRCs is a generalizable
phenomenon conserved across a wide range of surgical types and
patient classes. Second, we quantify the magnitude of fluid-attribu-
table risk for PRCs on a population level. Third, the size of the study
allowed us to examine incremental differences in fluid dosing and
demonstrate that risk for PRCs continuously increases with fluid
dosing with no clear threshold effect.
Acute Kidney Injury
The understanding that excessive intraoperative fluid admin-
istration may impair respiratory and gastrointestinal function35 has
already exerted an influence on clinical norms, driving more restric-
tive strategies. However, the safe lower limit of fluid restriction
remains unclear. Renal function is often considered uniquely
susceptible to hypovolemic states and postoperative AKI has been
implicated as a driver of morbidity and mortality in surgical popu-
lations.36,37 Evidence-based methods of estimating renal perfusion
are lacking: urine output is a poor indicator of volume status during
surgery38 and is not predictive of postoperative AKI.17,38 A recent
observational study of resuscitation practices in burn patients found
an increase in the incidence of AKI in the most restrictive forms of
practice.2 However, the generalizability of these findings to more
general surgical populations is limited and thus, despite the clinical
importance of AKI as an outcome, the relationship between intra-
operative fluid management and postoperative kidney function is not
well defined.
We found both restrictive and liberal extremes of intraoper-
ative fluid administration to be deleterious to kidney function. This
finding contradicts the dogma that intravascular volume expansion is
uniformly renal-protective, but has strong biologic plausibility. On

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ANNSURG-D-16-02308
Annals of Surgery  Volume XX, Number XX, Month 2017
FIGURE 4. Provider-level practice variation in intraoperative
fluid dosing. Fluid administration practices ranged widely
across practitioners within our cohort. Each anesthesia provider
identified in 50 or more cases in the dataset is represented as a
single point on the horizontal axis. The vertical axis represents
the individual probability of that provider administering a fluid
dose within the moderate range (quintiles 2, 3, or 4) versus a
very liberal (quintile 5) or restrictive (quintile 1) range. A small
number of anesthesia providers consistently administer fluid
volumes within the range found to optimize outcomes in this
cohort (left). The majority deliver fluid volumes in the optimal
range in 50% to 65% cases (middle). A smaller group of
providers consistently dose fluids in a range that appears
excessively restrictive or liberal with regard to the outcomes
considered in this study (right). A similar distribution is
observed both with (black circles) and without (grey circles)
propensity-matched adjustment for patient- and case-specific
factors which may influence fluid requirements (including
fasting status, patient weight, age, blood loss, urine output,
surgical body site, procedure duration, and hypotension).
one hand, untreated hypovolemia and prerenal azotemia may prog-
ress to acute tubular necrosis and renal dysfunction.39 Conversely,
excess fluid may impair renal function by mechanisms similar to
those observed in the pulmonary and gastrointestinal systems:
increases in central venous pressure elevate renal subcapsular press-
ures, reduce renal blood flow and glomerular filtration, and promote
renal parenchymal edema1,40,41
Cost and Length of Stay
We sought to quantify the summative economic impact of
differing practices in fluid administration by examining associations
with PLOS and total cost of hospitalization. PLOS and cost were
significantly increased in patients receiving liberal volumes, pre-
sumably because of the need to treat complications arising from
hypervolemia and await the resolution of edema. A recent analysis of
colorectal and lower extremity joint replacement surgeries included
in the Premier Research Database suggested that, compared mod-
erate volumes, both high and low fluid volumes on the day of surgery
were associated with increased cost and length of stay.42 Our findings
are generally in agreement with these studies and economic studies
of GDFT43– 45 and Enhanced Recovery After Surgery (ERAS)
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Intraoperative Fluid Management
protocols,46 which show similar reductions in costs and length of
stay associated with changes in fluid management. Of note, our
results are derived from a cohort that predates the implementation of
ERAS protocols at our institution.
Provider Variability
We observed marked variability in the management of intra-
operative fluid administration across individual anesthesia providers.
Our data confirm the findings of another large study of fluid
administration practice12 suggesting that this variability is driven
more by individual preference than by patient and procedural
characteristics. Institution-specific protocols for fluid therapy should
be developed and rigorously implemented based on our data and
other data recently published in the Annals of Surgery.42,47,48
Strengths and Limitations
Our study derives its strength from the size and diversity of
surgical cohort analyzed, increasing the finding’s generalizability
and permitting the rigorous analysis of uncommon but important
postoperative complications. Distinct from most existing studies, we
implemented robust confounder control using data extracted directly
from perioperative records. This methodology and the PRC endpoint
have been utilized and validated by our research group.16,49,50
Limitations include the use of diagnostic and procedure codes which
may be user-dependent, the observational nature of the study design,
and the potential for residual confounding of the reported associ-
ations. To address these challenges, we conducted quality control
checks of codes through a randomized audit of medical records and
performed sensitivity analyses to assess the impact of several vari-
ables on the reported associations
The diverse nature of the cohort and the stability of the findings
across several subgroups support the generalizability of the findings.
However, the study population included only patients extubated at the
end of surgery and different approaches to fluid management may be
required in patients who are not extubated at the end of the case but
remain mechanically ventilated. Similarly, the predominance of elec-
tive outpatients and non-urgent surgical inpatients in this cohort limits
the applicability of the findings to emergency situations and the
comparatively small number of such cases the precluded meaningful
analysis of emergency cases as an independent subgroup. Fluid deficits
in emergency surgery may be greater and optimal fluid management in
such cases may require larger volumes for resuscitation. Finally,
because only a small fraction of patients received any colloid, we
were not adequately powered to independently reproduce the associ-
ation between various colloid products and outcomes (eg, HES on
mortality and renal failure rate).
Implications for Clinicians and Researchers
Differences in intraoperative fluid dosing within the range of
routine clinical practice are associated with significant differences in
postoperative outcomes. Mortality, cost, and PLOS are each opti-
mized with moderate fluid restriction. These differences appear to
arise from the distinct effects of fluid administration on various organ
systems. Liberal fluid administration is strongly predictive of pul-
monary complications. Fluid restriction increases the risk of AKI, but
extreme efforts to drive urine output with intravenous volume
expansion may paradoxically promote renal dysfunction via an
independent mechanism.
These trends persist across a range of subgroups, suggesting
that the optimum range for intraoperative fluid therapy may be
influenced more modestly by the preoperative medical comorbidities
and procedure-specific factors than is commonly believed. Recent
population-based studies in colorectal, gynecologic, arthroplastic,
and endovascular surgery have also demonstrated the adverse effects
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ANNSURG-D-16-02308
Shin et al
of both restrictive and liberal perioperative fluid administration on
postoperative outcomes42,47 and are in keeping with the results of a
large meta-analysis of fluid therapy protocols in abdominal pro-
cedures which highlighted the importance of a ‘‘balanced’’ approach
to fluid therapy.6 Taken together, these findings suggest that, in the
absence of compelling case-specific considerations or the use of
well-validated GDFT protocols, a moderately restrictive intraoper-
ative fluid administration strategy should be the default standard of
care. In our population, optimum dose consistently fell in the second
quintile of clinical practice. In absolute terms, this range was
characterized by an infusion rate of approximately 6–7 mL/kg/hr,
a fluid balance of 40% less than traditional textbook estimates
(Supplementary Equation 1, http://links.lww.com/SLA/B202), or
roughly 1 L for the average three-hour case in the absence of excess
blood loss or other extenuating circumstances.
Our findings have several practical implications for ongoing
work in the field. Based on the U-shaped distribution of risk observed
in this study, we suggest that quality improvement and enhanced
recovery efforts might achieve the greatest benefit by first working to
identify and understand extremes of practice among providers.
Because both restrictive and liberal fluid management appear to
yield suboptimal outcomes, future prospective trials should consider
including multiple comparison arms. Finally, the value of moderately
restrictive, outcome-oriented dosing strategies versus cardiac output-
driven GDFT protocols remains an important question. A recent
meta-analysis in major abdominal surgery has suggested that simpler
protocols for standardization of fluid management (as part of an
ERAS pathway) may be equivalent to GDFT strategies relying on
physiologic measures.48
In summary, we identified a U-shaped distribution of risk
associated with intravenous fluid dosing during surgery. Although
the intraoperative period comprises a relatively brief portion of the
surgical encounter, it represents a uniquely vulnerable physiologic
state and is paradoxically a period in which the surgical team may be
less directly involved in fluid management. As an easily modifiable
factor that significantly influences surgical outcomes, we submit that
intraoperative fluid management strategy should routinely be dis-
cussed preoperatively in consultation with the anesthesia team. For
most patients, a moderately restrictive approach to intraoperative
fluid management may yield improved postoperative outcomes.
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