ORIGINAL INVESTIGATION

Preoperative Hyponatremia and

Perioperative Complications
Alexander A. Leung, MD; Finlay A. McAlister, MD, MSc; Selwyn O. Rogers Jr, MD, MPH;
Valeria Pazo, MD; Adam Wright, PhD; David W. Bates, MD, MSc
Background: Although hyponatremia has been linked
to increased morbidity and mortality in a variety of medi-
cal conditions, its association with perioperative out-
comes remains uncertain.
Methods: To determine whether preoperative hypona-
tremia is a predictor of 30-day perioperative morbidity
and mortality, we conducted a cohort study using the
American College of Surgeons National Surgical Qual-
ity Improvement Program database to identify 964 263
adults undergoing major surgery frommore than200 hos-
pitals (fromJanuary 1, 2005, to December 31, 2010) and
observed them for 30-day perioperative outcomes. We
used multivariable logistic regression to estimate rela-
tive risks for death, major coronary events, wound in-
fections, and pneumonia occurring within 30 days of sur-
gery and quantile regression to estimate differences in
average length of hospital stay.
Results: A total of 75 423 patients with preoperative hy-
ponatremia (sodiumlevel 135 mEq/L[to convert to mil-
limoles per liter, multiply by 1.0]) were compared with
888840 patients withnormal baseline sodiumlevels (135-
144 mEq/L). Preoperative hyponatremia was associated
with a higher risk of 30-day mortality (5.2% vs 1.3%; ad-
justedodds ratio [aOR], 1.44; 95%CI, 1.38-1.50), andthis
finding was consistent in all the subgroups. This associa-
tion was particularly marked in patients undergoing non-
emergency surgery (aOR, 1.59; 95%CI, 1.50-1.69; P.001
for interaction) and American Society of Anesthesiolo-
gists class 1 and 2 patients (aOR, 1.93; 95% CI, 1.57-
2.36; P.001 for interaction). Furthermore, hyponatre-
mia was associatedwitha greater riskof perioperative major
coronary events (1.8%vs 0.7%; aOR, 1.21; 95%CI, 1.14-
1.29), wound infections (7.4%vs 4.6%; 1.24; 1.20-1.28),
and pneumonia (3.7%vs 1.5%; 1.17; 1.12-1.22) and pro-
longed median lengths of stay by approximately 1 day.
Conclusion: Preoperative hyponatremia is a prognostic
marker for perioperative 30-day morbidity and mortality.
Arch Intern Med. 2012;172(19):1474-1481.
Published online September 10, 2012.
doi:10.1001/archinternmed.2012.3992
H
YPONATREMIA IS COM-
mon, is potentiallyrevers-
ible, and has important
consequences in a variety
of clinical conditions.
1-3
Furthermore, the concept of asymptom-
atic hyponatremia has beenquestioned, as
eventhose withmildhyponatremia are rec-
ognized to be at increased risk for serious
adverse outcomes.
4-6
Among hospitalized
patients, the presence of hyponatremia has
been associated with increased mortal-
ity,
7-13
prolongedlengths of stay,
8,10,12,13
and
greater utilization costs.
12
However, most existing studies have fo-
cusedonpatients admittedto medical ser-
vices.
7
As such, the association between
preoperative hyponatremia andperiopera-
tive outcomes remains largely unex-
plored. Although the preoperative period
offers unique opportunities for physi-
cians to performrisk stratification,
14,15
an-
ticipate complications, improve periopera-
tive care,
16,17
and, insome cases, intervene
on modifiable risks,
18
the implications of
hyponatremia detected preoperatively are
unclear. Therefore, we designedthis study
to evaluate the prognostic implications of
preoperative hyponatremia on selected
perioperative outcomes across a broad
range of surgical conditions.
METHODS
This study was approved by the institutional
review board at Partners HealthCare.
STUDY DESIGN AND DATA SOURCE
We assembled a cohort through the American
College of Surgeons National Surgical Quality
Improvement Program (ACS NSQIP) Partici-
pant Use Data Files. The ACS NSQIP is a na-
tionally validated, outcome-based, risk-
See Invited Commentary
at end of article
Author Affil
General Med
Care (Drs Le
and Bates) a
Surgery, Cen
Public Healt
Brigham and
Boston, Mas
Division of G
Medicine, D
Medicine, U
Edmonton, A
McAlister).
Author Affiliations: Division of
General Medicine and Primary
Care (Drs Leung, Pazo, Wright,
and Bates) and Department of
Surgery, Center for Surgery and
Public Health (Dr Rogers),
Brigham and Womens Hospital,
Boston, Massachusetts; and
Division of General Internal
Medicine, Department of
Medicine, University of Alberta,
Edmonton, Alberta, Canada
(Dr McAlister).
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adjusted program developed to improve the quality of surgical
care for adults in the United States.
19
Presently, there are nearly
300 participating academic and community hospitals. This da-
tabase provides patient-level informationfor major surgical pro-
cedures, in the inpatient and outpatient setting, across different
surgical specialties. One of the strengths of this database is that
preoperative, intraoperative, andpostoperative data are prospec-
tively collected for each surgical case through trained nurse re-
viewers usingstandardizedmethods, definitions, andendpoints.
Data are monitored weekly to ensure appropriate case selection,
and data validation is performed through audits to ensure a rich
source of reliable clinical information.
19,20
For cases collectedbe-
tweenJanuary 1, 2005, andDecember 31, 2010, the ACS NSQIP
database excluded all the surgical procedures directly related to
acutetrauma, transplantationcases, surgical procedures for brain-
death organ donors, and concurrent cases. Furthermore, cases
of inguinal herniorrhaphies exceeding 3 in 8 days and breast
lumpectomies exceeding 3 in 8 days were excluded from each
participating site to ensure a diverse case mix of procedures.
20
PATIENT POPULATION
The study cohort consisted of adult patients (18 years old)
from all the participating sites undergoing any major surgery
between January 1, 2005, and December 31, 2010.
21
We ex-
cluded patients who had undergone any other major surgical
procedure in the previous 30 days and patients for whom we
could not verify the surgical history. We defined hyponatre-
mia as a sodium measurement less than 135 mEq/L (to con-
vert to millimoles per liter, multiply by 1.0), and we further
classified hyponatremia according to mild (130-134 mEq/L) and
moderate to severe (130 mEq/L) categories. To explore the
association between preoperative hyponatremia and periopera-
tive outcomes, we excluded patients who did not have a pre-
operative serum sodium level recorded and those with hyper-
natremia (sodiumlevel 145 mEq/L) fromthe primary analysis.
The preoperative laboratory value was defined as the most re-
cent sodium level measured within 90 days of surgery.
BASELINE CHARACTERISTICS
The following baseline data were retrieved for each patient: date
of birth, sex, surgical profile (eg, principal procedure, inpa-
tient vs outpatient status, emergency vs nonemergency sur-
gery, and surgical specialty), preoperative characteristics (eg,
height, weight, smoking history, alcohol consumption, func-
tional healthstatus, AmericanSociety of Anesthesiologists [ASA]
classification,
22
and history of comorbidities, such as diabetes
mellitus, pulmonary disease, hepatobiliary disease, cardiac dis-
ease, renal disease, and cerebrovascular disease), and preop-
erative laboratory data (eg, serum sodium and creatinine lev-
els). These data were collected according to strict definitions
from medical records, operating room logs, anesthesia rec-
ords, telephone interviews, and letters.
OUTCOMES
The primaryoutcome was 30-daymortality(definedas anydeath
occurring within 30 days of surgery regardless of cause, in or
out of the hospital, and included intraoperative and postopera-
tive deaths). Secondary outcomes, which were events occurring
within 30 days of surgery (in the intraoperative and postopera-
tiveperiods), includedmajor coronaryevent (acompositeof myo-
cardial infarctionandcardiacarrest), stroke, postoperativewound
infection (a composite of superficial incisional, deep incisional,
andorgan-space surgical site infections), pneumonia, andlength
of hospital stay. Detailed definitions are online.
20
STATISTICAL ANALYSES
Descriptive statistics were reported for baseline characteristics
between patients with normal sodiummeasurements and those
with hyponatremia. All study outcomes were dichotomized, ex-
cept lengthof stay, whichremained as a continuous variable. For
the discrete outcomes, crude comparisons were made using the

2
test, and odds ratios (ORs) were reported. We used multi-
variable logistic regression, accounting for all measured pa-
tient- and procedure-related factors, to calculate adjusted ORs
(aORs) with 95%CIs. The data were then fit according to a non-
parametric quantile regressionmodel, and adjusted estimates for
the median change in length of stay were determined according
to baseline sodium category. (In contrast to multiple linear re-
gression, where there is an assumption that residuals are nor-
mally distributed, this model assumptionis not requiredfor quan-
tile regression.) Data were mostly complete, but missing values
were handled in the analysis by dummy coding.
23
We subse-
quently conducted a secondary analysis for the primary out-
come according to the number of days fromthe preoperative so-
dium measurement to the time of operation. Furthermore,
sensitivity analyses for potential selection bias were performed
to account for the patients who were excluded from the initial
cohort assembly because they did not have a preoperative so-
dium measurement recorded. Finally, we performed stratified
analyses to screenfor effect modification. All the statistical analy-
ses were performed using a commercially available software pro-
gram (SAS, version 9.3; SAS Institute, Inc).
RESULTS
A total of 1 334 886 surgical cases were identified from
the ACS NSQIP database during the study. We ex-
cluded 137 575 patients because they were younger than
18 years, had undergone surgery inthe preceding 30 days,
or had preoperative hypernatremia. Of the remaining
1 197 311 patients, 233 048 did not have any docu-
mented preoperative sodiummeasurements and were, ac-
cordingly, excluded from the primary analysis. A final
cohort of 964 263 patients was assembled.
Preoperative hyponatremia was present in 75423 sur-
gical patients (7.8%), and most cases were mild inseverity
(Table 1). The greatest prevalence of preoperative hypo-
natremia was inthose undergoingcardiac surgery(11.8%)
andvascular surgery (11.2%), followedby general (7.5%),
orthopedic (7.1%), and other (6.1%) procedures. Patients
with hyponatremia were typically older, were more likely
to be male, had greater comorbidity, and were more likely
to be inpatients or those undergoing emergency surgery.
Nearlyall thepatientshadtheirpreoperativebloodworkper-
formedwithin1monthof surgery. Sodiummeasurements
wereperformedwithin1dayof surgeryin95.0%of all emer-
gency patients and in30.6%of all nonemergency patients.
For the binary endpoints, the outcome incidences were
rare (10%). Thus, the aORs approximate adjusted rela-
tive risks.
24
As such, we refer to relative ratios between
odds and risks interchangeably throughout the presen-
tation of the results.
MORTALITY
During the study, 15 630 deaths were observed within
30 days of surgery. The risk of death was related to the
magnitude of preoperative hyponatremia (Figure 1).
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Table 1. Baseline Characteristics of 964 263 Patients Who Underwent Major Surgery Categorized by Preoperative
Serum Sodium Levels
Baseline Characteristic
a
Normal Sodium
(135-144 mEq/L)
(n = 888 840)
Hyponatremia
Any
(135 mEq/L)
(n = 75 423)
Mild
(130-134 mEq/L)
(n = 66 877)
Moderate to Severe
(130 mEq/L)
(n = 8546)
Demographics
Age, y, %
40 17.0 11.5 12.2 5.7
40-59 37.2 31.4 31.6 29.2
60-79 36.8 41.9 41.3 46.5
80 9.0 15.3 14.9 18.7
Male sex, % 42.8 48.1 48.0 49.1
Race, %
White 60.0 60.5 60.3 61.7
Black 8.2 7.7 7.9 6.2
Asian 1.6 1.8 1.8 1.9
Other or unknown 30.3 30.1 30.1 30.3
Surgical Profile
Surgical subspecialty, %
General 71.8 68.1 68.3 66.2
Vascular 12.2 18.2 17.8 20.9
Orthopedic 5.9 5.4 5.4 5.5
Cardiac 0.7 1.2 1.2 1.2
Other 9.4 7.2 7.3 6.3
Work relative value unit, median (IQR)
b
15.67 (12.46) 16.22 (11.86) 16.18 (11.94) 17.27 (11.58)
Inpatient status, % 70.1 85.3 84.6 90.4
Nonemergency case, % 87.5 71.2 72.5 60.9
Emergency case, % 12.5 28.8 27.5 39.1
General anesthesia, % 92.5 93.1 93.2 92.7
Preoperative assessment, %
Do-not-resuscitate status 0.6 1.8 1.7 2.4
ASA class
None assigned 0.2 0.2 0.2 0.3
1-2 51.9 31.1 32.6 19.6
3 41.2 51.2 50.9 53.3
4-5 6.6 17.5 16.3 26.8
Functional health status, %
Independent 68.1 63.5 63.8 61.0
Partially dependent 2.0 5.1 4.9 7.0
Totally dependent 0.3 0.9 0.8 1.2
Unknown 29.6 30.6 30.5 30.8
BMI, median (IQR) 28.5 (9.5) 26.6 (8.7) 26.8 (8.9) 25.5 (7.9)
Loss of 10% of body weight in last
6 mo, %
2.2 5.2 5.0 6.3
Comorbidities, %
Current smoker within 1 y 20.0 26.4 25.8 30.5
Alcohol consumption 2 drinks per day
in the 2 wk before admission
2.5 5.7 5.2 9.5
Preoperative delirium/impaired
sensorium
0.6 2.3 2.0 4.6
Preoperative pneumonia 0.4 1.6 1.4 2.6
Preoperative sepsis 7.5 25.4 24.1 35.3
Diabetes mellitus 16.1 25.4 25.4 25.5
Severe COPD 5.0 9.4 9.0 12.7
Ascites within 30 d before surgery 0.8 3.6 3.2 6.3
Esophageal varices in previous 6 mo 0.1 0.4 0.3 0.8
Congestive heart failure within 30 d
before surgery
0.8 2.7 2.5 3.6
Coronary artery disease
c
7.0 10.3 10.2 11.2
Cerebrovascular disease
d
7.0 10.3 10.2 11.8
Hypertension requiring medication 49.8 62.8 61.9 69.5
Acute renal failure 0.4 1.9 1.6 4.0
Dialysis recipient
e
1.8 5.2 5.2 5.2
Creatinine, median (IQR), mg/dL 0.9 (0.4) 0.9 (0.5) 0.9 (0.5) 0.9 (0.6)
(continued)
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Compared with patients with normal preoperative
sodium levels (1.3% deaths), those with mild hypona-
tremia (4.6% deaths; aOR, 1.38; 95% CI, 1.32-1.45)
and moderate to severe hyponatremia (9.6% deaths;
aOR, 1.72; 95% CI, 1.58-1.88) exhibited higher mor-
tality rates, even after adjustment for baseline imbal-
ances in patient and procedural characteristics
(P .001 for pairwise comparison between mortality
risk in mild and moderate to severe categories)
(Table 2).
SECONDARY OUTCOMES
Compared with patients with normal sodium levels,
the presence of preoperative hyponatremia was like-
wise associated with a higher risk of major coronary
events (1.8% vs 0.7%; aOR, 1.21; 95% CI, 1.14-1.29),
wound infections (7.4% vs 4.6%; 1.24; 1.20-1.28), and
pneumonia (3.7% vs 1.5%; 1.17; 1.12-1.22). As with
all-cause mortality, patients with more severe levels of
hyponatremia exhibited higher event rates than those
with milder degrees of hyponatremia, even after
adjustment (Table 2). Only the rate of stroke was not
significantly higher in patients with hyponatremia
(0.5% vs 0.3%; P = .23), although this may be related
to inadequate power since this outcome was rare.
We subsequentl y exami ned l engths of stay
(Table 3). The unadjusted median lengths of stay were
2.0 to 4.0 days longer in patients with hyponatremia vs
those with normal sodium levels, varying according to
surgical specialty and year. After controlling for all the
covariates to account for differences in case mix, hypo-
natremia was typically associated with longer median
lengths of stay by approximately 1 day for most surgical
procedures during the study, and it was never associated
with decreased length of stay.
SECONDARY ANALYSES
Sodium levels are subject to change over time. There-
fore, we restricted the analysis to patients with recent (ie,
2 weeks before surgery), very recent (ie, 1 week be-
fore surgery), and same-day (ie, 1 day before surgery)
sodium measurements, and the overall risks remained
broadly similar. The odds of death within 30 days of sur-
gery was consistently higher in patients with hyponatre-
mia regardless of time of blood sample collection (aOR,
1.42; 95% CI, 1.36-1.49 for recent; 1.40, 1.34-1.46 for
very recent; and 1.35, 1.29-1.41 for same day).
SENSITIVITY ANALYSES
During initial cohort assembly, 233 048 patients were ex-
cluded because their sodium levels were not measured
Table 1. Baseline Characteristics of 964 263 Patients Who Underwent Major Surgery Categorized by Preoperative
Serum Sodium Levels (continued)
Baseline Characteristic
a
Normal Sodium
(135-144 mEq/L)
(n = 888 840)
Hyponatremia
Any
(135 mEq/L)
(n = 75 423)
Mild
(130-134 mEq/L)
(n = 66 877)
Moderate to Severe
(130 mEq/L)
(n = 8546)
Surgical Profile (continued)
Days from sodium measurement to time
of operation, %
1 37.3 64.8 63.4 75.4
7 64.6 82.3 81.6 87.9
14 80.7 90.1 89.7 92.9
28 92.0 95.3 95.1 96.8
42 95.7 97.4 97.3 98.4
Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared);
COPD, chronic obstructive pulmonary disease; IQR, interquartile range.
SI conversion factors: To convert creatinine to micromoles per liter, multiply by 88.4; sodium to millimoles per liter, multiply by 1.0.
a
The BMI was not available for 3.4% of the normal sodium group and 5.0% of the hyponatremia group; baseline creatinine was not collected for 2.1% of the
normal sodium group and 1.4% of the hyponatremia group; and sex was not recorded for 0.3% of the normal sodium group and 0.3% of the hyponatremia group.
b
The work relative value unit is a measure of case complexity that accounts for physician time and effort.
c
Coronary artery disease is defined as a history of myocardial infarction in the past 6 months, previous percutaneous coronary intervention/percutaneous
transluminal coronary angiography, or a history of angina within 30 days before surgery.
d
Cerebrovascular disease is defined as history of transient ischemic attack or cerebrovascular accident.
e
Any patient with acute or chronic renal failure requiring treatment with peritoneal dialysis, hemodialysis, hemofiltration, hemodiafiltration, or ultrafiltration
within 2 weeks before surgery.
20
10
0
120 125 130 135 140 145
Preoperative Sodium, mEq/L
R
i
s
k

o
f

D
e
a
t
h

(
N
o
.

o
f

D
e
a
t
h
s
/
N
o
.

a
t

R
i
s
k
)
,

%
Figure 1. Crude risk of 30-day postoperative mortality according to
preoperative sodium level. To convert sodium to millimoles per liter,
multiply by 1.0.
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preoperatively (eTable 1 and eTable 2; http://www
.archinternmed.com). Thus, we performed sensitivity
analyses with a total cohort of 1 197 311 individuals, as-
suming that the initially excluded patients all had nor-
mal sodiumlevels, and the odds of death was still higher
in patients with hyponatremia (aOR, 1.43; 95%CI, 1.37-
1.50). We again repeated the analyses with the assump-
tion that all these patients had hyponatremia at base-
line. The risk of death in patients with hyponatremia
remained elevated (aOR, 1.39; 95%CI, 1.33-1.45). These
2 estimates reflect the range of possible outcomes given
the 2 extremes of selection bias.
SUBGROUP ANALYSES
Finally, we conducted subgroup analyses for the primary
outcome (Figure 2). None of the baseline patient char-
acteristics or procedural factors changed the overall asso-
ciation between preoperative hyponatremia and the in-
creased risk of 30-day mortality. As was consistent with
the main study estimates, there was an increased risk of
death in all the subgroups. The association was particu-
larly marked in patients undergoing nonemergency sur-
gery (P .001 for interaction) and in patients classified
as ASA class 1 or 2 (P .001 for interaction) (for defini-
tions of the ASA classification, see eTable 3).
COMMENT
In this observational study of nearly 1 million patients
undergoing major surgery, we found that preoperative
hyponatremia was present in approximately 1 in 13
patients, and this group had a 44% increased risk of
30-day perioperative mortality, even after adjustment
for all other potential risk factors. Furthermore, preop-
erative hyponatremia was common and was an inde-
pendent negative prognostic factor in patients undergo-
ing nonemergency surgery (with an incidence of 1 in 16
patients and an associated 59% increased risk of death)
and in those classified as ASA class 1 or 2 (with an inci-
dence of 1 in 21 patients and an associated 93%
increased risk of death). Moreover, the excess risk was
present even for patients with mild hyponatremia. Pre-
operative hyponatremia was also associated with an
increased risk of perioperative major coronary events,
surgical site wound infections, pneumonia, and pro-
longed hospital stays.
Previous studies
7-12
examining the prognosis related
to hyponatremia have mostly been in the inpatient set-
ting; these studies have focused on medical services or
have examined hospitalwide admissions to single cen-
ters. Hyponatremia has been documented to be a nega-
Table 2. Association of Selected 30-Day Postoperative Outcomes With Preoperative Hyponatremia
30-d Postoperative
Outcome
a
Normal Sodium
(135-144 mEq/L)
(n = 888 840)
Hyponatremia
P Value
b
Any
(135 mEq/L)
(n = 75 423)
Mild
(130-134 mEq/L)
(n = 66 877)
Moderate to Severe
(130 mEq/L)
(n = 8546)
All-cause mortality
No. (%) 11 742 (1.3) 3888 (5.2) 3064 (4.6) 824 (9.6) ND
OR
crude
1 [Reference] 4.06 (3.91-4.21) 3.59 (3.44-3.74) 7.97 (7.40-8.58) ND
OR
age and sex adjusted
1 [Reference] 3.31 (3.19-3.44) 2.96 (2.84-3.09) 5.92 (5.49-6.39) ND
OR
fully adjusted
1 [Reference] 1.44 (1.38-1.50) 1.38 (1.32-1.45) 1.72 (1.58-1.88) .001
Major coronary event
c
No. (%) 5883 (0.7) 1340 (1.8) 1110 (1.7) 230 (2.7) ND
OR
crude
1 [Reference] 2.72 (2.56-2.88) 2.53 (2.38-2.70) 4.15 (3.63-4.74) ND
OR
age and sex adjusted
1 [Reference] 2.24 (2.11-2.38) 2.12 (1.99-2.26) 3.11 (2.72-3.56) ND
OR
fully adjusted
1 [Reference] 1.21 (1.14-1.29) 1.20 (1.12-1.29) 1.28 (1.11-1.47) .001
Stroke
No. (%) 2354 (0.3) 398 (0.5) 346 (0.5) 52 (0.6) ND
OR
crude
1 [Reference] 2.00 (1.80-2.22) 1.96 (1.75-2.19) 2.31 (1.75-3.04) ND
OR
age and sex adjusted
1 [Reference] 1.65 (1.48-1.84) 1.64 (1.46-1.84) 1.71 (1.30-2.25) ND
OR
fully adjusted
1 [Reference] 1.07 (0.96-1.20) 1.10 (0.98-1.23) 0.91 (0.69-1.21) .23
Wound infection
d
No. (%) 41 109 (4.6) 5600 (7.4) 4927 (7.4) 673 (7.9) ND
OR
crude
1 [Reference] 1.65 (1.61-1.70) 1.64 (1.59-1.69) 1.76 (1.63-1.91) ND
OR
age and sex adjusted
1 [Reference] 1.63 (1.58-1.68) 1.62 (1.57-1.67) 1.71 (1.58-1.85) ND
OR
fully adjusted
1 [Reference] 1.24 (1.20-1.28) 1.25 (1.21-1.29) 1.14 (1.05-1.23) .001
Pneumonia
No. (%) 13 026 (1.5) 2778 (3.7) 2280 (3.4) 498 (5.8) ND
OR
crude
1 [Reference] 2.57 (2.47-2.68) 2.37 (2.27-2.48) 4.16 (3.79-4.56) ND
OR
age and sex adjusted
1 [Reference] 2.24 (2.14-2.33) 2.08 (1.99-2.18) 3.37 (3.07-3.69) ND
OR
fully adjusted
1 [Reference] 1.17 (1.12-1.22) 1.16 (1.10-1.22) 1.23 (1.11-1.36) .001
Abbreviations: ND, not determined; OR, odds ratio.
a
Effect estimates are reported as ORs (95% CIs).
b
The P values compare groups with normal sodium vs any hyponatremia.
c
Major coronary event is defined as a composite of myocardial infarction and cardiac arrest requiring cardiopulmonary resuscitation.
d
Wound infection is defined as a composite of superficial incisional surgical site infection, deep incisional surgical site infection, and organ-space surgical site
infection.
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tive prognostic factor in congestive heart failure,
25
liver
disease,
26-28
chronic kidney disease,
29,30
pneumonia,
13
and
hospitalized
10,11
populations. Until now, however, there
has been little evidence to link preoperative hyponatre-
mia with adverse perioperative outcomes, as previous
research has been limited to exploratory subgroup analy-
ses. In a previous single-center study,
10
community-
acquired hyponatremia was associated with a higher risk
of in-hospital mortality in a subgroup of 6393 patients
admitted to surgical services (aOR, 2.21; 95% CI, 1.49-
3.29). Similarly, a more recent study
11
reported that in-
hospital mortality was increased with hyponatremia in
a subgroup of 11 079 patients admitted for orthopedic
procedures (aOR, 2.31; 95%CI, 1.25-4.27), but it did not
differentiate between preoperative and postoperative hy-
ponatremia. The magnitude of risk that we report is
smaller compared with that of previous work (although
the present crude estimates were larger) likely because
(1) we adjusted for confounders that were not mea-
sured in previous studies (such as functional status and
procedural factors), (2) we restricted the exposure to pre-
operative laboratory work, and (3) we examined 30-day
outcomes rather than index hospitalization events only.
In favor of this reasoning, Greenblatt and colleagues
31
ob-
served that preoperative hyponatremia was indepen-
dently associated with surgical site infection, control-
ling for patient demographic characteristics, preoperative
comorbidities, and operative variables; their reported risk
(aOR, 1.20; 95% CI, 1.02-1.42) was nearly identical to
that of the present study (aOR, 1.24; 95% CI, 1.20-
1.28). Altogether, the present study is consistent withpre-
vious work and provides a more refined estimate of the
true risk of perioperative complications associated with
preoperative hyponatremia.
Controversy exists over whether hyponatremia is a
marker or a mediator of mortality and other adverse
events.
30,32
Physiologically, hyponatremia results fromdis-
turbances in water balance, which is normally regulated
by the actions of antidiuretic hormone. Accordingly, some
possible causes of preoperative hyponatremia include vol-
ume depletion, pain and nausea, and predisposing medi-
cal conditions (eg, congestive heart failure), which are
all marked by higher levels of circulating antidiuretic
hormone.
1-3
Addressing this, Waikar and colleagues
30
re-
cently demonstrated that the association between hypo-
natremia and mortality was independent of any antidi-
uretic hormonemediated mechanism. However, it
remains to be proved whether hyponatremia itself is a
causal determinant of adverse events or whether it solely
indicates the presence of other serious underlying con-
ditions (overt or subclinical) that, in turn, mediate mor-
bidity and mortality. Although it is clear that sodiumcon-
centrations are critical to various cellular functions in the
body,
1,30
there is still no known pathogenic mechanism
to explain howhyponatremia could directly cause the ob-
served increased risk of perioperative morbidity and mor-
tality. Given the present state of information, hypona-
tremia should be considered as a sensitive surrogate
marker for comorbidity and disease severity.
Althoughthis studyprovides evidencethat preoperative
hyponatremia is associated with perioperative morbidity
andmortality, furtherresearchisneededtoestablishwhether
correcting preoperative hyponatremia will mitigate risks.
Legitimate concernshouldbe raisedabout the safetyof in-
Table 3. Impact of Preoperative Sodium Levels on Average Length of Stay According to Surgical Year
a
Surgical Year
and Type
b
No. of Cases
c
Length of Stay,
Median (25th-75th percentile), d
Increase in Lengths of Stay,
Median, d
Normal Sodium Any Hyponatremia Crude Adjusted (95% CI)
2010
All 282 990 2.0 (1.0-5.0) 4.0 (2.0-10.0) 2.0 0.61 (0.57-0.66)
General 183 960 2.0 (0-5.0) 5.0 (1.0-10.0) 3.0 0.59 (0.54-0.65)
Vascular 32 050 3.0 (1.0-7.0) 6.0 (2.0-11.0) 3.0 0.78 (0.66-0.89)
2009
All 259 478 2.0 (1.0-5.0) 5.0 (2.0-10.0) 3.0 0.73 (0.69-0.77)
General 180 381 2.0 (0-5.0) 5.0 (2.0-11.0) 3.0 0.70 (0.63-0.77)
Vascular 31 705 3.0 (1.0-7.0) 6.0 (2.0-12.0) 3.0 0.92 (0.83-1.01)
2008
All 207 017 2.0 (1.0-5.0) 5.0 (2.0-11.0) 3.0 0.71 (0.65-0.77)
General 151 019 2.0 (1.0-5.0) 5.0 (2.0-11.0) 3.0 0.72 (0.63-0.80)
Vascular 28 310 3.0 (1.0-7.0) 6.0 (2.0-12.0) 3.0 1.25 (1.03-1.46)
2007
All 158 972 2.0 (1.0-5.0) 5.0 (2.0-11.0) 3.0 0.75 (0.70-0.80)
General 126 870 2.0 (1.0-5.0) 5.0 (2.0-11.0) 3.0 0.78 (0.71-0.84)
Vascular 22 624 3.0 (1.0-7.0) 6.0 (2.0-13.0) 3.0 0.79 (0.57-1.01)
2005 and 2006
All 55 291 2.0 (1.0-6.0) 5.0 (2.0-11.0) 3.0 0.58 (0.47-0.69)
General 46 519 2.0 (1.0-5.0) 5.0 (2.0-11.0) 3.0 0.52 (0.40-0.65)
Vascular 7087 3.0 (1.0-7.0) 7.0 (3.0-14.0) 4.0 1.18 (0.78-1.59)
a
For all, P .001 comparing adjusted median lengths of stay between groups with normal sodium vs any hyponatremia.
b
Orthopedic, cardiac, and other surgical procedures were intentionally omitted as individual categories because these cases were not required to be reported
from every hospital during the study; however, these cases are included in the analysis of all surgical procedures.
c
The total number of cases in this cohort is different from that in the primary analysis because 0.05% of cases were missing length of hospital stay information
and were, therefore, excluded from this analysis.
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tervention as overly rapid or large changes to sodiumlev-
els over a short time can be potentially disastrous.
33
Con-
versely, if monitored correction of hyponatremia is found
to be safe and beneficial, it would strengthen causal infer-
ence andwouldbe transformative toroutine care since se-
rumsodiumis not presentlyrecognizedas anindependent
andreversibleriskfactor for perioperativecomplications.
18
These findings must be interpreted in the context of
the study design. As with all nonexperimental designs,
this study is subject to potential confounding. Although
information on many clinically relevant variables was col-
lected and we performed careful statistical adjustments
in the analyses to account for differences between ex-
posure groups, unmeasured confounders may still be
present. Second, we reported 30-day perioperative out-
comes because these were routinely reported, checked,
and validated by the ACS NSQIP. As such, complica-
tions that occurred after that period were not consid-
ered. However, more distant events are also less likely
to be direct sequelae of surgery itself or the preoperative
state. Third, althoughthe data we usedare richandmostly
complete, there are some inherent limitations to the data
set, some of which were deliberately introduced to safe-
guard the privacy of patients, such as removal of unique
patient identifiers. We also lacked medication data and,
therefore, could not determine how risk may vary ac-
cording to various drug exposures. Moreover, it was im-
possible to completely ensure that some individuals did
not contribute more than once to the analysis during the
study interval, although it would be improbable based
on the sampling methods used and the exclusion of pa-
tients with recent surgical histories.
20
Furthermore, the
results of the sensitivity analyses suggest that any selec-
tion bias resulting frommissing laboratory data was un-
likely to be significant. Finally, hyponatremia is a hetero-
geneous disorder with a variety of potential etiologies,
yet a limitation of this data set is that we did not classify
study participants according to serumosmolality or clini-
cal volume status. As such, although these findings may
not be specific to any particular subgroup, it can also be
Odds Ratio (95% CI) Subgroup
Surgical subspecialty
ASA class
Functional health status
Body mass index
Diagnoses
Events, No. Sample Size, No.
0.5 5.0 1.0
Decreased Risk Increased Risk
1.44 (1.38-1.50) Full cohort
Age, y
15 630 964 263
1.61 (1.22-2.13) <40 326 159 957
1.47 (1.33-1.63) 40-59 2508 354 090
1.48 (1.40-1.58) 60-79 7498 358 961
1.28 (1.18-1.38) 80 5298 91 255
1.41 (1.32-1.50) Female sex 7529 544 921
1.44 (1.36-1.53) Male sex 8056 416 868
1.45 (1.37-1.52) General 10 336 689 111
1.30 (1.19-1.42) Vascular 3817 121 850
1.56 (1.22-1.99) Orthopedic 454 56 877
1.88 (1.35-2.63) Cardiac 237 7490
1.69 (1.39-2.04) Other 786 88 935
1.44 (1.38-1.50) Inpatient status 15 303 687 333
1.52 (1.08-2.14) Outpatient status 327 276 930
1.25 (1.18-1.33) Emergency case 7284 132 625
1.59 (1.50-1.69) Nonemergency case 8346 831 638
1.93 (1.57-2.36) 1-2 772 484 963
1.58 (1.49-1.69) 3 6383 404 965
1.25 (1.18-1.32) 4-5 8444 72 196
1.48 (1.39-1.57) Independent 8459 653 536
1.28 (1.14-1.43) Partially dependent 2217 21 242
1.44 (1.13-1.85) Dependent 526 3652
1.43 (1.34-1.52) Low (<25) 6488 267 221
1.49 (1.40-1.58) High (25) 7721 662 789
1.31 (1.21-1.42) Diabetes mellitus 4155 161 853
1.40 (1.27-1.55) Severe COPD 3038 51 750
1.26 (1.11-1.44) Ascites 1615 9871
1.76 (1.08-2.86) Esophageal varices 130 1249
1.33 (1.15-1.53) Congestive heart failure 1429 9421
1.38 (1.25-1.54) Coronary artery disease 2769 70 048
1.36 (1.29-1.43) Hypertension on medications 11 295 489 683
1.16 (1.02-1.32) Dialysis dependent 1601 19 457
Figure 2. Association of 30-day postoperative mortality with hyponatremia in the full cohort and subgroups. Body mass index is calculated as weight in kilograms
divided by height in meters squared. ASA indicates American Society of Anesthesiologists; COPD, chronic obstructive pulmonary disease.
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said that the broad inclusion of all types of hyponatre-
mia potentially enhances the generalizability of the study.
In conclusion, we found that preoperative hypona-
tremia (even to a mild degree) is common and predicts
postoperative morbidity and mortality, even in rela-
tively healthy patients (ie, classified as ASA class 1 or 2)
and those undergoing nonemergency surgery. These find-
ings give rise to several key implications. First, these re-
sults illustrate that even mild perturbations of serumso-
diumare not inconsequential and should not be ignored.
Hyponatremia, when detected preoperatively, should be
considered a prognostic marker for perioperative com-
plications, and its presence should alert physicians to a
situation of increased risk necessitating closer surveil-
lance in the perioperative period. Second, whenever pos-
sible, the underlying cause of hyponatremia should be
determined. Although the effectiveness and safety of in-
tervening onpreoperative hyponatremia have not yet been
established, one reasonable approach is to monitor for
perioperative complications in all patients at risk and to
selectively treat hyponatremia before nonemergency sur-
gical procedures when a reversible cause is found. Ac-
cordingly, further studies on how to best address hypo-
natremia in the perioperative setting are needed.
Accepted for Publication: June 7, 2012.
Published Online: September 10, 2012. doi:10.1001
/archinternmed.2012.3992
Correspondence: David W. Bates, MD, MSc, Division of
General Internal Medicine andPrimary Care, Brighamand
Womens Hospital, BrighamCircle, 1620Tremont St, Third
Floor, Boston, MA 02120 (dbates@partners.org).
Author Contributions: Study concept and design: Leung,
McAlister, Wright, and Bates. Acquisition of data: Rog-
ers. Analysis and interpretation of data: Leung, McAlister,
Rogers, Pazo, Wright, and Bates. Drafting of the manu-
script: Leung. Critical revision of the manuscript for im-
portant intellectual content: Leung, McAlister, Rogers, Pazo,
Wright, and Bates. Statistical analysis: Leung. Obtained
funding: Bates. Administrative, technical, and material sup-
port: Rogers andBates. Study supervision: Rogers andBates.
Financial Disclosure: None reported.
Funding/Support: Dr Leung is supported by a Clinical
Fellowship Award fromAlberta InnovatesHealth Solu-
tions and by a Fellowship Award from the Canadian In-
stitutes for Health Research. Dr McAlister is supported
by a career salary award from Alberta InnovatesHealth
Solutions as a senior health scholar.
Disclaimer: The American College of Surgeons Na-
tional Surgical Quality Improvement Programandthe hos-
pitals participating in the ACS NSQIP are the source of
the data used herein; they have not verified and are not
responsible for the statistical validity of the data analy-
sis or the conclusions derived by the authors.
Online-Only Material: The eTables are available at http:
//www.archinternmed.com.
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