J Neurosurg 119:1478–1483, 2013
©AANS, 2013
Factors predicting postoperative hyponatremia and efficacy
of hyponatremia management strategies after more than 1000
pituitary operations
Clinical article
Arman Jahangiri, B.S., Jeffrey Wagner, B.S., Mai T. Tran, B.S., Liane M. Miller, B.S.,
Maxwell W. Tom, B.S., Sandeep Kunwar, M.D., Lewis Blevins Jr., M.D.,
and Manish K. Aghi, M.D., Ph.D.
Department of Neurosurgery and California Center for Pituitary Disorders, University of California, San
Francisco, California
Object. Syndrome of inappropriate antidiuretic hormone secretion–induced hyponatremia is a common morbidity after pituitary surgery that can be profoundly symptomatic and cause costly readmissions. The authors calculated
the frequency of postoperative hyponatremia after 1045 consecutive operations and determined the efficacy of interventions correcting hyponatremia.
Methods. The authors performed a retrospective review of 1045 consecutive pituitary surgeries in the first 946
patients treated since forming a dedicated pituitary center 5 years ago. Patients underwent preoperative and daily
inpatient sodium checks, with outpatient checks as needed.
Results. Thirty-two patients presented with hyponatremia; 41% of these patients were symptomatic. Postoperative hyponatremia occurred after 165 operations (16%) a mean of 4 days after surgery (range 0–28 days); 19% of
operations leading to postoperative hyponatremia were associated with postoperative symptoms (38% involved dizziness and 29% involved nausea/vomiting) and 15% involved readmission for a mean of 5 days (range 1–20 days). In a
multivariate analysis including lesion size, age, sex, number of prior pituitary surgeries, surgical approach, pathology,
lesion location, and preoperative hypopituitarism, only preoperative hypopituitarism predicted postoperative hyponatremia (p = 0.006). Of patients with preoperative hyponatremia, 59% underwent medical correction preoperatively
and 56% had persistent postoperative hyponatremia. The mean correction rates were 0.4 mEq/L/hr (no treatment; n =
112), 0.5 mEq/L/hr (free water restriction; n = 24), 0.7 mEq/L/hr (salt tablets; n = 14), 0.3 mEq/L/hr (3% saline; n =
20), 0.7 mEq/L/hr (intravenous vasopressin receptor antagonist Vaprisol; n = 22), and 1.2 mEq/L/hr (oral vasopressin receptor antagonist tolvaptan; n = 9) (p = 0.002, ANOVA). While some patients received more than 1 treatment,
correction rates were only recorded when a treatment was given alone.
Conclusions. After 1045 pituitary operations, postoperative hyponatremia was associated exclusively with preoperative hypopituitarism and was most efficiently managed with oral tolvaptan, with several interventions insignif
icantly different from no treatment. Promptly identifying hyponatremia in high-risk patients and management with
agents like tolvaptan can improve safety and decrease readmission. For readmitted patients with severely symptomatic hyponatremia, the intravenous vasopressin receptor antagonist Vaprisol is another treatment option.
(http://thejns.org/doi/abs/10.3171/2013.7.JNS13273)
P
Key Words
•
transsphenoidal
hyponatremia
•
tolvaptan
ituitary surgery is often accompanied by disturbances of osmoregulation, which may result from
manipulation or vascular alterations of the neurohypophysis. These disturbances can manifest as postoperative hypernatremia or hyponatremia. Postoperative hypernatremia is typically caused by diabetes insipidus due to
deficient antidiuretic hormone (ADH) secretion. Hyponatremia after pituitary surgery is typically due to syndrome
of inappropriate antidiuretic hormone secretion (SIADH)
and is typically associated with a euvolemic state. There
Abbreviations used in this paper: ADH = antidiuretic hormone;
SIADH = syndrome of inappropriate ADH secretion.
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•
pituitary surgery
•
postoperative
•
are, however, rare cases of cerebral salt wasting and the associated contraction of extracellular volume that have been
reported after pituitary surgery.2 Hyponatremia after pituitary surgery can be profoundly symptomatic with symptoms including headache, dizziness, nausea, and vomiting,
which can lead to costly readmissions after otherwise successful elective pituitary surgeries.3,4,11
Previous studies have suggested tumor size or patient
age as risk factors for postoperative hyponatremia after
pituitary surgery,11 but these studies have been based on
small sample sizes of 88–150 patients and did not adequately represent the range of typical pathologies operated on during pituitary surgery. Furthermore, prior studies
did not focus on the contribution of other factors such as
J Neurosurg / Volume 119 / December 2013
Postoperative hyponatremia after pituitary surgery
preoperative pituitary function or whether a patient had
undergone prior pituitary surgeries. Studies to date have
also not reported the efficacy of commonly used interventions, with treatments such as 3% saline and salt tablets
continuing to be used despite little evidence for their efficacy. To fully calculate the frequency of postoperative
hyponatremia and the efficacy of various interventions in
correcting hyponatremia in a comprehensive series of pituitary patients representative of the wide spectrum seen
in practice, we retrospectively analyzed postoperative hy
ponatremia after 1045 consecutive operations done in the
past 5 years since the establishment of our dedicated pituitary center of excellence.
Methods
Case Collection
This study was approved by our institutional Committee on Human Research. We retrospectively reviewed
1045 consecutive pituitary surgeries in the first 946 patients treated in the 5 years since the establishment of
the California Center for Pituitary Disorders, a dedicated
multidisciplinary center of pituitary expertise. Per institutional protocol, patients underwent preoperative and daily
sodium checks while hospitalized after surgery, which for
the patients in this series lasted for a mean period of 3
days (median 2 days), with outpatient checks performed
in patients with mild hyponatremia or high urine output
at the time of discharge or in patients who contacted the
center reporting symptoms that could be consistent with
SIADH or diabetes insipidus. Hyponatremic patients readmitted to the hospital for corrective measures underwent sodium checks every 6 hours as inpatients until
symptoms of hyponatremia resolved or near normalization of serum sodium occurred (133 mEq/L or higher),
while hyponatremic outpatients, who were asymptomatic, underwent twice weekly sodium checks until near
normalization of serum sodium. Parameters recorded for
each case included lesion size, age, sex, number of prior
pituitary surgeries, surgical approach (endoscopic endonasal, microscopic endonasal, or craniotomy), lesion type
(endocrine-inactive adenoma, endocrine-active adenoma,
Rathke cleft cyst, apoplexy, craniopharyngioma, or other),
lesion location (sellar, suprasellar, or sellar with suprasellar extension), and the presence of preoperative hypopituitarism. Preoperative hypopituitarism was defined by low
levels of an anterior pituitary lobe laboratory value on
the blood work checked closest to the time of surgery or
preoperative diabetes insipidus and was noted in 210 patients. Because our center does not routinely correct preoperative hormone deficits until after surgery, only 8% (n
= 16) of patients were started on hormone replacement for
all hormone deficits noted on their last set of preoperative
pituitary laboratory values.
Postoperative Variables Recorded
Postoperative hyponatremia was defined as a serum
sodium below normal (< 135 mEq/L) occurring within
30 days of surgery. The efficacies of treatment measures
were documented by recording the rate of correction in
J Neurosurg / Volume 119 / December 2013
cases in which the treatment was used as the sole treatment for hyponatremia. This rate of correction was calculated by taking the units that the sodium increased
during correction and dividing it by the number of hours
that the correction was implemented, which in the case
of medications such as tolvaptan and Vaprisol included
the half-life of the medication added on to the time of the
last dose.
Statistical Analysis
Binary logistic regression was used to determine the
correlation between these parameters and postoperative
hyponatremia, defined as serum sodium levels lower than
135 mEq/L. Analysis of variance was used for parametric comparisons of more than 2 variables when the dependent variable was continuous while a chi-square test
was used to compare more than 2 proportions. Parametric
comparison between 2 variables was performed using the
Student t-test. The Fisher exact test was used to compare
2 proportions. The p values are 2-tailed and p < 0.05 was
considered statistically significant.
Results
Patient Preoperative Characteristics
The mean age of patients before the 1045 operations
was 46 years (range 4–93 years). There were 576 female
patients (55%). The mean lesion size was 2.0 cm (range 3
mm to 6.7 cm).
Preoperative Hyponatremia
Thirty-two patients (3%) presented with preoperative hyponatremia, 41% of whom were symptomatic. A
multivariate analysis including patient age, patient sex,
lesion size, lesion location (sellar, sellar with suprasellar
extension, or suprasellar), preoperative hypopituitarism,
operation number, and pathology revealed none of these
7 variables to be predictive of preoperative hyponatremia
(Table 1). Of 32 patients with preoperative hyponatremia,
only one had preoperative diabetes insipidus managed
with desmopressin prior to surgery, while another had
nephrogenic diabetes insipidus due to the use of lithium.
Nineteen (59%) of 32 patients with preoperative hyponatremia underwent medical correction preoperatively and
18 (56%) had postoperative hyponatremia.
Postoperative Hyponatremia
Pathologies included 340 endocrine-active adenomas, 381 endocrine-inactive adenomas, 124 Rathke cleft
cysts, 50 craniopharyngiomas, and 150 miscellaneous pa
thologies. Postoperative hyponatremia occurred after 165
of the 1013 operations performed in patients without preoperative hyponatremia (16%) a mean of 4 days after surgery (range 0–28 days), with the largest peak of incidence
occurring on postoperative Day 2, followed by a smaller
delayed peak on postoperative Day 7 (Fig. 1).
Thirty-one of the 165 operations leading to postoperative hyponatremia (19%) were associated with postoperative symptoms attributable to hyponatremia a mean of 6
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A. Jahangiri et al.
TABLE 1: Results of multivariate analysis of variables predicting
the presence of preoperative hyponatremia*
Variable
HR
p Value
age
male sex
lesion size (mean diameter)
suprasellar extension
preop hypopituitarism
op no.
pathological diagnosis
1.1 per decade
0.6
1.1 per cm
1.5
4.2
1.0
1.1
0.1
0.4
0.8
0.4
0.4
0.9
0.5
* HR = hazard ratio.
days after surgery (range 1–29 days; Fig. 1B). Twenty-four
of the 165 operations leading to postoperative hyponatremia (15%) involved readmission due to hyponatremia for
a mean of 5 days (range 1–20 days). Of the 31 cases of
symptomatic postoperative hyponatremia, 38% involved
dizziness and 29% involved nausea or vomiting. The risk
of permanent diabetes insipidus was comparable in patients with or without postoperative hyponatremia (1.6%
vs 0.9%; p = 0.2).
Risk Factors for Postoperative Hyponatremia
In a multivariate analysis including patient age, patient sex, lesion size, lesion location (sellar, sellar with
suprasellar extension, or suprasellar), preoperative hypopituitarism, operation number, surgical approach, and
pathological diagnosis, only preoperative hypopituitarism
predicted postoperative hyponatremia (p = 0.006) (Table
2). Patients with preoperative hypopituitarism had a 32%
(67 of 210) rate of postoperative hyponatremia compared
with a 24% (115 of 470) rate of postoperative hyponatremia in those without preoperative hypopituitarism (p <
0.05) (Fig. 2). We then looked at rates of postoperative
hyponatremia in patients with or without deficiencies in
each of the 5 individual endocrine axes (gonadal, thyroid,
adrenal, growth hormone, and prolactin). Of the 5 possi-
Fig. 1. Timing of postoperative hyponatremia after pituitary surgery. A: Postoperative hyponatremia most frequently occurred on postoperative Day 2, after which the incidence of postoperative hyponatremia decreased until a second smaller delayed peak occurring on postoperative Day 7. B: Symptomatic postoperative hyponatremia occurred most frequently on postoperative Day 1, after which the incidence remained relatively low until a second smaller delayed peak occurred on postoperative
Day 7. C: In this retrospective study, all inpatients received daily sodium checks, but outpatient sodium checks only occurred
as follow-up to document resolution of hyponatremia or to evaluate patients with symptoms suggestive of possible SIADH or
diabetes insipidus. Thus, the number of patients receiving sodium checks on each postoperative day declined over the course of
the first 29 postoperative days.
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Postoperative hyponatremia after pituitary surgery
TABLE 2: Results of multivariate analysis of variables predicting
the occurrence of postoperative hyponatremia
Variable
HR
p Value
age
male sex
lesion size (mean diameter)
suprasellar extension
preop hypopituitarism
op no.
surgical approach
pathological diagnosis
1.0 per decade
1.0
1.0 per cm
1.5
4.6
1.9
2.9
1.1
0.4
0.9
0.9
0.3
0.006
0.4
0.1
0.2
ble anterior pituitary hormone deficiencies, 3 elevated the
risk of postoperative hyponatremia (Fig. 2). First, patients
with preoperative central hypothyroidism had a 51% (42
of 83) rate of postoperative hyponatremia compared with
10% (33 of 322) in those without preoperative central hypothyroidism (p < 0.001) (Fig. 2). Second, patients with
preoperative central hypogonadism had a 37% (29 of 79)
rate of postoperative hyponatremia compared with 17%
(34 of 200) in those without central hypogonadism (p <
0.001) (Fig. 2). Third, patients with preoperative central
hypoadrenalism had a 38% (21 of 55) rate of postoper
ative hyponatremia compared with 10% (15 of 150) in
those without central hypoadrenalism (p < 0.001) (Fig. 2).
Correction of Hyponatremia
The mean correction rates in mEq/L/hour were 0.4
(no treatment, n = 112), 0.5 (free water restriction, n = 24),
0.7 (salt tablets, n = 14), 0.3 (3% saline, n = 20), 0.7 (intravenous vasopressin receptor antagonist Vaprisol, n = 22),
and 1.2 (oral vasopressin receptor antagonist tolvaptan, n
= 9) (p = 0.002 ANOVA; p < 0.05 for paired comparisons
of tolvaptan or Vaprisol vs no treatment; p > 0.05 for free
water restriction, salt tablets, or 3% saline vs no treatment) (Fig. 3). While some patients received more than
1 treatment, correction rates were only recorded when
a treatment was given alone. The mean time to sodium
normalization in all hyponatremic patients was 23 hours
(range 3 hours to 27 days). Hyponatremia in 1 patient receiving Vaprisol was overcorrected, with a resulting sodium of 150 mEq/L.
Discussion
After 1045 pituitary operations, postoperative hyponatremia was associated exclusively with preoperative hypopituitarism and was most efficiently managed with the
vasopressin receptor antagonists Vaprisol and tolvaptan,
with other interventions not significantly different from
no intervention. Preoperative hypopituitarism appears to
be a marker for lesions whose removal will require the
surgeon to dissect close to the posterior lobe of the gland
or pituitary stalk, potential risks factors for postoperative
SIADH. As such, patients with preoperative hypopituitarism may warrant closer follow-up for postoperative hyponatremia than patients with normal preoperative pituitary function.
Our finding that postoperative hyponatremia occurred
after 16% of pituitary surgeries is consistent with other recent series, which have reported 18%–23%6,15 incidences
of postoperative hyponatremia. An earlier study from our
institution reported a 2% incidence of postoperative hyponatremia in surgeries done between 1971 and 1993; the vast
majority of those cases were symptomatic.14 The more frequent identification of asymptomatic hyponatremia with
out change in incidence of symptomatic hyponatremia between that study and the current study likely results from
the implementation of standardized postoperative sodium
checks since the completion of that study, identifying more
asymptomatic cases of hyponatremia.
The timing of postoperative hyponatremia in our
study was comparable to that in other studies, which have
reported both an early incidence peak occurring around
postoperative Day 2,2 as well as a slightly more delayed
peak typically occurring between postoperative Days
7 and 9.3,8 While the fact that all patients underwent sodium checks in the hospital after surgery meant that the
first peak captured a number of asymptomatic patients, the
delayed peak only captured symptomatic patients since
Fig. 2. The frequency of postoperative hyponatremia in patients with various preoperative anterior pituitary deficits. Patients
with any anterior pituitary deficit (p < 0.05) or deficits in the gonadal (follicle-stimulating hormone, luteinizing hormone, estrogen,
progesterone, or testosterone), thyroid (thyroid-stimulating hormone, T3, or T4), or adrenal (adrenocorticotropic hormone or cortisol) axes had an increased risk of postoperative hyponatremia compared with those without. GH = growth hormone.
J Neurosurg / Volume 119 / December 2013
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A. Jahangiri et al.
Fig. 3. Rate of serum sodium correction (in mEq/L/hr) in patients as a function of individual treatments. Paired comparisons
revealed that only patients receiving tolvaptan or Vaprisol alone exhibited more rapid serum sodium correction than patients
receiving no treatment (p < 0.05). Bars denote the mean, and the whiskers denote the SD.
asymptomatic patients did not undergo outpatient serum
sodium checks; limiting the analysis to patients with symptomatic hyponatremia also revealed a large early peak and
a smaller delayed peak (Fig. 1B). The delayed peak has
been described in other studies as the predominant time
for postoperative hyponatremia, unlike in our study where
it was smaller than the postoperative Day 2 peak.8 The delayed peak has been reported to occur in patients who do
not excrete an administered water load and suppress plasma arginine vasopressin normally.8 In that same study, patients with postoperative hyponatremia occurring around
Day 7 were more natriuretic; had lowered dietary sodium
intake; and had similar fluid intake, cortisol, and atrial natriuretic peptide as normonatremic patients.8 The delayed
peak in postoperative hyponatremia occurring between
postoperative Days 7 and 9 could represent the antidiuretic
interphase seen in a triphasic progression of diabetes insipidus.5 Despite this possibility that postoperative hyponatremia occurring between postoperative Days 7 and 9
could be the second phase of a 3-phase process ultimately
leading to postoperative diabetes insipidus,5,8 we found the
rate of postoperative diabetes insipidus to be comparable in
patients with postoperative hyponatremia to those without.
In terms of risk factors for postoperative hyponatremia, our findings differ from other series that analyzed
smaller series of patients than ours and suggested that
factors such as age older than 60 years4 and lesion size11
contribute to postoperative hyponatremia after pituitary
surgery. Our multivariate analysis of more than 1000
operations revealed neither age nor lesion size to be risk
factors. A study that identified lesion size as a risk factor
for postoperative hyponatremia could reflect the fact that
larger lesions require manipulation of the pituitary stalk
for resection. However, the fact that neither lesion size nor
stratification of lesions as sellar, sellar with suprasellar
extension, or purely suprasellar proved predictive of postoperative hyponatremia in our large series argues against
this hypothesis. Another hypothesized risk factor would
be pathology, with lesions such as craniopharyngiomas
that typically occur closer to the pituitary stalk theoretically increasing the risk for postoperative hyponatremia.
However, our analysis failed to identify pathology as a
risk factor for postoperative hyponatremia. The one fac1482
tor we found to increase the risk of postoperative hyponatremia was preoperative hypopituitarism. Given that
lesion size, suprasellar location, and pathology failed to
predict postoperative hyponatremia, the correlation be
tween preoperative hypopituitarism and postoperative hyponatremia is unlikely to reflect lesion anatomy, but it is
possible that preoperative hypopituitarism could increase
the risk of postoperative hyponatremia after pituitary surgery through exacerbation of the underlying mechanisms
through which hypothyroidism13 or adrenal insufficiency10
increase the risk of hyponatremia.
Our findings also suggest that postoperative hyponatremia is often a transient self-correcting phenomenon,
but when medical intervention is indicated, measures designed to replete sodium or deplete water are no more
effective than no intervention and are far less effective
in terms of the rate of correction than medicines direct
ly targeting the downstream effects of the inappropriate
ADH secretion. These findings support SIADH rather
than cerebral salt wasting as the etiology of most cases of
postoperative hyponatremia after pituitary surgery.
Vasopressin receptor antagonists such as tolvaptan or
Vaprisol are a relatively new therapeutic class of agents
for the management of hyponatremia. Nephrologists
have long believed that vasopressin receptor antagonists
may be particularly effective at treating SIADH due to
CNS disorders, trauma, or neurosurgery since they are
the most physiological approach to the treatment of this
common electrolyte disturbance.7,9,12 While vasopressin
receptor antagonists are costly, with tolvaptan costing
$250 per day, recent analysis of the Study of Ascending
Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT-1
and SALT-2) trial showed that the reduction in admission
rates and durations associated with tolvaptan led to cost
reductions of nearly $700 per case in the US.1 Despite the
ability of tolvaptan to offset some of its cost by correcting hyponatremia more rapidly than other measures, mild
to moderate hyponatremia that is minimally symptomatic
should still be managed with measures that are less costly
and less aggressive, such as fluid restriction, with tolvaptan reserved for cases that are more severe in terms of the
magnitude of hyponatremia or symptoms.
There are a number of limitations of our study that
J Neurosurg / Volume 119 / December 2013
Postoperative hyponatremia after pituitary surgery
must be acknowledged. The percentage of patients with
hyponatremia after discharge that we report is not the true
prevalence since not every patient was tested on each of the
29 postoperative days for which we reported the percentage of patients with hyponatremia (Fig. 1C). While a previous publication reported the incidence of postoperative
hyponatremia using a standardized prospective protocol
in which 247 patients were screened for serum sodium on
postoperative Day 7,15 screening a sample size as large as
ours for 29 consecutive postoperative days would be cost
prohibitive. Thus, our early peak of hyponatremia shown
in Fig. 1A likely captured a number of asymptomatic
cases simply because all patients underwent daily sodium
checks while recovering from surgery. The fact that limiting the counts to cases of symptomatic hyponatremia still
revealed a larger early peak and a delayed later peak (Fig.
1B) would be consistent with the hypothesis of 2 distinct
peaks of slightly different magnitude, but even symptomatic cases may be more readily detected while a patient is
in the hospital recovering from surgery than when he or
she is at home and might not report symptoms to care providers. Furthermore, our findings of different rates of correction between different corrective measures could reflect
the fact that, while our frequency of sodium checks did
not vary depending on which corrective measure was being used, the frequency of sodium checks did vary between
inpatients and outpatients and some corrective measures
(3% saline and Vaprisol) could only be given to inpatients.
Conclusions
Despite these limitations, the information we report
on the 2 peaks of overall and symptomatic postoperative
hyponatremia and modern strategies for correcting this
phenomenon provides valuable insight for neurosurgeons
managing patients after transsphenoidal surgery. Our
findings suggest that prompt identification of hyponatremia in high-risk patients and management of significant
symptomatic cases with the oral vasopressin receptor
antagonist tolvaptan can improve patient safety and decrease the rates and duration of readmission to the hospital after otherwise successful elective pituitary surgery.
For readmitted patients with severely symptomatic hyponatremia, the intravenous vasopressin receptor antagonist
Vaprisol is another treatment option.
Disclosure
Arman Jahangiri is a Howard Hughes Medical Institute Re
search Fellow. The authors report no conflict of interest concerning
the materials or methods used in this study or the findings specified
in this paper.
Author contributions to the study and manuscript preparation
include the following. Conception and design: Aghi. Acquisition
of data: Aghi, Jahangiri, Wagner, Tran, Miller, Tom. Analysis and
interpretation of data: Aghi, Jahangiri, Wagner, Tran, Miller, Tom.
Drafting the article: Aghi. Critically revising the article: all authors.
Reviewed submitted version of manuscript: all authors. Approved
the final version of the manuscript on behalf of all authors: Aghi.
Statistical analysis: Aghi. Study supervision: Aghi.
J Neurosurg / Volume 119 / December 2013
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Manuscript submitted February 12, 2013.
Accepted July 11, 2013.
Please include this information when citing this paper: published online August 23, 2013; DOI: 10.3171/2013.7.JNS13273.
Address correspondence to: Manish K. Aghi, M.D., Ph.D., De
partment of Neurosurgery, University of California at San Francisco,
505 Parnassus Ave., Room M779, San Francisco, CA 94143-0112.
email: AghiM@neurosurg.ucsf.edu.
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