Pituitary surgery is often accompanied by distur-bances of osmoregulation, which may result from manipulation or vascular alterations of the neurohy-
pophysis. These disturbances can manifest as postopera-tive hypernatremia or hyponatremia. Postoperative hyper-natremia is typically caused by diabetes insipidus due to deficient antidiuretic hormone (ADH) secretion. Hypona-tremia after pituitary surgery is typically due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) and is typically associated with a euvolemic state. There
are, however, rare cases of cerebral salt wasting and the as-sociated contraction of extracellular volume that have been reported after pituitary surgery.2 Hyponatremia after pitu-itary surgery can be profoundly symptomatic with symp-toms including headache, dizziness, nausea, and vomiting, which can lead to costly readmissions after otherwise suc-cessful 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 ade-quately represent the range of typical pathologies operat-ed on during pituitary surgery. Furthermore, prior studies did not focus on the contribution of other factors such as
Factors predicting postoperative hyponatremia and efficacy of hyponatremia management strategies after more than 1000 pituitary operations
Clinical articleArmAn 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 morbid-ity 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 inter-ventions 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. Postopera-tive 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 dizzi-ness 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 hypo-natremia (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 vasopres-sin 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 pre-operative hypopituitarism and was most efficiently managed with oral tolvaptan, with several interventions insignificantly 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 symptom-atic hyponatremia, the intravenous vasopressin receptor antagonist Vaprisol is another treatment option.(http://thejns.org/doi/abs/10.3171/2013.7.JNS13273)
Key WordS • hyponatremia • pituitary surgery • postoperative • transsphenoidal • tolvaptan
1
Abbreviations used in this paper: ADH = antidiuretic hormone; SIADH = syndrome of inappropriate ADH secretion.
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preoperative pituitary function or whether a patient had undergone prior pituitary surgeries. Studies to date have also not reported the efficacy of commonly used interven-tions, with treatments such as 3% saline and salt tablets continuing to be used despite little evidence for their ef-ficacy. To fully calculate the frequency of postoperative hyponatremia and the efficacy of various interventions in correcting hyponatremia in a comprehensive series of pi-tuitary patients representative of the wide spectrum seen in practice, we retrospectively analyzed postoperative hy-po natremia after 1045 consecutive operations done in the past 5 years since the establishment of our dedicated pitu-itary center of excellence.
MethodsCase Collection
This study was approved by our institutional Com-mittee on Human Research. We retrospectively reviewed 1045 consecutive pituitary surgeries in the first 946 pa-tients treated in the 5 years since the establishment of the California Center for Pituitary Disorders, a dedicated multidisciplinary center of pituitary expertise. Per institu-tional 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 re-admitted to the hospital for corrective measures under-went sodium checks every 6 hours as inpatients until symp toms of hyponatremia resolved or near normaliza-tion of serum sodium occurred (133 mEq/L or higher), while hyponatremic outpatients, who were asymptom-atic, 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 endo-nasal, microscopic endonasal, or craniotomy), lesion type (endocrineinactive adenoma, endocrineactive adenoma, Rathke cleft cyst, apoplexy, craniopharyngioma, or other), lesion location (sellar, suprasellar, or sellar with suprasel-lar extension), and the presence of preoperative hypopitu-itarism. 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 pa-tients. Because our center does not routinely correct pre-operative 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 RecordedPostoperative 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
cases in which the treatment was used as the sole treat-ment for hyponatremia. This rate of correction was cal-culated 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 AnalysisBinary 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 paramet-ric comparisons of more than 2 variables when the de-pendent 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 2tailed and p < 0.05 was considered statistically significant.
ResultsPatient 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 HyponatremiaThirtytwo patients (3%) presented with preopera-
tive 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 hypona-tremia underwent medical correction preoperatively and 18 (56%) had postoperative hyponatremia.
Postoperative HyponatremiaPathologies included 340 endocrine-active adeno-
mas, 381 endocrineinactive 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 pre-operative hyponatremia (16%) a mean of 4 days after sur-gery (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).
Thirtyone of the 165 operations leading to postoper-ative hyponatremia (19%) were associated with postoper-ative symptoms attributable to hyponatremia a mean of 6
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Postoperative hyponatremia after pituitary surgery
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days after surgery (range 1–29 days; Fig. 1B). Twentyfour of the 165 operations leading to postoperative hyponatre-mia (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 pa-tients with or without postoperative hyponatremia (1.6% vs 0.9%; p = 0.2).
Risk Factors for Postoperative HyponatremiaIn a multivariate analysis including patient age, pa-
tient sex, lesion size, lesion location (sellar, sellar with suprasellar extension, or suprasellar), preoperative hy-popituitarism, 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 hyponatre-mia 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-
TABLE 1: Results of multivariate analysis of variables predicting the presence of preoperative hyponatremia*
Variable HR p Value
age 1.1 per decade 0.1male sex 0.6 0.4lesion size (mean diameter) 1.1 per cm 0.8suprasellar extension 1.5 0.4preop hypopituitarism 4.2 0.4op no. 1.0 0.9pathological diagnosis 1.1 0.5
* HR = hazard ratio.
Fig. 1. Timing of postoperative hyponatremia after pituitary surgery. A: Postoperative hyponatremia most frequently oc-curred on postoperative Day 2, after which the incidence of postoperative hyponatremia decreased until a second smaller de-layed peak occurring on postoperative Day 7. B: Symptomatic postoperative hyponatremia occurred most frequently on post-operative 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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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 hy-pothyroidism (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 postoperative hyponatremia compared with 10% (15 of 150) in those without central hypoadrenalism (p < 0.001) (Fig. 2).
Correction of HyponatremiaThe 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 (intra-venous 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 treat-ment) (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 re-ceiving Vaprisol was overcorrected, with a resulting so-dium of 150 mEq/L.
natremia was associated exclusively with preoperative hy-popituitarism 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 hypopituita-rism may warrant closer follow-up for postoperative hy-ponatremia than patients with normal preoperative pitu-itary function.
Our finding that postoperative hyponatremia occurred after 16% of pituitary surgeries is consistent with other re-cent series, which have reported 18%–23%6,15 incidences of postoperative hyponatremia. An earlier study from our institution reported a 2% incidence of postoperative hypo-natremia in surgeries done between 1971 and 1993; the vast majority of those cases were symptomatic.14 The more fre-quent identification of asymptomatic hyponatremia without change in incidence of symptomatic hyponatremia be-tween 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 de layed peak typically occurring between postoperative Days 7 and 9.3,8 While the fact that all patients underwent so-dium 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
TABLE 2: Results of multivariate analysis of variables predicting the occurrence of postoperative hyponatremia
Variable HR p Value
age 1.0 per decade 0.4male sex 1.0 0.9lesion size (mean diameter) 1.0 per cm 0.9suprasellar extension 1.5 0.3preop hypopituitarism 4.6 0.006op no. 1.9 0.4surgical approach 2.9 0.1pathological diagnosis 1.1 0.2
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 cor-tisol) axes had an increased risk of postoperative hyponatremia compared with those without. GH = growth hormone.
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Postoperative hyponatremia after pituitary surgery
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asymptomatic patients did not undergo outpatient serum sodium checks; limiting the analysis to patients with symp-tomatic 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 de-layed peak has been reported to occur in patients who do not excrete an administered water load and suppress plas-ma arginine vasopressin normally.8 In that same study, pa-tients with postoperative hyponatremia occurring around Day 7 were more natriuretic; had lowered dietary sodium intake; and had similar fluid intake, cortisol, and atrial na-triuretic 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 in-sipidus.5 Despite this possibility that postoperative hypo-natremia 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 hyponatre-mia, 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 post-operative 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 theoreti-cally increasing the risk for postoperative hyponatremia. However, our analysis failed to identify pathology as a risk factor for postoperative hyponatremia. The one fac-
tor we found to increase the risk of postoperative hypo-natremia was preoperative hypopituitarism. Given that lesion size, suprasellar location, and pathology failed to predict postoperative hyponatremia, the correlation be-tween preoperative hypopituitarism and postoperative hy-ponatremia is unlikely to reflect lesion anatomy, but it is possible that preoperative hypopituitarism could increase the risk of postoperative hyponatremia after pituitary sur-gery through exacerbation of the underlying mechanisms through which hypothyroidism13 or adrenal insufficiency10 increase the risk of hyponatremia.
Our findings also suggest that postoperative hypona-tremia is often a transient self-correcting phenomenon, but when medical intervention is indicated, measures de-signed 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 (SALT1 and SALT2) 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 correct-ing 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 tolvap-tan 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
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.
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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 percent-age of patients with hyponatremia (Fig. 1C). While a pre-vious 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 limit-ing 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 symptom-atic 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 pro-viders. Furthermore, our findings of different rates of cor-rection between different corrective measures could reflect the fact that, while our frequency of sodium checks did not vary depending on which corrective measure was be-ing 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.
ConclusionsDespite 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 hyponatre-mia in highrisk patients and management of significant symptomatic cases with the oral vasopressin receptor antagonist tolvaptan can improve patient safety and de-crease the rates and duration of readmission to the hos-pital after otherwise successful elective pituitary surgery. For readmitted patients with severely symptomatic hypo-natremia, 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.
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Manuscript submitted February 12, 2013.Accepted July 11, 2013.Please include this information when citing this paper: pub-
lished online August 23, 2013; DOI: 10.3171/2013.7.JNS13273.Address correspondence to: Manish K. Aghi, M.D., Ph.D., De
part ment of Neurosurgery, University of California at San Francisco, 505 Parnassus Ave., Room M779, San Francisco, CA 941430112. email: [email protected].
