Evaluation of a protocol-based treatment strategy for postoperative diabetes insipidus in craniopharyngioma
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.166533
Source of Support: None, Conflict of Interest: None
Background: Postoperative diabetes insipidus (DI) is a significant cause of morbidity in craniopharyngiomas (CP) and its effective management improves outcome.
Keywords: Craniopharyngioma; diabetes insipidus; hypernatremia; hyponatremia
Diabetes insipidus (DI) occurs in 60–93%,,, of patients undergoing surgery for craniopharyngiomas (CP) and contributes to significant morbidity and mortality if improperly managed.,, Although some authors have recommended management guidelines for DI,,,,, there is limited literature on the effectiveness of these protocols., Hyponatremia, an important component of the water-electrolyte disturbances following CP surgery should be considered together with DI since both are due to disturbances of antidiuretic hormone (ADH) secretion. From 2004, we have modified our treatment strategy for CPs to a more radical excision, reserving radiation therapy for those with subtotal excisions or with recurrences. In an attempt to manage an increased incidence of DI, we instituted a strict protocol from 2010. In this paper, we evaluate the effectiveness of this protocol, identifying the incidence of inadequate DI control as defined by abnormal serum Na+ values or wide intra-day serum Na+ fluctuations. We compared these findings with retrospective data obtained from patients operated by the same surgeon between 2004 and 2010 in whom DI was managed on an ad hoc basis.
We conducted this prospective study from March 2010 to March 2012 and included 26 patients who developed DI from among 30 patients undergoing transsphenoidal or transcranial surgery for CP (Group 1). Clinical data pertaining to age, preoperative DI, and hypothalamic involvement were noted. Hypothalamic involvement was defined as the presence of one or more of the following: Obesity, hyperphagia, memory impairment, disturbances of thermoregulation, behavioral problems, and disturbance of sleep-wake cycle. Tumor size, appearance (solid, cystic or mixed), and Yasargil et al.,'s grade were based on the magnetic resonance imaging (MRI) findings. All patients were initially kept in the neurosurgical intensive care unit for 36–48 h and were closely followed up after transfer to the high dependency area and wards.
Protocol for diabetes insipidus
This protocol was developed after analyzing the data from patients operated prior to 2010 and it was applied for all patients in Group 1.
Diagnosis and characterization of diabetes insipidus
A patient was identified as having DI on a particular day if their urine output was more than 4 ml/kg/h over a 6-h period or if the serum Na+ level was more than 145 mEq/L with a urine specific gravity <1.005. Since there are no published criteria for classifying the severity of DI, we defined our own criteria as shown in [Table 1].
Monitoring of diabetes insipidus
Patients with DI, especially if drowsy and unable to maintain adequate fluid intake, can rapidly become dehydrated. Fluid intake and urine output were, therefore, measured hourly and summed up every 6 h. The patient had an indwelling urinary catheter until urine output was under reasonable control. An intraoperative serum Na+ measurement, if the surgery lasted more than 6 h, determined the type of fluid to be replaced and whether injection pitressin was required in the operation room. On the day of surgery (day 1), serum Na+ was measured every 6 h. From the 2nd day onward, serum Na+ was checked every 12 h until the patient remained stable for 3 days. Subsequently, serum Na+ was measured daily for a further week.
Treatment of diabetes insipidus
Proper early treatment of DI requires the institution of appropriate measures to bring excess urine output under control and the administration of the correct type and volume of intravenous (IV) fluids. To avoid the danger of hypovolemia in these patients, fluid needs to be administered to compensate for the previous hour's output, and the use of normal saline to compensate for water loss in DI may increase the serum Na+ at a dramatic rate. Therefore, our protocol dictates that the fluid be changed from normal saline to 0.45% saline when the output is 4–6 ml/kg/h and to plain dextrose if the output exceeds 6 ml/kg/h. This is particularly important until the patient is fully awake and demonstrates an intact thirst mechanism. In most cases, therefore, this frequent change of fluids is only required for the first 24–48 h following surgery.
Once the patient is established on a normal diet, it is not possible to measure the total fluid intake accurately since solid food has significant water content. In this situation, serum Na+ measurement assumes greater significance, and patients may maintain normonatremia even in the presence of a measured negative fluid balance.
Over the period in which this protocol was developed, we steadily moved to a treatment regimen where oral 1-desamino-8-D-arginine vasopressin (DDAVP) was instituted as early as possible, usually on the 2nd day following surgery. On the day of surgery, DI was controlled with 5 unit IV boluses of pitressin in adults and pitressin infusion beginning at 0.2 units per hour in children. Oral DDAVP was administered as tablets (100 µg) or fractions of tablets in adults; and, in children by making a suspension and administering as little as 10 µg per dose.
Adequacy of control of diabetes insipidus
We used serum Na+ as a parameter to establish the quality of DI control rather than intake/output data as it was difficult to determine the volume of intake when the patient was taking solid food. Twice daily serum Na+ values for each patient were entered into a database and the number of times the serum Na+ level fluctuated above 150 mEq/l or less than 130 mEq/l was noted until the eighth postoperative day. In addition, we noted the number of times serum Na+ levels fluctuated by more than 10 mEq/l in a single day during the same period. The electrolyte values for the first postoperative day were excluded, as intraoperative fluid management by the anesthetist could be a confounding factor. The first postoperative week was chosen since the DI usually started to stabilize by the end of this period.
Eighty-two patients with CPs were operated by the same surgeon between 2004 and February 2010. Fifty-two (63%) of these patients developed DI, but complete intake-output records, serum Na+ level, and medication history were available for only 34 patients who formed the control group (Group 2). The definition of DI and criteria for categorization of DI were the same for Group 1 and Group 2. The neurosurgical unit and intensive care personnel treated patients who developed DI in Group 2 without a fixed protocol.
The surgical strategy for Group 1 (prospective cohort) was to excise as much of the tumor as possible leaving behind bits of tumor that were tightly adherent to the hypothalamus, vessels of the circle of Willis or the brainstem. During this period, we favored the medial subfrontal approach. Patients in Group 2 (historical controls) were operated through a pterional approach. Although our surgical strategy in Group 2 was to remove as much of the tumor as was safely possible, it is likely that we were less radical than those in Group 1 considering we were in the learning curve of the procedure. Tumor excision was classified as radical, if the surgeon was convinced that there was no residual tumor and if the postoperative MRI at 3 months showed no tumor; subtotal, when the tumor residue was <1 cm in size and if the surgeon documented an intraoperative residue regardless of whether they were seen on the postoperative MRI. A partial excision was when the tumor residue was >1 cm in size.
Bivariate analysis was done using various parameters including age, preoperative DI, hypothalamic involvement, tumor size and consistency, and extent of excision, to ascertain if both the groups were comparable. The quality of DI control in relation to the incidence of abnormal serum Na+ levels and wide fluctuation of serum Na+ were compared between the two groups using the Mann–Whitney U-test.
There were 26 cases in Group 1 and 34 cases in Group 2. Both groups were similar with regard to nearly all parameters on bivariate analysis [Table 2]. However, Group 1 had a significantly higher number of patients with preoperative DI. The incidence of preoperative hypopituitarism and hypothalamic involvement in Group 1, although higher, was not statistically significant. The majority of patients in Group 2 were operated via a pterional approach while most patients in Group 1 were operated via the medial subfrontal approach. The mean duration of postoperative hospital stay was 14.1 days (range 5–27 days) in Group 1 and 14 days (range 3–63 days) in Group 2.
Adequacy of diabetes insipidus control
The incidence of abnormal serum Na+ levels and wide intra-day Na+ fluctuations in the 1st week for both groups are compared in [Table 3]. A Mann–Whitney U-test compared the abnormal serum Na+ levels in Groups 1 and 2 [Table 4]. There was a statistically significant difference between the two groups in the total number of high and low Na+ level counts with the new protocol (Group 1) having much lower counts (P = 0.032).
Hypernatremia and wide fluctuations of serum Na+
The incidence of serum Na+ >150 mEq/l was significantly more on the second and third postoperative days in Group 2 as compared to Group 1 (25% versus 7.6%, P = 0.0008, Fisher's exact test). The incidence of wide intra-day fluctuations was higher in Group 2, but did not reach statistical significance on the Mann–Whitney U-test (P = 0.9).
In the 1st week following surgery, we documented a larger number of episodes of hyponatremia (serum Na+ <130 mEq/l) in Group 2 (8%) as compared to Group 1 (3%), but this did not reach statistical significance. However, patients in Group 2 tended to develop hyponatremia toward the end of the week, while the incidence was almost evenly distributed through the postoperative course in Group 1. On analyzing days 6, 7, and 8 separately we found that there was significantly higher incidence of hyponatremia on these days in Group 2 as compared to those in Group 1 (14.2% vs. 3.2%; P = 0.0004, Fisher's exact test). Interestingly, in Group 2 we noted that the same patients who had hypernatremia (>150 mEq/l) on day 2, 3 and 4 developed hyponatremia in the later part of the week. The hyponatremia was probably due to a combination of factors including over-treatment of the DI in the early stages, excessive oral fluid intake in the face of reduced severity of DI, syndrome of inappropriate ADH, and cerebral salt wasting. It was managed by stopping all DI medication, increasing salt intake, and in some cases controlling oral fluid intake.
Temporal profile and severity of diabetes insipidus
The temporal profile of DI for both the groups (60 cases) showed that the highest incidence of DI was on the first postoperative day (58 cases), followed by a steady decline. [Figure 1] plots the incidence of severe DI against postoperative days in both the groups during the hospital stay. Group 2 had a significantly higher incidence of severe DI on day 1 (24 cases, 70%), followed by a sharp decline of about 62% from day 3 (21 cases) to day 6 (8 cases). Patients in Group 1 had a lower initial incidence of severe DI on day 1 (10 cases, 38%), followed by a steady decline after day 10.
DI after surgery for CP is a challenging complication,, that may be a significant cause of mortality., The incidence of DI is related to the extent of excision and some series report an incidence of up to 93% in the postoperative period. From 2004, we changed our surgical technique favoring a more radical excision of tumor and the subsequent incidence of DI was 70%. Further, children have been found to have a higher rate of postoperative DI (80%) when compared with adults (63%). Our results show that the implementation of a strict management protocol in the intensive care unit and high dependency area improved the quality of DI control. Better outcomes have been demonstrated with N/2 saline as the fluid of choice in the perioperative period for CP, when compared with normal saline or 5% dextrose. Our protocol supports the administration of N/2 saline as the preferred IV fluid in the immediate postoperative period for mild DI, with 5% dextrose being reserved for severe DI based on urine output.
Group 1 had lower incidences of episodes of hypernatremia, hyponatremia and wide intra-day fluctuations of serum Na+ levels. This better control in Group 1 was in spite of the higher incidence of preoperative DI, preoperative hypopituitarism, and preoperative hypothalamic involvement, all of which are risk factors for postoperative DI. The strikingly lower incidence of severe DI in Group 1 is a reflection of the awareness of the intraoperative onset of DI and immediate initiation of treatment by anesthesiologists. An interesting finding was the sharp decrease in the severity of DI from day 3 to day 6 in patients in Group 2 (historical controls) [Figure 1]. This coincided with the cessation of postoperative dexamethasone treatment around this time. Glucocorticoids have been shown to exert a direct inhibitory effect on vasopressinergic neurons reducing ADH release,, and possibly worsening or “unmasking” mild DI. This finding was not apparent in Group 1 possibly because of the lower incidence of severe DI at the beginning of the week.
The management of DI in CPs is further complicated by a diminished thirst sensation, possibly due to hypothalamic damage, seen in 13–25% of cases., Adipsic patients are at a higher risk of developing hypernatremia and require round the clock vasopressin analogs. In addition, they need to be trained to drink 2–3 l of water per day and the adipsia gradually resolves with partial or complete thirst recovery by about 9 months. We had one pediatric patient who developed adipsia and she recovered over 2 weeks.
Another frequently encountered problem is the polydipsic patient with a very high urine output who is compensating with increased oral intake and has normal or even low serum Na+. Such patients are at risk for water intoxication and hyponatremia. We suggest the use of oral rehydration solution (containing electrolytes) rather than plain water to avoid hyponatremia. Some patients in Group 2 (historical controls) had hypernatremia initially and then developed hyponatremia at the end of the first postoperative week probably as a result of overzealous management of DI. This phenomenon was not seen in Group 1 since we advised these patients to consume a normal diet and reduce the intake of free water upon initiating DDAVP. We also found that the usual daily dosage of oral DDAVP ranged from 100 to 200 µg for adults and 50–100 µg for children. This is much lower than the dose of 200–400 µg, 2–4 times/day as suggested by Robinson and Verbalis.
This study employed historical controls. Changes in management over time of other factors unrelated to the particular intervention could have occurred and could not be controlled for. An inherent problem with the collation of retrospective data for the historical controls was a sampling error, since full intake-output data was available for only 34 of the 52 patients with DI in the retrospective cohort. In addition, it can always be argued that patients treated prospectively according to a strict protocol will get greater personal attention from the treating physician and this fact may itself improve outcomes.
The treatment of DI following aggressive surgical management of CP will continue to challenge neurosurgeons, endocrinologists and neurointensivists. A strict protocol-based management with meticulous fluid/electrolyte measurements and timely intervention with medications can result in smooth control of DI following surgery.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]