Prevalence of Diabetes Insipidus and Other Complications in Early Period After Pituitary Surgery: Analysis of 259 Patients

Eugeniya Galina Moisak. Prevalence of Diabetes Insipidus and Other Complications in Early Period After Pituitary Surgery: Analysis of 259 Patients. Biomed The purpose of this study was to describe complications associated with the endoscopic transsphenoidal approach and to determine a relation between postoperative central diabetes insipidus (DI) and the characteristics of adenomas. Methods: Results:

pituitary adenomas is the endoscopic transnasal transsphenoidal approach. This technique is becoming more popular and refined due to better lighting and endoscope's superior visualization [3][4][5].
These factors have significantly reduced surgical complications and improved tumor removal. The aim of this study was to determine the relation between postoperative central diabetes insipidus (DI) and the characteristics of adenomas, tumor removal extent and surgical complications. Central DI has been one of the most common forms of transient or permanent disorder of fluid homeostasis after transsphenoidal surgery. Any disturbance of the posterior pituitary, pituitary stalk or neurons originating in the paraventricular or supraoptic hypothalamic nuclei can lead to DI [6,7].

Material and Methods
This study was a retrospective analysis of 259 patients with

Surgical Technique
All the operations had been planned using the data collected from preoperative CT, contrast-enhanced MRI and MR-angiography.
In every case intraoperative navigation (Integra, Radionics) was used. All the patients underwent a fully endoscopic endonasal approach. The operations took place with the patient's head fixed in a three-pin Mayfield holder. Both nostrils were prepared with a topical vasoconstrictor. Between July 2014 and July 2015, we used a mononostril approach. Generally, the approach was through the right nostril, the left one was used only in a case of major septal deviation to the right. The initial step included lateralization of middle turbinate, but not resection. We removed the rostrum and small back part of the septum. At that moment the endoscope irrigating system (ClearVision system, Karl Storz) was additionally used as the monomanual technique was performed. In cases of intraoperative CSF-leakage, a fat-graft and fibrin-glue were applied for skull base reconstruction. After July 2015 we have begun applying a binostril approach, using the bimanual technique with an assistant surgeon holding the endoscope. The middle turbinate was lateralized on the left side and resected on the right side after injection in mucosa a solution of 2% lidocain and adrenalin. On the right side a nasal septal flap was formed using unipolar coagulation.
The anterior wall of the sphenoid sinus was opened bilateraly.
Nasal cavity and sinus were disinfected with Octenisept. The septum and mucosa from sphenoid sinus were removed totally and then the bone of floor of sella turcica was removed rather wide. In all the cases we used a high-speed drill (2 or 4 mm in diameter). The dura was opened with a telescopic knife and microscissors under direct visual control. Before July 2015, the tumor was removed with curettes and after July 2015 -with suction and microforceps or using the two-suction technic. In all the cases the Karl Storz hard endoscopes (180/4 mm) with 0°, 30°, 45° angulations attached to high-definition cameras was used. In the case of unimanual technique the surgeon held the endoscope in his left hand and the instrument -in the right one, while an assistant held a suction tube, but in the case of bimanual technique the assistant held an endoscope and the surgeon -one suction tube in his left hand and in right hand -a second suction tube or any other instrument. In a case of high bleeding the assistant could help, holding one more suction tube. For skull base reconstruction vascularized flaps or mucosa from the resected middle turbinate were used. In presence of middle-flow intraoperative CSF-leakage, a fascia lata graft was applied. In some cases, we used a fat graft or a bone part or suture on dura mater for reconstruction, as well as artificial dura (Duraform), fibrin glue and a Foley catheter. The patients were not routinely given corticosteroids before surgery. Antibiotics administration continued for 24 hours.

Postoperative Evaluation
In 48 hours after surgery a full endocrinological assessment was performed. Within 72 hours postoperatively all the patients underwent MRI brain scans to assess the volume of removal. In cases of non-functional adenomas our main interest was control of cortisol, thyroxin, prolactin and testosterone. In case of growthhormone secreting adenomas, we additionally controlled the patients' growth hormone, in case of ACTH-hormone secretingadrenocorticotropic hormone, and in case of TSH-hormon secreting adenomas -thyroid stimulating hormone and threeiodthyronin.

Statistical Analysis
Data analysis was performed using the R 3.3.3 statistical package [8]. Bivariate analysis was performed to identify the predictive factors of DI among the collected variables. It included Fisher's exact test (asymptotic implementation) for qualitative variables and Wilcoxon rank sum test for quantitative variables.
All the tests were 2-sided. Univariate analysis was carried out to test the covariates predictive of outcome (DI onset). The factors predictive in the univariate analysis (p<0.25) were entered into stepwise logistic regression analysis. Additionally based on some clinical considerations and graphical analysis, we tested a number of hypotheses about the nonlinear entry of variables into the logit function [9]. To select the final model AUC and ANOVA were used.

Results
All the 259 patients were operated at the same hospital by the

Extent of Tumor Removal
The radicality of tumor removal was evaluated using contrastenhanced MRI within the first 72 hours. The resection extent is presented in (  per day) or vancomycin (2.0 per day) and meropenem (6.0 per day). The treatment was successful and no neurological deficit after meningitis was observed.

Epistaxis
One patient (0.4%) developed postoperative epistaxis in 6 hours after surgery and required reoperation. This patient was operated using a unonostril approach. The sphenoidal sinus was opened on both sides but the mucosa on the opposite side was left intact. The bleeding originated from the opposite -side ramus of sphenopalatina artery. In 5 cases, these new symptoms were gone after treatment. One patient did not have any improvement despite of the treatment.

Hemorrhage/Swelling of Residual Tumor
There was one case of thalamus hemorrhage that required external ventricular drainage. This patient developed a new neurological deficit (diencephalon syndrome), which regressed after the treatment. One more patient developed an asymptomatic ventricular hemorrhage after total removal of the macroadenoma that did not require any additional treatment. A third patient had swelling of residual tumor after partial resection and was reoperated.

Surgical Mortality
The surgical mortality rate was 0.8% (2 patients). The first patient had macroadenoma and Cushing's disease. The tumor had an invasive growth. It was almost unsuctionable and therefore was not totally removed. After the operation, the patient developed hemiparesis followed in 8 days by deep vein thrombosis and cavafilter implantation. Within the next 7 days, the patient developed pulmonary embolism and on the 34th day after the operation he died.
The second patient was a 54-year-old woman with a nonfunctional macroadenoma. During the operation we had no difficulties, and the tumor was removed gross totally. The first day after the surgery she was verticalized and developed pulmonary embolism. A cavafilter was implanted, and thrombus fragmentation was performed.
The patient died on the 4 th day after the surgery.
The rate of surgical mortality varies from 0.6 to 1.8% [33].
The main reasons of mortality are hemorrhage, somatic pathology (cardio-vascular disease, acute pancreatitis etc.), meningitis, ischemic stroke due to the damage of internal carotid artery, hard electrolytes irregularities (because of involvement of diencephalon region), pulmonary embolism, subarachnoid hemorrhage (in case of undiagnosed aneurism) [33]. In our study we did not find of cases. Acquired CDI is more common than congenital one, and about 25% of adult CDI cases are idiopathic. Children with acute injury to the nervous system and CDI have a high mortality rate. Traumatic brain injury is associated with high mortality and acute and chronic morbidity [34]. Pituitary surgery results in CDI with a wide range of incidence (1-67%). Minimally invasive surgery has a low incidence of postoperative CDI (transient CDI 13.6% and permanent CDI 2.7%). Abnormalities in the secretion of AVP usually begin during the intraoperative period. The incidence of immediate postoperative DI is higher among the patient's undergoing surgery by the traditional method than by the endoscopic transsphenoidal method (36% vs. 15%). The incidence of long-term DI did not vary significantly between the groups [34].  In our study, we revealed the influence of adenomas size relative to a patient's age. For older patients the size of the adenoma was a stronger factor than for the younger ones. In other words, in the elderly patients the tumor size has a greater effect on the risk of DI development. These data contradict to the results obtained by Sigounas et al. in 2008 who has not revealed any correlation between DI and tumor size. In our opinion our findings are related to the anatomy of a pituitary gland. The older a patient the more prone the gland is to hypoplasia while the risk its injury is lower, especially in case of microadenomas. Macroadenomas and giant adenomas are often found in close proximity to the pituitary gland that increases the risk of its injury and DI development after surgery. In case of giant adenomas, the last squeeze the gland a lot, but in case of microadenomas, when we usually observe healthy hypophysis tissue, the hypoplasia will play a major role.
The second important factor was consistence of tumor. The unsuctionable adenomas increased the risk of DI 2.89 times. This dependency also can be related to the tumor's intimacy to the gland making the last more prone to injury and increasing the risk of DI development. The rate of all complications also depends on the surgeon's experience. Ciric et al. analyzed complications in three groups of patients who were operated by surgeons with experience less than 200, 200-500 and more than 500 cases respectively. It has been demonstrated that those patients who were operated by surgeons with experience less than 200 surgeries (as in our study) had higher incidence of not only surgical complications, but also higher rate of DI (19%).

Conclusion
The endoscopic transsphenoidal surgery is the treatment of