A randomized controlled trial to determine the role of intraoperative lumbar cerebrospinal fluid drainage in patients undergoing endoscopic transsphenoidal surgery for pituitary adenomas
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.222823
Source of Support: None, Conflict of Interest: None
Keywords: Cerebrospinal fluid leak, endoscopic transsphenoidal surgery, lumbar subarachnoid drain, pituitary adenoma
Pituitary adenomas are the most common brain tumors after gliomas and meningiomas, and the transsphenoidal approach is preferred for these tumors because of the lower morbidity compared to transcranial surgery. Intraoperative cerebrospinal fluid (CSF) leak due to arachnoid tears commonly complicates transsphenoidal surgery, requiring meticulous dural repair to prevent postoperative CSF rhinorrhea and meningitis. Postoperative CSF leaks occur due to failure to recognize an intraoperative CSF leak or a failure of the primary repair. The incidence of intraoperative CSF leak ranges from 18% to 52% in most contemporary reports.,,,,,,,,,
Mehta and Oldfield  reported a marked reduction in intraoperative CSF leaks in a retrospective cohort of 114 patients with pituitary macroadenomas and intraoperative lumbar drainage. However, there remain concerns regarding the safety of lumbar drain insertion, which is an invasive procedure with infrequent complications. In addition, the insertion of a drain into the subarachnoid space may be challenging, particularly in obese patients, thereby prolonging anesthesia and operating times. Thus, the current standard of care varies among pituitary surgeons, and there is no consensus on whether intraoperative lumbar drainage should be used routinely. We sought to evaluate the efficacy of intraoperative lumbar drainage by performing a randomized controlled trial at our institution. Furthermore, we hypothesized that CSF drainage could prevent bulging of the arachnoid pouches into the operating field, thus enabling enhanced resection of the suprasellar component of the tumor.
The protocol for this randomized controlled study was evaluated and approved by the Institutional Review Board of our institution. The trial was registered with the Clinical Trial Registry of India (CTRI/2014/09/005021). An informed written consent was taken from all the patients participating in the study.
Inclusion and exclusion criteria
All patients with pituitary adenomas and planned for endoscopic transsphenoidal surgery were eligible for inclusion. Patients who had undergone previous transsphenoidal surgery or radiation therapy were excluded from the study. We also excluded patients undergoing extended transsphenoidal surgery in which case an intraoperative CSF leak was obligatory.
Randomization of patients
Patients were assigned to the LSAD or no LSAD group using permuted block randomization of sizes 2, 4, or 6 using SAS 9.1.3 software(version 9.1.3; SAS Institute, Inc., Cary, NC, USA). Allocation was concealed using serially numbered opaque sealed envelopes.
Between June 2013 and June 2014, 80 consecutive patients underwent endoscopic transsphenoidal surgery for pituitary adenomas at the Christian Medical College Vellore. All procedures were performed by the senior author (A.G.C.). Twenty cases were excluded from the study, leaving 60 patients eligible for recruitment in the study. All patients underwent a thorough neurological examination and preoperative endocrinological evaluation prior to surgery.
Radiological assessment was performed in all patients using a 3-Tesla magnetic resonance imaging (MRI) scanner. All patients underwent preoperative MRI of the brain with gadolinium contrast. All patients with nonfunctional pituitary macroadenomas and those with functional adenomas with a large suprasellar component underwent early nonenhanced postoperative MRI within 6 hours after surgery. Volumetric analysis was performed by an experienced neuroradiologist (S.M.). The volume of the tumor was calculated on contiguous post-gadolinium MRI sections by outlining the tumor on all slices that showed the tumor and the sum of the areas was calculated. This was multiplied by the slice thickness to calculate the tumor volume. Extent of resection was classified as radical, when there was no evidence of residual tumor on the postoperative imaging done after 3 months at follow-up; subtotal, when tumor residue was <10% of the preoperative tumor volume; and partial, when >10% of tumor was left behind. Tumors were classified as microadenomas or macroadenomas, and their size was denoted by the maximum anteroposterior, craniocaudal, or transverse dimension. Hardy's system graded suprasellar extension, and Knosp grades of 3 and 4 defined cavernous sinus (CS) invasion.
In patients assigned to the LSAD group, the patient was positioned lateral after induction of anesthesia and a lumbar subarachnoid catheter was inserted under sterile conditions by the anesthetist. A 16-G epidural catheter with a 16-G Tuohy needle (16-G Portex Epidural Catheter Set; Smiths Medical ASD Inc., Keene, NH) was inserted at the L3-L4 interspace. After positioning the patient supine for the pituitary surgery, the lumbar subarachnoid catheter with a 100-cm extension, and a three-way cannula was connected to a burette set and left at ground level to drain. After draining an initial 30 ml of CSF, the drain was temporarily closed and re-opened when the surgeon began the sellar stage of the surgery. The ETCO2 was maintained constantly at 35 mmHg throughout the procedure. After performing a posterior septectomy and removing the vomer, we used the binostril technique to enter the sphenoid sinus through both sphenoid ostia. The sphenoid sinus septae along with the sellar floor were drilled using a high-speed drill up to the edge of the internal carotid arteries on both sides but stopped just short of the tuberculum sellae. The dura was opened as a flap based superiorly. CSF was drained if the arachnoid bulged into the field obscuring view of the tumor or if the surgeon felt that it was at a risk of tearing during the dissection.
Our strategy was to achieve intracapsular resection of the tumor while preserving pituitary function. In patients with CS invasion, aggressive tumor removal was attempted using 30 and 45-degree endoscopes. However, no attempt was made to go lateral to the intracavernous segment of the internal carotid artery. At the end of the tumor resection, the otolaryngologist independently determined if there was an intraoperative CSF leak. If doubtful, this was confirmed by injecting fluorescein dye through the lumbar subarachnoid drain in patients assigned to the LSAD group. In the no LSAD group, this was confirmed by a Valsalva maneuver.
If no CSF leak was noted at surgery, the drain was removed on the operating table immediately after extubation in the LSAD group. In the event of a CSF leak in the LSAD group, the sella was packed with fat and the drain was left in-situ for 5 days. For patients suffering CSF leaks in the no LSAD group, a lumbar drain was inserted within 6 hours of surgery after transfer to the postoperative intensive care unit.
All patients underwent an endoscopic inspection by the otolaryngologist (R.T.) 1 week after surgery. All patients were advised a 3-month postoperative follow-up. Functional tumors were assessed with fasting and postsuppression human growth hormone (HGH) levels, insulin-like growth factor-1 (IGF-1) levels for growth hormone (GH) adenomas, and serum cortisol and adrenocorticotrophic hormone (ACTH)levels for the Cushing's disease. If there was biochemical evidence of residual disease based on current remission criteria, a gadolinium-enhanced MRI was done. All patients with nonfunctional tumors were followed with a contrast brain MRI.
The primary outcome was the incidence of intraoperative CSF leak determined by endoscopic inspection at the end of the surgery. Secondary outcome measures included the occurrence of postoperative CSF leaks and extent of tumor resection using volumetric analysis on MRI.
Data is presented as mean ± standard deviation (SD) for continuous variables and as frequencies for categorical variables. Continuous and categorical variables were examined for statistically significant differences using the Student t-test and the Fisher's exact test respectively. A P value <0.05 was considered significant. was considered significant. Analysis was performed using the Statistical Package for the Social Sciences (SPSS version 22.0, CA).
All 60 patients initially recruited completed the study protocol. Baseline demographics and preoperative variables are summarized in [Table 1]. With the exception of 1 patient with pediatric Cushing's disease who was 16 years old, all were adults and there was an equal distribution of males and females. The mean preoperative body mass index (BMI) was 27.9 ± 5.9 kg/m2. Most tumors were macroadenomas with significant suprasellar extension, and functional tumors were more common. There were no statistically significant differences in the patients' age, sex, BMI, tumor size, extrasellar extension, tumor consistency, or pathology when the LSAD group was compared with the no LSAD group, demonstrating adequate randomization.
Intraoperative CSF leak was seen in a quarter of cases overall, occurring in both microadenomas (n = 5) and macroadenomas (n = 10). There was no significant difference in the frequency of intraoperative CSF leaks in microadenomas when compared to macroadenomas (35.7% versus 21.7%; P = 0.309). The intraoperative CSF leak rate in the LSAD group was 3.3%, which was significantly lower when compared to the no LSAD group, where the leak rate was 46.7% (P< 0.001). There were no cases of postoperative CSF rhinorrhea in the LSAD group, whereas 3.3% of patients suffered this complication in the no LSAD group.
Thirty patients were eligible to undergo postoperative MRI. The overall extent of tumor resection in this subcohort was 94.73 ± 9.9%. Insertion of a drain did not impact resection rates (P = 0.541). There were no instances of catheter-related complications, including meningitis, retained catheter fragments, and epidural or subdural hematomas. However, two patients in the LSAD group complained of low-pressure headache, which was managed conservatively without an epidural blood patch.
The goal of transsphenoidal surgery for pituitary adenomas is maximal resection of tumor to decompress the optic apparatus while preserving endocrine function. Postoperative outcomes after surgery for pituitary adenomas are intimately related to the extent of resection because it allows remission of hormone excess in functional tumors, while delaying recurrence in nonfunctional tumors. Most pituitary surgeons use the endoscopic endonasal transsphenoidal approach effectively, with excellent outcomes and low perioperative morbidity.,,,,, In an earlier study, using the microscopic transsphenoidal technique, we showed that the extent of resection depends on the configuration of the suprasellar component of the tumor. If a greater part of the tumor was not visible through the transsphenoidal trajectory, radical resection was less likely.
To enable more complete tumor resection, various strategies have been described to elevate intracranial pressure to force the suprasellar portion of the tumor inferiorly into the sella. Nath et al., studied the effect of injecting saline and air through the lumbar subarachnoid catheter to increase the intracranial pressure, thereby aiding the descent of the suprasellar component into the sella. They noted improvements in the extent of tumor resection but report an intraoperative CSF leak rate of 25%. Korula et al., achieved similar results solely by increasing the end tidal carbon di oxide (ETCO2) to 50 mmHg. These methods of raising the intracranial pressure often resulted in bulging of the arachnoid pouch, which can obscure the surgeon's view of the tumor, leading to inadvertent arachnoid injury. The incidence of postoperative CSF leak in endoscopic and microscopic series of transsphenoidal surgery for pituitary adenomas described in literature varies from 0% to as high as 27%.,,,,,,,,,,
A recent study  recommended the use of a lumbar subarachnoid catheter to drain CSF intraoperatively. They arrived at this conclusion from a retrospective analysis of 114 transsphenoidal operations for pituitary macroadenoma performed without intraoperative CSF drainage. They compared this with findings from 44 cases in which CSF was drained through a lumbar subarachnoid catheter. They noted a dramatic decrease in the intraoperative CSF leak rate from 41% to less than 5% in patients who underwent intraoperative lumbar subarachnoid catheter. They did not report any catheter-related complications in their series, but did not comment on the extent of tumor resection. They  postulated that lumbar CSF diversion reduces the turgor of the suprasellar arachnoid that is typically expanded in pituitary adenomas and makes it less susceptible to tearing during surgery. The results of our randomized trial confirm this finding, and strongly favor the routine use of intraoperative lumbar drainage in transsphenoidal surgery.
The incidence of intraoperative CSF leak in the no LSAD group was 46.7%, which is in the higher end of the ranges described in the literature. In our country, we commonly deal with large and invasive tumors; this combined with our aggressive surgical strategy may be responsible for the relatively high incidence of this complication. Nevertheless, extent of resection did not differ significantly between the two groups, confirming that the surgeon was not biased towards a more conservative resection in the LSAD group.
As with any invasive procedure, there are certain risks associated with lumbar drain placement, although most are minor and can be managed conservatively. The placement of lumbar drains in patients with normal pressure hydrocephalus is associated with a 1.7% risk of subdural hygroma and subdural hemorrhage and 0.8% risk of developing meningitis. Approximately 5% of patients experience minor complications such as low pressure headache, local site infection, and nerve root irritation. Ransom et al., in their study on prospective placement of lumbar drain for different pathologies reported a complication rate of 12.3% in their series. They reported persistent peritubal CSF leak around the insertion site in 7.7% of their patients. Other complications included retained catheter fragments in 1.5%, significant overdrainage in 1.5%, and inadvertent disconnection in 1.5% patients. In our series, we had no catheter-related complications, similar to the results published by other authors.,, Insertion of the catheter may be theoretically problematic in obese patients, where localization of the interspinous space may be difficult, especially if fluoroscopy is avoided. In such patients, we advocate catheter insertion following induction of general anesthesia, which allows administration of an intravenous muscle relaxant that may facilitate easier insertion of the lumbar drain. Despite the fact that most of our patients had elevated BMI values, we did not encounter any difficulties in inserting lumbar drains in overweight patients. This should, in particular, encourage the use of lumbar drainage in overweight patients, who may be at a higher risk for postoperative CSF rhinorrhea following endoscopic transsphenoidal surgery.
Although we hypothesized that intraoperative CSF drainage reduces the bulging of arachnoid folds into the operative field, thereby facilitating tumor resection, there was no significant difference in the extent of tumor resection between the two groups. Having made a full transition to endoscopic transsphenoidal surgery more than a decade ago, we feel that our increased experience with this technique allowed us to displace the bulging folds of arachnoid using cottonoids to remove seemingly inaccessible tumor. This might have confounded the impact of a lumbar subarachnoid drain on the extent of resection. In addition, in the setting of elevated intracranial pressure, tumor is often forced down into the sella, which may also account for why there was no difference in the extent of resection between the two groups.
Strengths and limitations of this study
Despite its prospective design, our study is limited by its small sample size and by the fact that the surgeon was not blinded to the intervention. Nevertheless, this is the first randomized trial to evaluate the efficacy of lumbar subarachnoid drainage in reducing the incidence of intraoperative CSF leaks following an endoscopic transsphenoidal approach to pituitary adenomas. Moreover, extent of resection was determined in nonfunctional and large functional adenomas by volumetric analysis on MRI as opposed to surgeon's intraoperative impression, which is often inaccurate. As patients were recruited over a relatively short time frame, it is also unlikely that the surgeon experience would have impacted our results.
Controlled intraoperative drainage of CSF via an LSAD significantly reduces the incidence of CSF leaks during endoscopic transsphenoidal surgery for pituitary adenomas, thereby eliminating subsequent morbidity associated with this complication.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
Financial support and sponsorship
The Institutional Research Board of the Christian Medical College, Vellore provided financial support in the form of funding the equipment used in this study (Grant No. 8638). The sponsor had no role in the design or conduct of this research.
Conflicts of interest
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or nonfinancial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.