2007 Número: 2

Original. THE VALUE OF INTRAOPERATIVE MONITORING OF INTACT-PTH IN SURGERY FOR RENAL HYPERPARATHYROIDISM ECHENIQUE-ELIZONDO, Miguel *, MD, PhD, FACS DÍAZ - AGUIRREGOITIA, Francisco Javier ** MD, PhD AMONDARAIN, José Antonio *** MD VIDAUR, Fernando****, MD Institutional Affiliations: (*) Department of Surgery. San Sebastián. Gipuzkoa. Basque Country University. Spain (**) Department of Surgery. Basque Country University. Department of Surgery. Bilbao. Spain. (***) Department of Surgery. Donostia Hospital. San Sebastian. Gipuzkoa. Spain (****) Department of Nephrology. Donostia Hospital. San Sebastián. Gipuzkoa. Spain

Correspondence ECHENIQUE ELIZONDO, Miguel MD, FACS Basque Country University. School of Medicine P. Dr. Beguiristain, 105 20014 San Sebastian. Spain Email: gepecelm@sc.ehu.es Phone +34-943017319 Fax +34-943017330 ABSTRACT Background: In the setting of total parathyroidectomy and autotransplantation surgery (TPTxAS) treatment for secondary hyperparathyroidism (SHPT) we evaluated if intraoperative parathyroid hormone (iPTH) monitoring is an useful tool as a reference for total parathyroid removal. Design: Prospective open single value measurement efficacy study of one intraoperative (i.o.) diagnostic monitoring method (iPTH ) on a cohort of surgical patients. Patients: All patients (n=35) undergoing TP&SCTx at the Department of Surgery. Donostia Hospital from January 2002 to Decdmber 2006. Main outcome measures: Serum levels of iPTH during surgery and prediction time of the of descent of PTH levels (measured in the clinic, at admission day and intra-operatively during induction of anesthesia, and every 5 &10 minutes after removal of adenoma and 24 hours thereafter) were analyzed. Results: iPTH levels dropped clearly at ten minutes in all 35 patients and were non-measurable at 24 hours. iPTH decreased from pathological (1302.24 + 424.9 pg/mL.) to a half (50%) values at the third intra-operative determination - minute 10 - (614.8+/-196.62) and was undetectable at 24 hours. Conc lusions: Intraoperative measurement of iPTH is useful in the prediction complete removal of all parathyroid tissue prior autotransplantation thus avoiding persistence because of incomplete surgery INTRODUCTION Several techniques are employed currently in the management of secondary hyperparathyroidism following re nal failure (SHP) since the proposals of Wells (1) : Subtotal Parathyroidectomy. (STPT) (2), Total Parathyroidectomy. (TPT )(3), TPT with cervical auto-transplantation, TPT with muscular antebrachial auto- transplantation (4,5), TPT with subcutaneous auto-transplantation : ante-brachial (6), abdominal (7) or prester nal (8,9,10) and TPT without transplantation advocated by some Authors for dialysis patients non candidates for renal transplantation (3,11,12,13,14). Intraoperative determinations of parathyroid hormone (iPTH) in order to evaluate the efficacy of surgery to correct increased levels of PTH in primary hyperparathyroidism (PHPT) is a well established procedure ( 15-20) with impact on minimally invasive and oriented for single adenoma (18), geriatric patients (19) and also was accepted as an ambulatory procedure in selected cases (20).One of the accepted criteria for success is a decrease of at least 50% of pre-operative iPTH values at the minute 10 after gland removal. Recently new approaches on the validation methods of the descent have been reported (21) Purpose of the work In the setting of total parathyroidectomy and autotransplantation surgery (PTxAS) for secondary hyperparathyroidism (SHP) we wanted to study if intraoperative parathormone (iPTH) monitoring is effective in demonstrating complete parathyroid glands removal, a method commonly considered as the new standard in order to evaluate the efficacy of surgical procedures for treating renal hyperparathyroidism and establish an adequate timing to avoid unnecessary determinations. The final purpose of TPTxAS in SHPT is to localize and remove all the pathological glands decreasing therefore the levels of PTH to undetectable levels so grafted gland can resume the whole role on PTH secretion. PATIENTS AND METHODS Design Prospective single value measurement efficacy study of one intraoperative diagnostic monitoring method (iPTH) on a cohort of surgical patients. Setting University referral center with an Endocrine Surgical Unit and specialized Endocrine Biochemistry Unit. Patients From January 2002 to December 2007 Thirty-five (19 females and 16 males, age 52.7 + 7.9 mean±sd years) operated on for renal hyperparathyroidism underwent total parathyroidectomy and subcutaneous presternal autologous autotransplantation for RHP at the Department of General Surgery and Department of Nephrology. Donostia Hospital. San Sebastián. Gipuzkoa. Spain. Laboratory criteria for secondary hyperparathyroidism in dication for surgery was the existence of severe clinical symptoms with an elevated iPTH > 500pg/mL. Associ ated clinical symptoms included: pruritus: 11 patients, bone pain: 6, calcyphylaxis: 2, tumoral calcinosis:1. Surgery was performed in all patients when prophylactic treatment with calcium and cholecalciferol supplements failed because of spontaneous or induced hypercalcemia and a high blood phosphorus level. Patients underwent the excision of all visible parathyroid glands and the subcutaneous implantation of autologous parathyroid tissue in front of the middle third of the sternum. Glands removed during the procedure were confirmed by microscopic examination of all resected specimens. Parathyroid glands showing macroscopic diffuse hyperplasia were used for grafting. Gland presenting grossly nodular appearance were excluded. All patients were included in a prospective control approved by the Ethics Committee of the Hospital and signed an ad hoc consent for the procedure. Methods involved in the study did not increase the morbidity or the surgical time of the procedure when possible. Preoperative localization and demonstration of enlarged parathyroid glands In all cases neck ultrasound examination was performed to demonstrate parathyroid gland enlargement and complemented by dye enhanced CT-scan - 11 cases – and Tc99 sestamibi in 19 cases – with not a fixed protocol. US demonstrated gland enlargement in all cases. Surgical procedure All procedures were done by the same surgical team. Patients were admitted to the Hospital on the same or the day before of operation. Surgery was done under general anesthesia and oro-tracheal intubation. A Kocher’s incision 8 to 10 cm long was made over the anterior aspect of the neck 2 cmts above the sternal notch. All four glands were removed along with the thymus in all patients except in two were three glands were encountered and the fourth was localized on the removed thymus during pathology examination Three and one half glands were submitted to the Department of Pathology, as required by the Pathology Commission of the Hospital, for a frozen section confirmation of parathyroid tissue and afterwards cryo-preserved for eventual further use. As soon as results were available surgical team was notified. 20 fragments -1mm3 - each of parathyroid tissue taken for the one most likely showing diffuse hyperplasia were obtained from the preserved half gland - Images 1 & 2 – and implanted in the subcutaneous tissue in front of the mid sternum. Aliquots All aliquots were taken from a peripheral vein placed in the other extremity to the one used for anesthetic iv. management. Nine aliquots were taken from each patient and recorded following a protocol: the first at hospital admission, the second during anesthesia induction and at cut time (minute 0) and 6 determinations every five minutes after removal of all glands (5,10,15,20, at 30 minutes and at 24 hours). Intraoperative Assays iPTH determination was done using a chemoluminiscent immunometric technique. After the incubation of two antibodies against PTH, one of them linked to a ball of polystyrene molecule recognizes and reacts with the corresponding fragment of the segment 44-84 aminoacids. The other antibody is marked with phosphatase alkaline and recognizes the fragment 1-34 in order to make a photometric assay with the immuno-analyzer Immulite-turbo (DPC-Dipesa©) (19,20). The mean life of iPTH is about 3-5 minutes (15, 27, 28) and a decrease of 50% of PTH values at minute 10 after adenoma removal is related to successful surgical treatment in 97.7% in cases for primary hyperparathyroidism as known (29,30). Costs The cost of each determination in our Institution as a Reference Hospital with Endocrine Surgery Unit is of $5.5, what results in a total cost of $44 for each patient, for this study. Data was obtained on regular personnel working hours and as a non-regular procedure. Main outcome measures 1- Kinetic levels iPTH (measured at admission, and intraoperatively during induction of anesthesia or at cut time, and every 5 & 10 & 15 & 20 & 30 minutes after removal of all parathyroid tisue and the thymus). 2- The value of the method for success of surgery confirmation. Statistical analysis All results are expressed as mean ± standard deviation. Values of each method were determined in every time interval and the kinetic levels are therefore time dependent. RESULTS Surgical procedures The study group included 35 patients and PTH levels were successfully corrected in all of them. Total parathyroidectomy and thymectomy was performed in all patients followed by presternal subcutaneous transplantation. Mean time for surgery was 47.46 (±25.3) minutes, and the patient was in the operative field an average of 79.89 minutes (± 28.3) minutes. iPTH levels Mean iPTH showed a decrease from pathological (1302.24 + 424.9 pg/mL.) to a half at 10 minutes (614.8+/-196.62).and undetectable values at 24 hours. (Figures 1 & 2). Pathological findings Intraoperative pathology findings confirmed that parathyroid glands were removed successfully in 25 out of 25 cases. Definitive pathological diagnosis was made an average of 20.56 ± 10.3 minutes after surgical removal. Mean weight of the parathyroid tissue analyzed was of 786.48 ± 554.2 mg. In two cases a gland was found on removed thymus. DISCUSSION Persistence and recurrence of hyperparathyroidism after surgery for renal hyperparathyroidism is a frequent problem encountered by experienced surgeons dealing with this disease. Whether total pa rathyroidectomy without transplantation or total parathyroidectomy with auto-grafting is done, all para- thyroid glands must be exposed and removed. The exact number of existing glands further compli- cates the problem as known (27). Also, ectopic glands may exist in up to 5% of patients thus leading to persistence of the disease despite correct total parathyroidectomy is presumably performed. The most common surgical procedures used currently to treat renal hyperparathyroidism are subtotal parathyroidectomy and total parathyroidectomy with intramuscular implantation of parathyroid tissue (28). A small amount of abnormal parathyroid tissue is left in the patient with both techniques (29). As chronic renal failure persists after the operation, this glandular tissue is continually stimulated, and hyperparathyroidism may recur (30). Some researchers presently advocate total parathyroidectomy with out grafting , thus avoiding these recurrences in patients non-candidates for renal transplantation (3). They state that the absence of PTH has no significant clinical consequence on bone of patients who undergo hemodialysis and who are treated with calcium and cholecalciferol supplements. These conclusions are, however, questioned by other investigators (51). The ideal blood concentration of intact PTH is not known for uremic subjects, but the levels advocated by different researchers varied from 75 to 175 pg/mL (9). As some secretion of PTH seems necessary, we elected to continue our program of autotransplantation of endocrine tissue, but instead of placing the parathyroid pieces into a muscle where their later resection if recurrence occurs can be difficult, we Implanted the grafts subcutaneously in front of the lower third of the sternum where they can be easy located and excised under local anesthesia if recurrence exists as reported (9). Previous excision of all parathyroid tissue is essential to evaluate correctly the function of these grafts. In the present study, all patients underwent the resection of 4 parathyroid glands except the two cases were the fourth gland was encountered in the removes thymus. Reviews on the subject (28) including large number of patients report rates of late hypercalcemia ranging from 5.8% to 6.6% after subtotal parathyroiddectomy and from 6.6% to 10.7% after total parathyroidectomy and intramuscular autotransplantation. Other studies found late reoperation rates of 6% to 8% after subtotal parathyroidectomy and from 5% to 15% after total parathyroidectomy and intramuscular auto transplantation. As an average it can be stated that after 5 years the parathyroid grafts had been ex cised in 30% of patients who underwent hemodialysis and treated by total parathyroidectomy and in tramuscular auto-transplantation. Indeed, most of the series included patients in whom fewer than 4 glands had been discovered during cervical exploration. In a prospective, randomized, clinical trial, Rothmund et al (28) compared 20 cases of subtotal parathy- roidectomy with 20 cases of total parathyroidectomy and intra-muscular auto-transplantation followed up for a mean duration of more than 40 months. Hypercalcemia was less frequent and no patient underwent another operation after the latter procedure. The quick intact PTH assay is not used frequently during surgery in patients with secondary hyperpara thyroidism; however, published results (32) suggest that a quick whole PTH assay may be a more useful adjunct to parathyroidectomy in both secondary HPT and primary HPT (33). Another question deals with the number of determinations to perform . A drop in PTH levels to “normal” values is delayed until 30 minutes after total parathyroidectomy; however, a rapid PTH assay 10 min- utes after removal of the last parathyroid gland seems as accurate as an assay performed at 30 minutes thereafter(34). Intraoperative PTH monitoring demonstrates relevant decreases in rapid PTH levels after total parathyroid removal similar to those previously reported in patients with primary hyperparathyroidism. (35). Our results confirm this findings and encourage the use of iPTH as an assessment of complete parathyroid removal in secondary renal hyperparathyroidism. 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Depósito Legal BI-8989-909
ISSN 1138-252X

Referencia: Miguel Echenique