POLSKI 2013, 85, 10, Paweł Mroczkowski 1

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1 POLSKI PRZEGLĄD CHIRURGICZNY 2013, 85, 10, /pjs Comparison of outcome between older and younger patients following surgery for primary hyperparathyroidism Olof Jannasch 1, Christian Voigt 2, Kirsten Reschke 3, Hans Lippert 1, Paweł Mroczkowski 1 Department of General, Abdominal and Vascular Surgery, University Hospital, Magdeburg, Germany 1 Vitos Orthopaedic Hospital Kassel, Kassel, Germany 2 Department of Nephrology and Hypertension, Diabetes and Endocrinology, University Hospital, Magdeburg, Germany 3 The aim of the study was to compare preoperative findings, serum levels of calcium and parathormone (PTH) and outcome of patients undergoing surgery for primary hyperparathyroidism (phpt) aged over 70 years with younger patients. Material and methods. Between January 1, 1996 and September 30, patients underwent surgery for phpt. Patient data were collected from chart reviews and an electronically stored database. Groups were defined as patients aged 70 years or older and patients younger than 70 years. Outcome comparison included operation time, tumor size, pre- and postoperative serum levels of calcium and PTH and length of stay in hospital. Complications were defined as clinical and laboratory signs of hypocalcemia, persistent elevated serum calcium, temporary or persistent recurrent laryngeal nerve paralysis, bleeding with need for reoperation, surgical site infection or need of tracheotomy. Results. Parathyroidectomy alone was performed in 39.2% of patients. In 60.8% partial or total thyroidectomy was conducted simultaneously. More older patients had history of stroke and/or suffered from diabetes. Preoperative serum calcium and PTH did not differ between groups, but older patients displayed higher postoperative serum calcium (p=0.01). No significant differences between the two groups were observed regarding duration of surgery, surgical success rates, postoperative complications and hospitalization time. Conclusions. Even though older patients had more risk factors, our data suggest that there was no difference in surgical management and outcome. Decision for surgical management of phpt should be done regardless of age. Key words: primary hyperparathyroidism, parathormone, parathyroidectomy, elderly, postoperative complications Surgery for phpt has changed during the last decades. One reason is improvement of preoperative localization diagnostics. Use of high-resolution or contrast-enhanced ultrasound, sestamibi scans, single photon emission computed tomography (SPECT), magnetic resonance tomography and super-selective venous blood sampling allow a correct preoperative assignment to the side of interest in more than 95% of patients (1, 2, 3). Therefore standard bilateral neck exploration has been replaced by unilateral approach or minimally invasive parathyreoidectomy. This has been supported by introduction of intraoperative quick PTH measurement (4), allowing prompt verification of biochemical cure. Reduction of surgical procedure is of importance in relation to duration of operation and risk of postoperative complications (5). PHPT most often occurs in patients older than 55 years. Prevalence of phpt was found to be 7 times higher in women aged years compared to the general population (6). Due to population development the percentage of

2 Comparison of outcome between older and younger patients following surgery for primary hyperparathyroidism599 older patients is continuously increasing. Therefore, surgery in the elderly will be a main focus of future surgical activity. But age has been detected as an independent risk factor for surgical complications and nosocomial infections (7, 8). Therefore decision for surgery and risk assessment in the elderly should be done carefully. This study aimed to compare clinical characteristics, surgical course and outcome between patients undergoing surgery for phpt aged more than 70 years and younger patients. MATERIAL AND METHODS In this study all patients of the Department of General, Abdominal and Vascular Surgery, University Hospital Magdeburg, undergoing surgery from January 1, 1996 to September 30, 2011 for phpt were included. Surgical options comprised parathyroidectomy and combination of parathyroidectomy and partial or total thyroidectomy. Diagnosis was based on finding of hypercalcemia (calcium > 2.55 mmol/l) and elevated PTH (PTH > 55 pg/ml). Two patients were excluded. One presenting with hypercalcemic hypocalcuria, the other with normocalcemic hyperparathyroidism. Patients were assigned to groups according to age at admission to hospital. Younger patients were defined being up to 69 years of age, Older patients were 70 years or older. Data were recorded in a structured data entry form using stored patient charts and the electronic information system of the University hospital Magdeburg. Demographic characteristics of patients included age, gender and comorbidities (history of stroke, hyperlipoproteinemia, cardiac diseases heart failure, coronary disease and dilated cardiomyopathy, hypertension, diabetes mellitus, chronic renal failure with need of dialysis, multiple endocrine neoplasia, diffuse or nodular goiter and thyroid carcinoma). Surgical outcome was defined by duration of operation, postoperative length of stay in hospital, pre- and postoperative serum calcium and parathormone levels. Complications were defined as clinical (paresthesia or tetany) and laboratory signs of hypocalcemia (< 2.15 mmol/l), persistent elevated serum calcium (> 2.55 mmol/l), temporary or persistent recurrent laryngeal nerve (RLN) paralysis (verified as missing or reduced mobility of vocal cord in laryngoscopy), bleeding with need for reoperation, surgical site infection or need of tracheotomy. For intraoperative success control quick histological evaluation of frozen section was used. Examination during operation, as well as final assessment, were performed in the Institute for Pathology of the University hospital Magdeburg. In some cases, following meticulous preoperative localization diagnostics, estimation of responsible endocrine surgeon was considered sufficient. In August 1998 intraoperative parathormone monitoring (iopth) using Quick-Intraoperative Intact PTH Assay (Nichols-Institute Diagnostics, San Clemente, CA, USA) was introduced. Peripheral venous blood samples were taken at least prior to surgery and 10 minutes after removal of altered parathyroid gland. Success was defined as decline of more than 50% of parathormone level and concentration being within normal range. Analyses of iopth were carried out in the Institute of Clinical Chemistry and Pathobiochemistry of the University hospital Magdeburg. Results were delivered via telephone call to operating surgeon. Statistical analyses were performed using Microsoft Office Excel 2003 (Microsoft Corporation, Redmond, WA, USA). Descriptive statistics were calculated as frequency with percentage (patient gender, operations, comorbidities, postoperative outcome) and mean with standard deviation (age, laboratory findings, operation duration, length of stay in hospital). Dependence between categorical variables of patient groups was evaluated using Fisher s exact test (patient gender, proportion of performed operations, comorbidities, postoperative outcome). For normally distributed data two sample t-test for two independent samples was used (age, laboratory findings, operation duration, length of stay in hospital). Statistical significance was defined as a two-tailed p value of RESULTS From January 1, 1996 to September 30, patients were operated for phpt. Of these, 6 patients had history of former thyroid surgery. 2 patients were operated twice for phpt after

3 600 O. Jannasch et al. missing success in initial operation. For both intraoperative frozen section result of adenoma was finally corrected to hyperplasia. Because of persistent elevation of serum parathormone reoperation was performed. Mean age of all patients was 64 years (± 12 years). 81.2% of patients were older than 55 years, 38.2% older than 70 years. The age difference between the two groups was significant (p<0.0001). Distribution of age of operated patients is given in fig. 1. Distribution of gender and of operations performed did not differ statistically between groups. Comparison of comorbidities yielded a higher percentage of patients with history of stroke (p=0.007) and diabetes mellitus (p=0.0005) in the elderly. Details are given in tab. 1. There were no statistical differences in preoperative serum calcium and parathormone levels between both groups. Mean operation duration was 107 (± 51) minutes. Combined parathyroid-thyroid resections 120 (± 49) minutes were longer than sole parathyroidectomies 88 (± 49) minutes. Group differences were not significant. Postoperatively, serum calcium returned to normal limits in both groups (younger patients 2.28 mmol/l, SD ± 0.20; older patients 2.35 mmol/l, SD ± Postoperative serum calcium was higher in the older patients (all operations p=0.01, sole parathyroidectomy p=0.02). Mean postoperative parathormone levels also returned to normal and did not differ between groups. The majority of patients had no major complications (> 94%). Frequency of complications and length of stay in hospital did not differ significantly between groups. Frequency of RLN paralysis was 10 for 333 nerves at risk (3%) including one permanent paralysis (0%). Details are given in tab. 2. DISCUSSION This study presents an unselected cohort of patients with phpt treated either by parathyroidectomy or combined resection of a goiter and parathyroidectomy. Most patients were female (73.4%). This was more pronounced in the elderly (81.4%) with a trend towards significance (p=0.06). A large study of 687 patients with parathyroidectomies demonstrated similar results about three fourth were female. This study also displayed a trend of a higher percentage of female patients in the elderly (78%, p=0.07) (9). Older patients showed more comorbidities. A History of stroke might be of importance. Persisting residua in form of impaired mobility or limited compliance might effect ASA score and risk for surgical site infections, thrombosis and pneumonia (10). Diabetes mellitus is an independent risk factor for surgical site infections if blood sugar levels are elevat- Mean age 64 years < 70 years (n = 115) 70 years (n = 71) frequency (n) age (years) Fig. 1. Age distribution of patients operated for primary hyperparathyroidism

4 Comparison of outcome between older and younger patients following surgery for primary hyperparathyroidism601 Patients (n) Female Male Table 1. Demographic characteristics, comorbidities and operations Total <70 years 70 years p (73,4%) 78 (68,4%) 57 (81,4%) p=0,06 ** 49 (26,6%) 36 (31,6%) 13 (18,6%) Age (years) (n=184) 63,6 (± 12,1) 56,8 (±10,4) 74,6 (± 3,7) p<0,0001 * Comorbidities (n=184): history of stroke hyperlipoproteinaemia cardiac disease hypertension diabetes mellitus chronic renal failure (renal replacement therapy) MEN diffuse goiter nodular goiter thyroid carcinoma 21 (11,4%) 81 (44%) 31 (16,8%) 97 (52,7%) 42 (22,8%) 1 (0,5%) 3 (1,6%) 23 (12,5%) 89 (48,4%) 10 (5,4%) 7 (6,1%) 47 (41,2%) 16 (14%) 55 (48,2%) 16 (14%) 1 (0,9%) 2 (1,8%) 17 (14,9%) 50 (43,9%) 6 (5,3%) 14 (20,0%) 34 (48,6%) 15 (21,4%) 42 (60%) 26 (37,1%) (8,6%) 39 (55,7%) 4 (5,7%) p=0,007 ** p=0,36 ** p=0,23 ** p=0,13 ** p=0,0005 ** p=1 ** p=0,53 ** p=0,25 ** p=0,13 ** p=1 ** Operations (n) sole parathyroidectomy combined operation (39,2%) 113 (60,8%) (40,9%) 68 (59,1%) (36,6%) 45 (63,4%) p=0,64 ** Values given as mean with standard deviation or n (%); * Two-sample-T-test, ** Fisher s exact test; MEN multiple endocrine neoplasia Table 2. Serum calcium and parathormone, postoperative outcome Total <70 years 70 years (n=186) (n=115) (n=71) p Preoperative calcium (mmol/l) 2,87 (± 0,32) 2,87 (± 0,26) 2,89 (± 0,4) p=0,69 * Preoperative PTH (pg/ml) 336 (± 489) 370,1 (± 581,7) 288,7 (± 325,1) p=0,27 * Operation duration (min) all operations sole parathyroidectomy combined operation 107 (± 51) 88 (± 49) 120 (± 49) 107 (± 51) 93 (± 55) 116 (± 46) 108 (± 52) 77 (± 32) 125 (± 54) p=0,89 * p=0,12 * p= 0,34 * Tumor size (cm) 1,8 (± 1,2) 1,7 (± 0,9) 2,0 (± 1,5) p=0,28 * Postop. calcium (mmol/l) all operations sole parathyroidectomy combined operation 2,30 (± 0,19) 2,35 (± 0,18) 2,27 (± 0,19) 2,28 (± 0,20) 2,32 (± 0,17) 2,25 (± 0,21) 2,35 (± 0,17) 2,41 (±0,17) 2,31 (± 0,16) p=0,01 * p=0,02 * p=0,08 * Postop. PTH (pg/ml) 30 (± 42) 29 (± 44) 33 (± 39) p=0,55 * Postop. elevated PTH (>65 pg/ml) 13 (7,9%) 9 (8,8%) 4 (6,5%) p=0,77 ** Postop. diminished PTH (<10 pg/ml) 47 (28,7%) 31 (30,4%) 16 (25,8%) p=0,60 ** Persistent hypercalcemia 16 (8,6%) 10 (8,7%) 6 (8,4%) p=1 ** Laboratory hypocalcemia 35 (18,8%) 26 (22,6%) 9 (12,7%) p=0,12 ** Clinical hypocalcemia 1 (0,5%) 1 (0,9%) 0 p=1 ** RLN paralysis (9x transient, 1x permanent) 10 (3%) n=333 nerves at risk 7 (3,4%) n=205 nerves at risk 3 (2,34%) n=128 nerves at risk p=0,75 ** Krwawienie / bleeding Surgical site infection 2 (1,1%) 2 (1,8%) 0 p= 0,53 ** Tracheotomy 1 1 (0,9%) 0 p=1 ** In-hospital mortality Postop. LOS in hospital 5,3 (± 4) 5,4 (± 4,9) 5,2 (± 1,9) p=0,83 * Values are given as mean with standard deviation or n (%), * Two-sample-t-test, ** Fisher s exact test; PTH parathormone, postop. postoperative, RLN recurrent laryngeal nerve, LOS length of stay ed (11). In this study differences in age, history of stroke and diabetes mellitus had no statistical effect on operation duration, length of stay in hospital or frequency of postoperative complications. This is consistent with other published data (12, 13).

5 602 O. Jannasch et al. Prevalence of phpt is higher in patients with thyroid disease (14). Therefore parathyroidectomy will often be combined with partial or total thyroidectomy. This is consistent with our findings. About 60% of patients received combined operation for nodular goiter or carcinoma and phpt. Frequency of thyroid carcinoma was high (5.4%), but this might be a selection bias of a university hospital. A literature review revealed a prevalence of approximately 3% of nonmedullary thyroid cancer in patients operated on for primary hyperparathyroidism (15). Operation duration for sole parathyroidectomy was 77 minutes in the elderly and 93 minutes in the younger patients. Other studies report minutes (9, 13). It is departmental practice that all operations for hyperparathyroidism are performed or assisted by a specialist endocrine surgeon. Having responsibility as a teaching hospital about one third of operations were assisted to younger surgeons without specialist status. These operations lasted approximately minutes longer. Postoperatively older patients displayed higher serum calcium levels. Subgroup analysis showed a difference after parathyroidectomy (p=0.02) but not after combined surgery (p=0.08). This phenomenon is not due to persisting hypercalcemia, which was 8.5% in both groups, but to postoperative hypocalcemia (22.6% in the younger patients and 13.7% in the elderly). In more than 90% serum calcium and parathormone were not elevated postoperatively. But laboratory testing displayed diminished serum calcium in 18.8% and parathormone in 28.7%. Only one patient reported clinical signs of hypocalcemia. Frequency of RLN paralysis was 3.0% (2.7% transient, 0.3% permanent). This rate has to be compared to data including parathyroidectomy, thyroidectomy and redo surgery. A prospective study of 100 patients yielded an incidence by nerve of 9.6% for transient RLN paralysis and 2% for permanent (unilateral) RLN paralysis (16). A large Quality assurance study including 7617 patients, reports a rate of 3.9% of transient and 1.1% of permanent RLN paralysis for benign goiter (17). The most serious complication was a bilateral RLN paralysis in a 60 year old patient leading to tracheotomy. In this patient unilateral RLN paralysis was present preoperatively. Weaning was prolonged because of pneumonia. This patient had the longest stay in hospital (54 days). To recommend surgery to patients means to balance risk of operation against advantages gained. Patients older than 70 years suffering from phpt primarily present with bone disease, mental impairment and fatigue (12). They often present in a more advanced disease, manifested by higher preoperative parathyroid hormone levels (12). Due to routine laboratory testing now more patients present with asymptomatic phpt. In these patients established indications for surgery should be applied (18). This includes serum calcium level 0.06mmol/l above upper limit of normal, reduction of creatinine clearance and bone mineral density T score below Furthermore, some authors doubt that these patients are asymptomatic at all (18). In particular diagnosis of cognitive and neurological symptoms might require thoroughly neurophysiological testing (19). Surgery is considered to be the only curative treatment of phpt (20). Focused surgical technique with preference for minimal invasive parathyroidectomy would be optimal to reduce surgical trauma. Barczynski et al. (21) and Udelsman et al. (22) reported convincing results with short operation times in selected patients. They estimated that approximately 90% of all patients referred with phpt will be appropriate candidates for minimally invasive approach (22). But this only applies for sole parathyroidectomy. In a large study including 6574 patients referred for thyroid surgery only 3.6% were eligible for minimally invasive video-assisted thyroidectomy (23). Preoperative diagnostics for localization of altered parathyroid glands including assessment of size and pathology of the thyroid gland is the base for decision of surgical approach. Advantages of surgery are return to normal of serum and urinary calcium levels. This reduces risk for nephrolithiasis (24). Bone mineral density improves within 3 to 4 years (25) resulting in reduction of risk of subsequent fractures (26). Additionally, 27% of patients without surgery are likely to experience exacerbation of disease (25). Otherwise, in asymptomatic patients without surgery disease progression will be slow (27). Additionally, Young et al. (9) reported older patients being more likely to have cardiac complications. But

6 Comparison of outcome between older and younger patients following surgery for primary hyperparathyroidism603 other studies could not demonstrate differences in postoperative complications (12, 13). CONCLUSIONS Surgery for phpt seems to be effective and safe for patients regardless of age. Higher frequency of comorbidities in the elderly did not result in higher complication rate or longer length of stay in hospital. In more than 90% of patients serum calcium and parathormone decreased postoperatively. Older patients had higher mean postoperative serum calcium levels, but this was mainly caused by higher rate of postoperative hypocalcemia in the younger patients. Longterm benefits for surgery in phpt are well documented. So, surgery for phpt should be treatment of choice in absence of severe comorbidities. references 1. Vaz A, Griffiths M: Parathyroid imaging and localization using SPECT/CT: initial results. J Nucl Med Technol 2011; 39(3): Agcaoglu O, Aliyev S, Heiden K et al.: A new classification of positive sestamibi and ultrasound scans in parathyroid localization. World J Surg 2012; 36(10): Agha A, Hornung M, Rennert J et al.: Contrast-enhanced ultrasonography for localization of pathologic glands in patients with primary hyperparathyroidism. Surgery 2012; 151(4): Nagar S, Reid D, Czako P et al.: Outcomes analysis of intraoperative adjuncts during minimally invasive parathyroidectomy for primary hyperparathyroidism. Am J Surg 2012; 203(2): Procter LD, Davenport DL, Bernard AC et al.: General surgical operative duration is associated with increased risk-adjusted infectious complication rates and length of hospital stay. J Am Coll Surg 2010; 210(1): Adami S, Marcocci C, Gatti D: Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 2002; 17 Suppl 2: Geubbels EL, Mintjes-de Groot AJ, van den Berg JM et al.: An operating surveillance system of surgical site infections in the Netherlands. Results of the PREZIES national surveillance network. Infect Control Hosp Epidemiol 2000; 21(5): Grogan RH, Mitmaker EJ, Hwang J et al.: A population-based prospective cohort study of complications after thyroidectomy in the elderly. J Clin Endocrinol Metab 2012; 97(5): Young VN, Osborne KM, Fleming MM et al.: Parathyroidectomy in the elderly population: does age really matter? Laryngoscope 2010; 120(2): Brandt C, Hansen S, Sohr D et al.: Finding a method for optimizing risk adjustment when comparing surgical-site infection rates. Infect Control Hosp Epidemiol 2004; 25(4): McConnell YJ, Johnson PM, Porter GA: Surgical site infections following colorectal surgery in patients with diabetes: association with postoperative hyperglycemia. J Gastrointest Surg 2009; 13(3): Egan KR, Adler JT, Olson JE et al.: Parathyroidectomy for primary hyperparathyroidism in octogenarians and nonagenarians: a risk-benefit analysis. J Surg Res 2007; 140(2): Bachar G, Gilat H, Mizrachi A et al.: Comparison of perioperative management and outcome of parathyroidectomy between older and younger patients. Head Neck 2008; 30(11): Wagner B, Begic-Karup S, Raber W et al.: Prevalence of primary hyperparathyroidism in patients with thyroid diseases, newly diagnosed by screening of serum calcium. Exp Clin Endocrinol Diabetes 1999; 107(7): Leitha T, Staudenherz A: Concomitant hyperparathyroidism and nonmedullary thyroid cancer, with a review of the literature. Clin Nucl Med 2003; 28(2): Périé S, Aït-Mansour A, Devos M et al.: Value of recurrent laryngeal nerve monitoring in the operative strategy during total thyroidectomy and parathyroidectomy. Eur Ann Otorhinolaryngol Head Neck Dis 2013; 130(3): Thomusch O, Sekulla C, Ukkat J et al.: Quality assurance study of benign and malignant goiter. Prospective multicenter data collection regarding 7,617 patients. Zentralbl Chir 2001; 126(9): Zarebczan B, Chen H: Influence of surgical volume on operative failures for hyperparathyroidism. Adv Surg 2011; 45: Babińska D, Barczyński M, Stefaniak T et al.: Evaluation of selected cognitive functions before and after surgery for primary hyperparathyroidism. Langenbecks Arch Surg 2012; 397(5): Chen H: Surgery for primary hyperparathyroidism: what is the best approach? Ann Surg 2002; 236(5): Barczyński M, Cichon S, Konturek A et al.: Comparison of two techniques of minimally invasive parathyreoidectomy: Video-assisted (MIVAP) and open (OMIP). Pol Przegl Chir 2007; 79:

7 604 O. Jannasch et al. 22. Udelsman R, Donovan PI, Sokoll LJ: One hundred consecutive minimally invasive parathyroid explorations. Ann Surg 2000; 232(3): Barczyński M, Konturek A, Stopa M et al.: Minimally invasive video-assisted thyroidectomy: seven-year experience with 240 cases. Wideochir Inne Tech Malo Inwazyjne 2012; 7(3): doi: /wiitm Starup-Linde J, Waldhauer E, Rolighed L et al.: Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables. Eur J Endocrinol 2012; 166(6): Silverberg SJ, Shane E, Jacobs TP et al.: A 10- year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999; 341(17): Vestergaard P, Mollerup CL, Frøkjaer VG et al.: Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism. BMJ 2000; 321(7261): Clarke BL: Epidemiology of primary hyperparathyroidism. J Clin Densitom 2013; 16(1): Received: r. Adress correspondence: Department of General, Abdominal and Vascular Surgery, Otto-von-Guericke-University, Leipziger Strasse 44, D Magdeburg, Niemcy pawel.mroczkowski@med.ovgu.de