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Pediatric thyroidectomy in a high volume thyroid surgery center: Risk factors for postoperative hypocalcemia
Journal of Pediatric Surgery 50 (2015) 1316–1319
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Pediatric thyroidectomy in a high volume thyroid surgery center: Risk factors for postoperative hypocalcemia☆ Yufei Chen a,⁎, Peter T. Masiakos a, Randall D. Gaz a, Richard A. Hodin a, Sareh Parangi a, Gregory W. Randolph a,b, Peter M. Sadow a, Antonia E. Stephen a a b
Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA
a r t i c l e
i n f o
Article history: Received 5 August 2014 Received in revised form 27 October 2014 Accepted 29 October 2014 Key words: Endocrine Thyroidectomy Hypocalcemia Pediatric
a b s t r a c t Introduction: Hypocalcemia is a common complication following thyroid surgery. We seek to report on our experience in pediatric thyroidectomy in a high volume thyroid surgery center and accurately assess the incidence of postoperative hypocalcemia. Materials and methods: A retrospective review of patients aged 18 and younger who underwent thyroid surgery between 1992 and 2013. The primary endpoints were the occurrence of postoperative hypocalcemia as by defined as a nadir calcium b8.0 mg/dL and being discharged on oral calcium supplementation, need for intravenous calcium and the occurrence of permanent hypoparathyroidism. Results: 171 patients who underwent 186 thyroid operations were analyzed. The average age was 15.4 years with 82.3% female. The most common indications for surgery were nodular disease (74.7%) and hyperthyroidism (12.4%). 24 patients (12.9%) experienced postoperative hypocalcemia with 13 (7.0%) requiring intravenous calcium infusion. One patient (0.9%) experienced permanent hypoparathyroidism. Risk factors for postoperative hypocalcemia included total thyroidectomy (OR 7.39, p b 0.01), central and bilateral lateral neck dissection (OR 22.26, p = 0.01), Graves’ disease (OR 3.99, p = 0.02), and malignancy (OR 2.96, p = 0.03). Conclusions: Pediatric patients who undergo total thyroidectomy for underlying malignancy or Graves’ disease and those who have more extensive nodal dissections are at increased risk of developing this postoperative hypocalcemia. These patients may benefit from more vigilant preoperative preparation and postoperative calcium and vitamin D supplementation. © 2015 Elsevier Inc. All rights reserved.
Thyroidectomy in the pediatric population is a less frequently performed procedure than in adults and published reports noting patient volume and postoperative complications are highly variable. Hypocalcemia is the most common postoperative complication following thyroid surgery in children and adults and is often the cause of prolonged hospital stay and significant morbidity. It is caused by transient or permanent hypoparathyroidism owing to either disruption of the blood supply to the parathyroid glands or inadvertent removal of one or more glands. Symptoms of hypocalcemia are predominantly based on increases in neuromuscular excitability and range from perioral and peripheral paresthesias to generalized tetany. The incidence of hypocalcemia varies widely depending on how it is defined in each study. In the adult population, rates ranging from 6% to 30% have often been reported [1–3]. Identified risk factors for postoperative hypocalcemia include total thyroidectomy [2,4], younger
patient age [3], Graves’ disease [5] and incidental parathyroidectomy [2,5]. Temporary hypocalcemia rates in children after thyroid surgery are reported to be between 7% and 52% [6–9]. However, these studies do not consistently define hypocalcemia. Published data indicates higher postoperative morbidity following pediatric thyroidectomy when compared to the adult population [10–12]. This may be compounded by the relative rareness of pediatric thyroid surgery when compared to adults. However, as we move toward referring children who require thyroidectomy to high volume thyroid surgery centers, the literature suggests that complication rates are becoming more comparable with adult series [8]. In this study, we report on our experience with pediatric thyroidectomy from a high volume thyroid surgery center. We aim to accurately assess the incidence of hypocalcemia following pediatric thyroidectomy and analyze risk factors for this postoperative complication.
☆ There are no conflicts of interest of sources of funding to declare from any authors. ⁎ Corresponding author at: GRB-425, 55 Fruit Street, Boston, MA 02114, USA. E-mail addresses: [email protected] (Y. Chen), [email protected] (P.T. Masiakos), [email protected] (R.D. Gaz), [email protected] (R.A. Hodin), [email protected] (S. Parangi), [email protected] (G.W. Randolph), [email protected] (P.M. Sadow), [email protected] (A.E. Stephen).
1. Materials and methods
http://dx.doi.org/10.1016/j.jpedsurg.2014.10.056 0022-3468/© 2015 Elsevier Inc. All rights reserved.
We performed a retrospective analysis of all patients aged 18 or younger who underwent thyroid surgery and had their pathology analyzed at the Massachusetts General Hospital between July 1992 and April 2013. Patients who underwent an indicated parathyroidectomy
Y. Chen et al. / Journal of Pediatric Surgery 50 (2015) 1316–1319
at the time of thyroidectomy were excluded from the study. Patient demographics, indications for surgery, and preoperative work-up were obtained from the medical records. Operative and pathology reports were utilized to determine the extent of surgery and final pathological diagnosis. We defined temporary hypocalcemia as a postoperative nadir calcium value b8.0 mg/dL and treatment with oral calcium supplementation or intravenous calcium during their hospitalization. Patients who were still taking oral calcium supplementation beyond 6 months postoperatively with a serum calcium value b8.0 mg/dL or parathyroid hormone (PTH) level b15 pg/mL were classified as having permanent hypoparathyroidism. Transient recurrent laryngeal nerve (RLN) injury was defined as postoperative hoarseness combined with a laryngoscopic diagnosis of RLN palsy although routine laryngeal examination was not performed. Patients were classified as having permanent RLN injury if these findings persisted beyond 6 months. All patient data was recorded in Microsoft Excel for Windows 2010 and analyzed using SPSS (version 20, IBM SPSS). Continuous values were compared using the Mann–Whitney U test with the chi-square test utilized for categorical variables. Variables with a p-value of b0.20 were entered into a multivariate analysis. A p-value of b 0.05 was considered statistically significant. Ethics approval for this study was obtained through the Partners Human Research Committee.
2. Results A total of 171 patients who underwent 186 thyroid operations were included in the study (Table 1). The mean age at time of operation was 15.4 years (range 2.5–18.9). 82.3% of patients were female. Indications for thyroid surgery were nodular disease (74.7%), hyperthyroidism (12.4%), completion thyroidectomy (8.1%) and multiple endocrine neoplasia (MEN) type 2 prophylaxis (4.8%). A family history of thyroid disease was reported by 75 of 160 patients (46.9%) with a specific history of thyroid malignancy in 19 (11.9%).
Table 1 Comparison of patients who did and did not experience postoperative hypocalcemia. Variable Gender Age Indication
Family hx thyroid disease Family hx thyroid cancer Operation
No hypocalcemia Hypocalcemia p-Value (n = 162) (n = 24) Female ≥14 Nodule Hyperthyroidism MEN2A prophylaxis Completion Yes
Yes
132 (81.5%) 124 (76.5%) 146 (90.1%) 16 (9.9%) 7 (4.3%) 11 (6.8%) 63 (38.9%)
21 (87.5%) 16 (66.7%) 17 (70.8%) 7 (29.2%) 2 (8.3%) 4 (16.7%) 12 (50%)
16 (9.9%)
3 (12.5%)
Hemithyroidectomy 79 (48.8%) Total thyroidectomy 65 (40.1%) Nodulectomy 7 (4.3%) Completion thyroid 11 (6.8%) LN dissection Yes 29 (17.9%) LN dissection No 133 (82.1%) extent Yes, central 18 (11.1%) Yes, unilateral 10 (6.2%) Yes, bilateral 1 (0.6%) Parathyroid No 133 (82.1%) Yes, reimplant 11 (6.8%) Yes, inadvertent 18 (11.1%) Pathology Benign 93 (57.4%) Graves 15 (9.3%) Hashimoto 8 (4.9%) Malignant 46 (28.4%) Median length Days (range) 1 (0–3) of stay
0 20 (83.3%) 0 4 (16.7%) 10 (41.7%) 14 (58.3%) 5 (20.1%) 2 (8.3%) 3 (12.5%) 17 (70.8%) 2 (8.3%) 5 (20.8%) 4 (16.7%) 7 (29.2%) 0 13 (54.2%) 2 (0–8)
0.69 0.42 b0.01
0.58
0.98
b0.01
0.01 b0.01
0.37
b0.01
b0.01
1317
Thyroid ultrasound was the most commonly used imaging modality performed prior to initial surgery and was utilized in 138 patients (80.7%). Thyroid cytology via FNA was obtained in 98 patients (57.3%) and scintigraphy in 42 (24.6%). Genetic testing was positive in 10 patients (5.9%), resulting in the preoperative diagnosis of MEN type 2 in 8 patients, Cowden syndrome in 1 patient, and familial adenomatous polyposis in another. The most common initial operation performed was a total thyroidectomy in 85 patients (45.7%). 15 patients (8.1%) underwent completion thyroidectomy following previous thyroid resection. A hemithyroidectomy was performed in 79 patients (42.5%) and a local excision or nodulectomy in 7 (3.8%). In addition to their thyroid resection, 39 patients (21.0%) also underwent a lymph node dissection. The extent of the neck dissection was limited to the central neck (level VI) alone in 23 patients (12.4%), while 12 patients (6.5%) underwent a central plus unilateral (levels II–IV) neck dissection and 4 patients (2.2%) underwent central plus bilateral neck dissection. Average lymph node yield for central neck dissection alone was 9, while it was 27 and 59 for dissection of the unilateral and bilateral lateral neck respectively. More than 85% of the operations were performed by adult thyroid surgeons. The final pathology was benign in 127 cases (68.3%) with follicular adenoma (31.4%) and Graves’ disease (11.9%) being the most common. The remaining 59 specimens (31.7%) were malignant, with 51 cases (27.4%) of papillary thyroid cancer, 5 (2.7%) of medullary thyroid cancer and 3 (1.6%) of follicular thyroid cancer. Of the patients with proven malignancy, 26 (44.1%) had evidence of lymph node metastases. There was evidence of inadvertent parathyroid gland removal in 36 patients (19.4%). 13 of these were autotransplanted back into the patient while the remaining 23 had parathyroid tissue reported in the final pathological specimen but were not reimplanted. Patients who had parathyroid gland resection were more likely to have had central and/or lateral nodal dissection (33% vs 18%, p = 0.04). Average postoperative follow-up was 3 years (range 0–17 years) with 59.1% of patients having N 6 months follow-up. In patients with malignant disease, mean follow-up was 4.6 years with 74.1% of patients having N6 months follow-up. 37 patients (19.9%) received postoperative radioactive iodine ablation therapy. At the time of last follow-up, 6 patients (10.1%) with malignant pathology had developed recurrent locoregional or metastatic disease. Preoperative vitamin D levels were available in 19 patients with a mean 25(OH)D level of 31.6 ng/mL (range 12–85). Five patients had vitamin D deficiency (b20 ng/mL) and six patients had vitamin D insufficiency (21–30 ng/mL) as defined by the Endocrine Society [13]. Two patients with vitamin D deficiency experienced postoperative hypocalcemia and none with vitamin D insufficiency. However, this variable was not included in the univariate analysis given inadequate power. Overall, 24 patients (12.9%) experienced temporary hypocalcemia in the immediate postoperative period with 13 patients (7.0%) requiring intravenous calcium administration. When considering only patients who underwent total or completion thyroidectomy, this rate was 24% and 13% respectively. At 6 months follow-up, only 1 patient (0.9%) had PTH b15 pg/mL and remained on calcium supplementation. This patient did eventually recover parathyroid function and her hypoparathyroidism had resolved by 12 months follow-up. As such, by 12 months months postoperatively, there were no cases of permanent hypoparathyroidism. There were 3 cases (1.6%) of temporary recurrent laryngeal nerve injury, but none was permanent. The overall median length of stay (LOS) was 1 day (range 0–8) following thyroid surgery. Patients who experienced temporary hypocalcemia had a median LOS of 2 days (p b 0.01). On univariate analysis (Table 2), factors associated with an increased risk of postoperative hypocalcemia included total thyroidectomy (odds ratio (OR) 7.39, p b 0.01), need for lymph node dissection particularly combined central and bilateral neck dissection (OR 22.26, p = 0.01), and a final pathological diagnosis of either Graves’ disease (OR 3.99, p = 0.02) or malignancy (OR 2.96, p = 0.03). Younger patients aged b 14
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Y. Chen et al. / Journal of Pediatric Surgery 50 (2015) 1316–1319
Table 2 Univariate logistic regression for risk factors of postoperative hypocalcemia. Variable Age Gender Indication
Family hx thyroid disease Family hx thyroid cancer Operation
LN dissection LN dissection extent
LN examined Parathyroid
Final pathology
b14 Female Nodule Hyperthyroidism MEN2A prophylaxis Completion Yes Yes Hemithyroid Total thyroid Nodulectomy Completion Yes None Central Unilateral Bilateral None Autotransplant Inadvertent Benign Graves Hashimoto Malignant
Odds ratio (95% CI)
p-Value
1.63 (0.56–4.41) 1.59 (0.43–8.84) 1 3.72 (1.13–11.36) 2.00 (0.19–11.47) 2.73 (0.58–10.39) 1.43 (0.53–3.95) 0.98 (0.15–4.60) 1 7.39 (2.33–31.09) 0.69 (0–4.79) 2.73 (0.58–10.39) 3.25 (1.17–8.80) 1 2.10 (0.54–6.81) 1.38 (0.14–7.13) 22.26 (1.70–1214.4) 1.03 (1.00–1.06) 1 1.51 (0.31–7.44) 2.31 (0.75–7.07) 1 3.99 (1.20–12.33) 0.59 (0–4.03) 2.96 (1.13–7.89)
0.42 0.69 0.03 0.65 0.22 0.58 0.98 b0.01 0.75 0.22 0.01 0.31 0.95 0.01 0.07 0.61 0.14 0.02 0.65 0.03
(OR 1.63, p = 0.42), patients who underwent central neck dissection alone (OR 2.10, p = 0.31) or central and unilateral neck dissection (OR 1.38, p = 0.95), parathyroid autotransplantation (OR 1.51, p = 0.61) or inadvertent parathyroid removal (OR 2.31, p = 0.14) were not found to have a statistically significant increase in the rate of postoperative hypocalcemia. On multivariate analysis, central and bilateral lymph node dissection and the presence of Graves’ disease or malignancy remained independent predictors of postoperative hypocalcemia (Table 3). 3. Discussion Pediatric thyroid surgery is a specialized procedure that should ideally be performed at high volume centers. Postoperative hypocalcemia is a well known complication that can lead to patient discomfort, prolonged length of hospital stay, and increased cost. In order to reliably follow trends and assess risk for postoperative hypocalcemia, accurate and consistent definitions need to be developed and followed. We elected to use objective data points that included a combination of serum calcium levels and changes in patient care such as being discharged on oral calcium supplements. Although the majority of pediatric thyroid surgery is in the adolescent population, this objective approach would allow for a uniform assessment of patients in all pediatric age groups. In our study, temporary hypocalcemia occurred only in patients who underwent total or completion thyroidectomy, as expected. This may account for some of the differences in our rates of hypocalcemia compared with other studies. Scholz et al. reported a hypocalcemia rate of 6.9%, but this was in a thyroidectomy population where just 29% Table 3 Multivariate analysis for independent predictors of postoperative hypocalcemia. Variable
Odds ratio (95% CI)
p-Value
OR — total thyroid LN dissection — yes LN — bilateral LN examined Parathyroid — inadvertent Path — graves Path — malignant
10.09 (0.93–109.31) 0.91 (0.20–4.29) 13.5 (1.27–143.64) 1.01 (0.96–1.05) 2.29 (0.65–8.11) 11.78 (3.08–45.13) 5.61 (1.67–18.85)
0.11 0.91 0.03 0.79 0.20 b0.01 0.01
underwent a total thyroidectomy compared to a combined total and completion thyroidectomy rate of 53.8% in our series [8]. There has been a trend toward more complete thyroid surgery, as opposed to a subtotal resection, in benign conditions such as Graves’ disease [6]. In fact, the procedure of a nodulectomy or subtotal thyroidectomy has essentially been abandoned over the last decade. We found a higher rate of postoperative hypocalcemia in our patients with Graves’ disease compared to the rest of the nonmalignant group. This may be attributed to the local inflammation from thyroiditis that makes the parathyroid glands more adherent and surgical dissection more difficult. Other proposed mechanisms include calcitonin release from operative manipulation and postoperative reversal of thyrotoxic osteodystrophy leading to hungry bone syndrome [14,15]. The latter has been described in a child following radioablation therapy for Graves’ disease [16]. Similar findings have also been demonstrated in the adult literature [17,18]. The indications and recommendations surrounding lymph node dissection in patients with malignant thyroid disease have changed dramatically in the last decade and remain controversial. Critics of prophylactic central lymph node dissection comment on the increased operative morbidity. In our study, patients who underwent central lymph node dissection alone did not have increased rates of postoperative hypocalcemia. In patients with established lymph node metastases, resection of all involved lymph nodes is currently standard of care and has been shown to be an important determinant of long term outcome and local recurrence rates and facilitates adjuvant radioactive iodine therapy [19,20]. Our study showed a significantly increased incidence of postoperative hypocalcemia in those patients who underwent bilateral lateral neck dissection with a trend toward a higher rate of hypocalcemia with an increasing number of lymph nodes removed. This may reflect more aggressive local disease requiring more extensive dissection which can compromise integrity of parathyroid gland vascular supply. There are no prior reported rates of incidental parathyroid excision during pediatric thyroidectomy. In our study, 36 patients (19.4%) had inadvertent parathyroid gland excision as noted intraoperatively by the surgeon or on the specimen by the pathologist. 13 of these patients (36.1%) subsequently underwent autotransplantation of the resected parathyroid gland. This compares favorably to several adult series which report an incidence of incidental parathyroid resection as high as 30% [2,4]. Interestingly, inadvertent parathyroid excision with or without autotransplantation did not significantly change rates of postoperative hypocalcemia in our study. Vitamin D deficiency has been hypothesized to contribute to the development of postoperative hypocalcemia although current literature in the adult population has been inconclusive [21–23]. Among children, the incidence of vitamin D deficiency has been increasing over time [24]. Future studies with more routine evaluation of preoperative vitamin D status in the pediatric population are required to establish the relationship between vitamin D deficiency and postoperative hypocalcemia, perhaps identifying higher risk subgroups who may benefit from preoperative supplementation. Thyroid surgery is increasingly being performed in higher volume centers by higher volume surgeons which has been shown to have a beneficial effect on complication rates [25]. This approach should also be translated to the pediatric thyroid surgery population especially given their relatively lower incidence. All the adult thyroid surgeons in our series routinely perform over 50 thyroid operations yearly in both the adult and pediatric population combined. A joint approach between high volume adult endocrine surgeons and pediatric surgeons with experience in thyroid and head and neck surgery is the ideal framework for pediatric thyroid surgery moving forward. Limitations of our study include its retrospective nature. The postoperative care of patients was surgeon dependent, e.g. some surgeons routinely send patients home on a short course of supplemental calcium therapy regardless of their postoperative calcium levels. In addition, as our patients did not undergo routine laryngoscopic evaluation, the reported RLN paralysis rate of 1.6% may be an underestimation of the
Y. Chen et al. / Journal of Pediatric Surgery 50 (2015) 1316–1319
true incidence. Most of the data available on surgical extent and long term outcomes have been performed in adults and may not be appropriately generalized to the pediatric population. Further research focused toward clinical outcomes in this population is needed to help direct appropriate multimodality therapy. 4. Conclusion This is one of the largest studies assessing the rates of hypocalcemia in pediatric patients following thyroid surgery. Postoperative hypocalcemia remains the most common postoperative complication but rates are acceptable and comparable with their adult counterparts when performed at a high volume institution. Risks of hypocalcemia are increased in patients who undergo a total thyroidectomy with central and bilateral neck dissection and in those with Graves’ disease or malignancy. Close attention to these risk factors and diligence in checking preoperative vitamin D levels may allow for preoperative supplementation and more stringent postoperative monitoring with prophylactic calcium or vitamin D supplementation in these specific patients. References [1] Vashishta R, Mahalingam-Dhingra A, Lander L, et al. Thyroidectomy outcomes: A national perspective. Otolaryngol Head Neck Surg 2012;147:1027–34. [2] Bergamaschi R, Becouarn G, Ronceray J, et al. Morbidity of thyroid surgery. Am J Surg 1998;176:71–5. [3] Bhattacharyya N, Fried MP. Assessment of the morbidity and complications of total thyroidectomy. Arch Otolaryngol Head Neck Surg 2002;128:389–92. [4] Sasson AR, Pingpank JF, Wetherington RW, et al. Incidental parathyroidectomy during thyroid surgery does not cause transient symptomatic hypocalcemia. Arch Otolaryngol Head Neck Surg 2001;127:304–8. [5] Nair CG, Babu MJC, Menon R, et al. Hypocalcaemia following total thyroidectomy: An analysis of 806 patients. Indian J Endocrinol Metab 2013;17:298–303. [6] Burke JF, Sippel RS, Chen H. Evolution of pediatric thyroid surgery at a tertiary medical center. J Surg Res 2012;177:268–74.
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[7] Raval MV, Browne M, Chin AC, et al. Total thyroidectomy for benign disease in the pediatric patient — Feasible and safe. J Pediatr Surg 2009;44:1529–33. [8] Scholz S, Smith JR, Chaignaud B, et al. Thyroid surgery at Children’s Hospital Boston: A 35-year single-institution experience. J Pediatr Surg 2011;46:437–42. [9] Wood JH, Partrick DA, Barham HP, et al. Pediatric thyroidectomy: A collaborative surgical approach. J Pediatr Surg 2011;46:823–8. [10] Bargren AE, Meyer-Rochow GY, Delbridge LW, et al. Outcomes of surgically managed pediatric thyroid cancer. J Surg Res 2009;156:70–3. [11] Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008;93:3058–65. [12] La Quaglia MP, Corbally MT, Heller G, et al. Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery 1988;104:1149–56. [13] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30. [14] See AC, Soo KC. Hypocalcaemia following thyroidectomy for thyrotoxicosis. Br J Surg 1997;84:95–7. [15] Lal G, Ituarte P, Kebebew E, et al. Should total thyroidectomy become the preferred procedure for surgical management of Graves’ disease? Thyroid 2005;15:569–74. [16] Lazareva O, Panayiotopoulos A, Kazachkova I, et al. A teenage boy with hypocalcemia after radioablation for Graves’ disease. J Pediatr Endocrinol Metab 2014;27:379–82. [17] Pesce CE, Shiue Z, Tsai H, et al. Postoperative hypocalcemia after thyroidectomy for Graves’ disease. Thyroid 2010;20:1279–83. [18] Edafe O, Antakia R, Laskar N, et al. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg 2014;101:307–20. [19] Hay ID, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993; 114:1050–7. [20] Esnaola NF, Cantor SB, Sherman SI, et al. Optimal treatment strategy in patients with papillary thyroid cancer: A decision analysis. Surgery 2001;130:921–30. [21] Kirkby-Bott J, Markogiannakis H, Skandarajah A, et al. Preoperative vitamin D deficiency predicts postoperative hypocalcemia after total thyroidectomy. World J Surg 2011;35:324–30. [22] Griffin TP, Murphy MS, Sheahan P. Vitamin d and risk of postoperative hypocalcemia after total thyroidectomy. JAMA Otolaryngol Head Neck Surg 2014;140:346–51. [23] Lin Y, Ross HL, Raeburn CD, et al. Vitamin D deficiency does not increase the rate of postoperative hypocalcemia after thyroidectomy. Am J Surg 2012;204:888–93. [24] Ginde AA, Liu MC, Camargo CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Intern Med 2009;169:626–32. [25] Gourin CG, Tufano RP, Forastiere AA, et al. Volume-based trends in thyroid surgery. Arch Otolaryngol Head Neck Surg 2010;136:1191–8.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Pediatric thyroidectomy in a high volume thyroid surgery center: Risk factors for postoperative hypocalcemia☆ Yufei Chen a,⁎, Peter T. Masiakos a, Randall D. Gaz a, Richard A. Hodin a, Sareh Parangi a, Gregory W. Randolph a,b, Peter M. Sadow a, Antonia E. Stephen a a b
Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114, USA
a r t i c l e
i n f o
Article history: Received 5 August 2014 Received in revised form 27 October 2014 Accepted 29 October 2014 Key words: Endocrine Thyroidectomy Hypocalcemia Pediatric
a b s t r a c t Introduction: Hypocalcemia is a common complication following thyroid surgery. We seek to report on our experience in pediatric thyroidectomy in a high volume thyroid surgery center and accurately assess the incidence of postoperative hypocalcemia. Materials and methods: A retrospective review of patients aged 18 and younger who underwent thyroid surgery between 1992 and 2013. The primary endpoints were the occurrence of postoperative hypocalcemia as by defined as a nadir calcium b8.0 mg/dL and being discharged on oral calcium supplementation, need for intravenous calcium and the occurrence of permanent hypoparathyroidism. Results: 171 patients who underwent 186 thyroid operations were analyzed. The average age was 15.4 years with 82.3% female. The most common indications for surgery were nodular disease (74.7%) and hyperthyroidism (12.4%). 24 patients (12.9%) experienced postoperative hypocalcemia with 13 (7.0%) requiring intravenous calcium infusion. One patient (0.9%) experienced permanent hypoparathyroidism. Risk factors for postoperative hypocalcemia included total thyroidectomy (OR 7.39, p b 0.01), central and bilateral lateral neck dissection (OR 22.26, p = 0.01), Graves’ disease (OR 3.99, p = 0.02), and malignancy (OR 2.96, p = 0.03). Conclusions: Pediatric patients who undergo total thyroidectomy for underlying malignancy or Graves’ disease and those who have more extensive nodal dissections are at increased risk of developing this postoperative hypocalcemia. These patients may benefit from more vigilant preoperative preparation and postoperative calcium and vitamin D supplementation. © 2015 Elsevier Inc. All rights reserved.
Thyroidectomy in the pediatric population is a less frequently performed procedure than in adults and published reports noting patient volume and postoperative complications are highly variable. Hypocalcemia is the most common postoperative complication following thyroid surgery in children and adults and is often the cause of prolonged hospital stay and significant morbidity. It is caused by transient or permanent hypoparathyroidism owing to either disruption of the blood supply to the parathyroid glands or inadvertent removal of one or more glands. Symptoms of hypocalcemia are predominantly based on increases in neuromuscular excitability and range from perioral and peripheral paresthesias to generalized tetany. The incidence of hypocalcemia varies widely depending on how it is defined in each study. In the adult population, rates ranging from 6% to 30% have often been reported [1–3]. Identified risk factors for postoperative hypocalcemia include total thyroidectomy [2,4], younger
patient age [3], Graves’ disease [5] and incidental parathyroidectomy [2,5]. Temporary hypocalcemia rates in children after thyroid surgery are reported to be between 7% and 52% [6–9]. However, these studies do not consistently define hypocalcemia. Published data indicates higher postoperative morbidity following pediatric thyroidectomy when compared to the adult population [10–12]. This may be compounded by the relative rareness of pediatric thyroid surgery when compared to adults. However, as we move toward referring children who require thyroidectomy to high volume thyroid surgery centers, the literature suggests that complication rates are becoming more comparable with adult series [8]. In this study, we report on our experience with pediatric thyroidectomy from a high volume thyroid surgery center. We aim to accurately assess the incidence of hypocalcemia following pediatric thyroidectomy and analyze risk factors for this postoperative complication.
☆ There are no conflicts of interest of sources of funding to declare from any authors. ⁎ Corresponding author at: GRB-425, 55 Fruit Street, Boston, MA 02114, USA. E-mail addresses: [email protected] (Y. Chen), [email protected] (P.T. Masiakos), [email protected] (R.D. Gaz), [email protected] (R.A. Hodin), [email protected] (S. Parangi), [email protected] (G.W. Randolph), [email protected] (P.M. Sadow), [email protected] (A.E. Stephen).
1. Materials and methods
http://dx.doi.org/10.1016/j.jpedsurg.2014.10.056 0022-3468/© 2015 Elsevier Inc. All rights reserved.
We performed a retrospective analysis of all patients aged 18 or younger who underwent thyroid surgery and had their pathology analyzed at the Massachusetts General Hospital between July 1992 and April 2013. Patients who underwent an indicated parathyroidectomy
Y. Chen et al. / Journal of Pediatric Surgery 50 (2015) 1316–1319
at the time of thyroidectomy were excluded from the study. Patient demographics, indications for surgery, and preoperative work-up were obtained from the medical records. Operative and pathology reports were utilized to determine the extent of surgery and final pathological diagnosis. We defined temporary hypocalcemia as a postoperative nadir calcium value b8.0 mg/dL and treatment with oral calcium supplementation or intravenous calcium during their hospitalization. Patients who were still taking oral calcium supplementation beyond 6 months postoperatively with a serum calcium value b8.0 mg/dL or parathyroid hormone (PTH) level b15 pg/mL were classified as having permanent hypoparathyroidism. Transient recurrent laryngeal nerve (RLN) injury was defined as postoperative hoarseness combined with a laryngoscopic diagnosis of RLN palsy although routine laryngeal examination was not performed. Patients were classified as having permanent RLN injury if these findings persisted beyond 6 months. All patient data was recorded in Microsoft Excel for Windows 2010 and analyzed using SPSS (version 20, IBM SPSS). Continuous values were compared using the Mann–Whitney U test with the chi-square test utilized for categorical variables. Variables with a p-value of b0.20 were entered into a multivariate analysis. A p-value of b 0.05 was considered statistically significant. Ethics approval for this study was obtained through the Partners Human Research Committee.
2. Results A total of 171 patients who underwent 186 thyroid operations were included in the study (Table 1). The mean age at time of operation was 15.4 years (range 2.5–18.9). 82.3% of patients were female. Indications for thyroid surgery were nodular disease (74.7%), hyperthyroidism (12.4%), completion thyroidectomy (8.1%) and multiple endocrine neoplasia (MEN) type 2 prophylaxis (4.8%). A family history of thyroid disease was reported by 75 of 160 patients (46.9%) with a specific history of thyroid malignancy in 19 (11.9%).
Table 1 Comparison of patients who did and did not experience postoperative hypocalcemia. Variable Gender Age Indication
Family hx thyroid disease Family hx thyroid cancer Operation
No hypocalcemia Hypocalcemia p-Value (n = 162) (n = 24) Female ≥14 Nodule Hyperthyroidism MEN2A prophylaxis Completion Yes
Yes
132 (81.5%) 124 (76.5%) 146 (90.1%) 16 (9.9%) 7 (4.3%) 11 (6.8%) 63 (38.9%)
21 (87.5%) 16 (66.7%) 17 (70.8%) 7 (29.2%) 2 (8.3%) 4 (16.7%) 12 (50%)
16 (9.9%)
3 (12.5%)
Hemithyroidectomy 79 (48.8%) Total thyroidectomy 65 (40.1%) Nodulectomy 7 (4.3%) Completion thyroid 11 (6.8%) LN dissection Yes 29 (17.9%) LN dissection No 133 (82.1%) extent Yes, central 18 (11.1%) Yes, unilateral 10 (6.2%) Yes, bilateral 1 (0.6%) Parathyroid No 133 (82.1%) Yes, reimplant 11 (6.8%) Yes, inadvertent 18 (11.1%) Pathology Benign 93 (57.4%) Graves 15 (9.3%) Hashimoto 8 (4.9%) Malignant 46 (28.4%) Median length Days (range) 1 (0–3) of stay
0 20 (83.3%) 0 4 (16.7%) 10 (41.7%) 14 (58.3%) 5 (20.1%) 2 (8.3%) 3 (12.5%) 17 (70.8%) 2 (8.3%) 5 (20.8%) 4 (16.7%) 7 (29.2%) 0 13 (54.2%) 2 (0–8)
0.69 0.42 b0.01
0.58
0.98
b0.01
0.01 b0.01
0.37
b0.01
b0.01
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Thyroid ultrasound was the most commonly used imaging modality performed prior to initial surgery and was utilized in 138 patients (80.7%). Thyroid cytology via FNA was obtained in 98 patients (57.3%) and scintigraphy in 42 (24.6%). Genetic testing was positive in 10 patients (5.9%), resulting in the preoperative diagnosis of MEN type 2 in 8 patients, Cowden syndrome in 1 patient, and familial adenomatous polyposis in another. The most common initial operation performed was a total thyroidectomy in 85 patients (45.7%). 15 patients (8.1%) underwent completion thyroidectomy following previous thyroid resection. A hemithyroidectomy was performed in 79 patients (42.5%) and a local excision or nodulectomy in 7 (3.8%). In addition to their thyroid resection, 39 patients (21.0%) also underwent a lymph node dissection. The extent of the neck dissection was limited to the central neck (level VI) alone in 23 patients (12.4%), while 12 patients (6.5%) underwent a central plus unilateral (levels II–IV) neck dissection and 4 patients (2.2%) underwent central plus bilateral neck dissection. Average lymph node yield for central neck dissection alone was 9, while it was 27 and 59 for dissection of the unilateral and bilateral lateral neck respectively. More than 85% of the operations were performed by adult thyroid surgeons. The final pathology was benign in 127 cases (68.3%) with follicular adenoma (31.4%) and Graves’ disease (11.9%) being the most common. The remaining 59 specimens (31.7%) were malignant, with 51 cases (27.4%) of papillary thyroid cancer, 5 (2.7%) of medullary thyroid cancer and 3 (1.6%) of follicular thyroid cancer. Of the patients with proven malignancy, 26 (44.1%) had evidence of lymph node metastases. There was evidence of inadvertent parathyroid gland removal in 36 patients (19.4%). 13 of these were autotransplanted back into the patient while the remaining 23 had parathyroid tissue reported in the final pathological specimen but were not reimplanted. Patients who had parathyroid gland resection were more likely to have had central and/or lateral nodal dissection (33% vs 18%, p = 0.04). Average postoperative follow-up was 3 years (range 0–17 years) with 59.1% of patients having N 6 months follow-up. In patients with malignant disease, mean follow-up was 4.6 years with 74.1% of patients having N6 months follow-up. 37 patients (19.9%) received postoperative radioactive iodine ablation therapy. At the time of last follow-up, 6 patients (10.1%) with malignant pathology had developed recurrent locoregional or metastatic disease. Preoperative vitamin D levels were available in 19 patients with a mean 25(OH)D level of 31.6 ng/mL (range 12–85). Five patients had vitamin D deficiency (b20 ng/mL) and six patients had vitamin D insufficiency (21–30 ng/mL) as defined by the Endocrine Society [13]. Two patients with vitamin D deficiency experienced postoperative hypocalcemia and none with vitamin D insufficiency. However, this variable was not included in the univariate analysis given inadequate power. Overall, 24 patients (12.9%) experienced temporary hypocalcemia in the immediate postoperative period with 13 patients (7.0%) requiring intravenous calcium administration. When considering only patients who underwent total or completion thyroidectomy, this rate was 24% and 13% respectively. At 6 months follow-up, only 1 patient (0.9%) had PTH b15 pg/mL and remained on calcium supplementation. This patient did eventually recover parathyroid function and her hypoparathyroidism had resolved by 12 months follow-up. As such, by 12 months months postoperatively, there were no cases of permanent hypoparathyroidism. There were 3 cases (1.6%) of temporary recurrent laryngeal nerve injury, but none was permanent. The overall median length of stay (LOS) was 1 day (range 0–8) following thyroid surgery. Patients who experienced temporary hypocalcemia had a median LOS of 2 days (p b 0.01). On univariate analysis (Table 2), factors associated with an increased risk of postoperative hypocalcemia included total thyroidectomy (odds ratio (OR) 7.39, p b 0.01), need for lymph node dissection particularly combined central and bilateral neck dissection (OR 22.26, p = 0.01), and a final pathological diagnosis of either Graves’ disease (OR 3.99, p = 0.02) or malignancy (OR 2.96, p = 0.03). Younger patients aged b 14
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Table 2 Univariate logistic regression for risk factors of postoperative hypocalcemia. Variable Age Gender Indication
Family hx thyroid disease Family hx thyroid cancer Operation
LN dissection LN dissection extent
LN examined Parathyroid
Final pathology
b14 Female Nodule Hyperthyroidism MEN2A prophylaxis Completion Yes Yes Hemithyroid Total thyroid Nodulectomy Completion Yes None Central Unilateral Bilateral None Autotransplant Inadvertent Benign Graves Hashimoto Malignant
Odds ratio (95% CI)
p-Value
1.63 (0.56–4.41) 1.59 (0.43–8.84) 1 3.72 (1.13–11.36) 2.00 (0.19–11.47) 2.73 (0.58–10.39) 1.43 (0.53–3.95) 0.98 (0.15–4.60) 1 7.39 (2.33–31.09) 0.69 (0–4.79) 2.73 (0.58–10.39) 3.25 (1.17–8.80) 1 2.10 (0.54–6.81) 1.38 (0.14–7.13) 22.26 (1.70–1214.4) 1.03 (1.00–1.06) 1 1.51 (0.31–7.44) 2.31 (0.75–7.07) 1 3.99 (1.20–12.33) 0.59 (0–4.03) 2.96 (1.13–7.89)
0.42 0.69 0.03 0.65 0.22 0.58 0.98 b0.01 0.75 0.22 0.01 0.31 0.95 0.01 0.07 0.61 0.14 0.02 0.65 0.03
(OR 1.63, p = 0.42), patients who underwent central neck dissection alone (OR 2.10, p = 0.31) or central and unilateral neck dissection (OR 1.38, p = 0.95), parathyroid autotransplantation (OR 1.51, p = 0.61) or inadvertent parathyroid removal (OR 2.31, p = 0.14) were not found to have a statistically significant increase in the rate of postoperative hypocalcemia. On multivariate analysis, central and bilateral lymph node dissection and the presence of Graves’ disease or malignancy remained independent predictors of postoperative hypocalcemia (Table 3). 3. Discussion Pediatric thyroid surgery is a specialized procedure that should ideally be performed at high volume centers. Postoperative hypocalcemia is a well known complication that can lead to patient discomfort, prolonged length of hospital stay, and increased cost. In order to reliably follow trends and assess risk for postoperative hypocalcemia, accurate and consistent definitions need to be developed and followed. We elected to use objective data points that included a combination of serum calcium levels and changes in patient care such as being discharged on oral calcium supplements. Although the majority of pediatric thyroid surgery is in the adolescent population, this objective approach would allow for a uniform assessment of patients in all pediatric age groups. In our study, temporary hypocalcemia occurred only in patients who underwent total or completion thyroidectomy, as expected. This may account for some of the differences in our rates of hypocalcemia compared with other studies. Scholz et al. reported a hypocalcemia rate of 6.9%, but this was in a thyroidectomy population where just 29% Table 3 Multivariate analysis for independent predictors of postoperative hypocalcemia. Variable
Odds ratio (95% CI)
p-Value
OR — total thyroid LN dissection — yes LN — bilateral LN examined Parathyroid — inadvertent Path — graves Path — malignant
10.09 (0.93–109.31) 0.91 (0.20–4.29) 13.5 (1.27–143.64) 1.01 (0.96–1.05) 2.29 (0.65–8.11) 11.78 (3.08–45.13) 5.61 (1.67–18.85)
0.11 0.91 0.03 0.79 0.20 b0.01 0.01
underwent a total thyroidectomy compared to a combined total and completion thyroidectomy rate of 53.8% in our series [8]. There has been a trend toward more complete thyroid surgery, as opposed to a subtotal resection, in benign conditions such as Graves’ disease [6]. In fact, the procedure of a nodulectomy or subtotal thyroidectomy has essentially been abandoned over the last decade. We found a higher rate of postoperative hypocalcemia in our patients with Graves’ disease compared to the rest of the nonmalignant group. This may be attributed to the local inflammation from thyroiditis that makes the parathyroid glands more adherent and surgical dissection more difficult. Other proposed mechanisms include calcitonin release from operative manipulation and postoperative reversal of thyrotoxic osteodystrophy leading to hungry bone syndrome [14,15]. The latter has been described in a child following radioablation therapy for Graves’ disease [16]. Similar findings have also been demonstrated in the adult literature [17,18]. The indications and recommendations surrounding lymph node dissection in patients with malignant thyroid disease have changed dramatically in the last decade and remain controversial. Critics of prophylactic central lymph node dissection comment on the increased operative morbidity. In our study, patients who underwent central lymph node dissection alone did not have increased rates of postoperative hypocalcemia. In patients with established lymph node metastases, resection of all involved lymph nodes is currently standard of care and has been shown to be an important determinant of long term outcome and local recurrence rates and facilitates adjuvant radioactive iodine therapy [19,20]. Our study showed a significantly increased incidence of postoperative hypocalcemia in those patients who underwent bilateral lateral neck dissection with a trend toward a higher rate of hypocalcemia with an increasing number of lymph nodes removed. This may reflect more aggressive local disease requiring more extensive dissection which can compromise integrity of parathyroid gland vascular supply. There are no prior reported rates of incidental parathyroid excision during pediatric thyroidectomy. In our study, 36 patients (19.4%) had inadvertent parathyroid gland excision as noted intraoperatively by the surgeon or on the specimen by the pathologist. 13 of these patients (36.1%) subsequently underwent autotransplantation of the resected parathyroid gland. This compares favorably to several adult series which report an incidence of incidental parathyroid resection as high as 30% [2,4]. Interestingly, inadvertent parathyroid excision with or without autotransplantation did not significantly change rates of postoperative hypocalcemia in our study. Vitamin D deficiency has been hypothesized to contribute to the development of postoperative hypocalcemia although current literature in the adult population has been inconclusive [21–23]. Among children, the incidence of vitamin D deficiency has been increasing over time [24]. Future studies with more routine evaluation of preoperative vitamin D status in the pediatric population are required to establish the relationship between vitamin D deficiency and postoperative hypocalcemia, perhaps identifying higher risk subgroups who may benefit from preoperative supplementation. Thyroid surgery is increasingly being performed in higher volume centers by higher volume surgeons which has been shown to have a beneficial effect on complication rates [25]. This approach should also be translated to the pediatric thyroid surgery population especially given their relatively lower incidence. All the adult thyroid surgeons in our series routinely perform over 50 thyroid operations yearly in both the adult and pediatric population combined. A joint approach between high volume adult endocrine surgeons and pediatric surgeons with experience in thyroid and head and neck surgery is the ideal framework for pediatric thyroid surgery moving forward. Limitations of our study include its retrospective nature. The postoperative care of patients was surgeon dependent, e.g. some surgeons routinely send patients home on a short course of supplemental calcium therapy regardless of their postoperative calcium levels. In addition, as our patients did not undergo routine laryngoscopic evaluation, the reported RLN paralysis rate of 1.6% may be an underestimation of the
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true incidence. Most of the data available on surgical extent and long term outcomes have been performed in adults and may not be appropriately generalized to the pediatric population. Further research focused toward clinical outcomes in this population is needed to help direct appropriate multimodality therapy. 4. Conclusion This is one of the largest studies assessing the rates of hypocalcemia in pediatric patients following thyroid surgery. Postoperative hypocalcemia remains the most common postoperative complication but rates are acceptable and comparable with their adult counterparts when performed at a high volume institution. Risks of hypocalcemia are increased in patients who undergo a total thyroidectomy with central and bilateral neck dissection and in those with Graves’ disease or malignancy. Close attention to these risk factors and diligence in checking preoperative vitamin D levels may allow for preoperative supplementation and more stringent postoperative monitoring with prophylactic calcium or vitamin D supplementation in these specific patients. References [1] Vashishta R, Mahalingam-Dhingra A, Lander L, et al. Thyroidectomy outcomes: A national perspective. Otolaryngol Head Neck Surg 2012;147:1027–34. [2] Bergamaschi R, Becouarn G, Ronceray J, et al. Morbidity of thyroid surgery. Am J Surg 1998;176:71–5. [3] Bhattacharyya N, Fried MP. Assessment of the morbidity and complications of total thyroidectomy. Arch Otolaryngol Head Neck Surg 2002;128:389–92. [4] Sasson AR, Pingpank JF, Wetherington RW, et al. Incidental parathyroidectomy during thyroid surgery does not cause transient symptomatic hypocalcemia. Arch Otolaryngol Head Neck Surg 2001;127:304–8. [5] Nair CG, Babu MJC, Menon R, et al. Hypocalcaemia following total thyroidectomy: An analysis of 806 patients. Indian J Endocrinol Metab 2013;17:298–303. [6] Burke JF, Sippel RS, Chen H. Evolution of pediatric thyroid surgery at a tertiary medical center. J Surg Res 2012;177:268–74.
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[7] Raval MV, Browne M, Chin AC, et al. Total thyroidectomy for benign disease in the pediatric patient — Feasible and safe. J Pediatr Surg 2009;44:1529–33. [8] Scholz S, Smith JR, Chaignaud B, et al. Thyroid surgery at Children’s Hospital Boston: A 35-year single-institution experience. J Pediatr Surg 2011;46:437–42. [9] Wood JH, Partrick DA, Barham HP, et al. Pediatric thyroidectomy: A collaborative surgical approach. J Pediatr Surg 2011;46:823–8. [10] Bargren AE, Meyer-Rochow GY, Delbridge LW, et al. Outcomes of surgically managed pediatric thyroid cancer. J Surg Res 2009;156:70–3. [11] Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab 2008;93:3058–65. [12] La Quaglia MP, Corbally MT, Heller G, et al. Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgery 1988;104:1149–56. [13] Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911–30. [14] See AC, Soo KC. Hypocalcaemia following thyroidectomy for thyrotoxicosis. Br J Surg 1997;84:95–7. [15] Lal G, Ituarte P, Kebebew E, et al. Should total thyroidectomy become the preferred procedure for surgical management of Graves’ disease? Thyroid 2005;15:569–74. [16] Lazareva O, Panayiotopoulos A, Kazachkova I, et al. A teenage boy with hypocalcemia after radioablation for Graves’ disease. J Pediatr Endocrinol Metab 2014;27:379–82. [17] Pesce CE, Shiue Z, Tsai H, et al. Postoperative hypocalcemia after thyroidectomy for Graves’ disease. Thyroid 2010;20:1279–83. [18] Edafe O, Antakia R, Laskar N, et al. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg 2014;101:307–20. [19] Hay ID, Bergstralh EJ, Goellner JR, et al. Predicting outcome in papillary thyroid carcinoma: Development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery 1993; 114:1050–7. [20] Esnaola NF, Cantor SB, Sherman SI, et al. Optimal treatment strategy in patients with papillary thyroid cancer: A decision analysis. Surgery 2001;130:921–30. [21] Kirkby-Bott J, Markogiannakis H, Skandarajah A, et al. Preoperative vitamin D deficiency predicts postoperative hypocalcemia after total thyroidectomy. World J Surg 2011;35:324–30. [22] Griffin TP, Murphy MS, Sheahan P. Vitamin d and risk of postoperative hypocalcemia after total thyroidectomy. JAMA Otolaryngol Head Neck Surg 2014;140:346–51. [23] Lin Y, Ross HL, Raeburn CD, et al. Vitamin D deficiency does not increase the rate of postoperative hypocalcemia after thyroidectomy. Am J Surg 2012;204:888–93. [24] Ginde AA, Liu MC, Camargo CA. Demographic differences and trends of vitamin D insufficiency in the US population, 1988–2004. Arch Intern Med 2009;169:626–32. [25] Gourin CG, Tufano RP, Forastiere AA, et al. Volume-based trends in thyroid surgery. Arch Otolaryngol Head Neck Surg 2010;136:1191–8.