Association of Hypocalcemia and Magnesium Disorders With Thyroidectomy in Commercially Insured Patients | Acid Base, Electrolytes, Fluids | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
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Table 1.  Demographic Characteristics of Patients
Demographic Characteristics of Patients
Table 2.  Multivariable Logistic Regression Model of Variables Associated With Short-term Hypocalcemia and Multivariable Random Effect Logistic Regression Analysis of Variables Associated With Long-term Hypocalcemia
Multivariable Logistic Regression Model of Variables Associated With Short-term Hypocalcemia and Multivariable Random Effect Logistic Regression Analysis of Variables Associated With Long-term Hypocalcemia
Table 3.  Generalized Linear Regression Analysis of Overall Costs in the 30-Day Initial Posttreatment Period
Generalized Linear Regression Analysis of Overall Costs in the 30-Day Initial Posttreatment Period
Table 4.  Generalized Linear Regression Analysis of 1-Year Overall Costs
Generalized Linear Regression Analysis of 1-Year Overall Costs
1.
Pattou  F, Combemale  F, Fabre  S,  et al.  Hypocalcemia following thyroid surgery: incidence and prediction of outcome.  World J Surg. 1998;22(7):718-724. doi:10.1007/s002689900459PubMedGoogle ScholarCrossref
2.
Puzziello  A, Rosato  L, Innaro  N,  et al.  Hypocalcemia following thyroid surgery: incidence and risk factors: a longitudinal multicenter study comprising 2,631 patients.  Endocrine. 2014;47(2):537-542. doi:10.1007/s12020-014-0209-yPubMedGoogle ScholarCrossref
3.
Stack  BC  Jr, Bimston  DN, Bodenner  DL,  et al.  American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management  [published correction appears in Endocr Pract. 2015;21(10):1187].  Endocr Pract. 2015;21(6):674-685. doi:10.4158/EP14462.DSCPubMedGoogle ScholarCrossref
4.
Reeve  T, Thompson  NW.  Complications of thyroid surgery: how to avoid them, how to manage them, and observations on their possible effect on the whole patient.  World J Surg. 2000;24(8):971-975. doi:10.1007/s002680010160PubMedGoogle ScholarCrossref
5.
Almquist  M, Ivarsson  K, Nordenström  E, Bergenfelz  A.  Mortality in patients with permanent hypoparathyroidism after total thyroidectomy.  Br J Surg. 2018;105(10):1313-1318. doi:10.1002/bjs.10843PubMedGoogle ScholarCrossref
6.
Edafe  O, Antakia  R, Laskar  N, Uttley  L, Balasubramanian  SP.  Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia.  Br J Surg. 2014;101(4):307-320. doi:10.1002/bjs.9384PubMedGoogle ScholarCrossref
7.
Chadwick  DR.  Hypocalcaemia and permanent hypoparathyroidism after total/bilateral thyroidectomy in the BAETS Registry.  Gland Surg. 2017;6(suppl 1):S69-S74. doi:10.21037/gs.2017.09.14PubMedGoogle ScholarCrossref
8.
Brophy  C, Woods  R, Murphy  MS, Sheahan  P.  Perioperative magnesium levels in total thyroidectomy and relationship to hypocalcemia.  Head Neck. 2019;41(6):1713-1718. doi:10.1002/hed.25644PubMedGoogle ScholarCrossref
9.
Cherian  AJ, Gowri  M, Ramakant  P, Paul  TV, Abraham  DT, Paul  MJ.  The role of magnesium in post-thyroidectomy hypocalcemia.  World J Surg. 2016;40(4):881-888. doi:10.1007/s00268-015-3347-3PubMedGoogle ScholarCrossref
10.
Garrahy  A, Murphy  MS, Sheahan  P.  Impact of postoperative magnesium levels on early hypocalcemia and permanent hypoparathyroidism after thyroidectomy.  Head Neck. 2016;38(4):613-619. doi:10.1002/hed.23937PubMedGoogle ScholarCrossref
11.
Luo  H, Yang  H, Zhao  W,  et al.  Hypomagnesemia predicts postoperative biochemical hypocalcemia after thyroidectomy.  BMC Surg. 2017;17(1):62. doi:10.1186/s12893-017-0258-2PubMedGoogle ScholarCrossref
12.
Nellis  JC, Tufano  RP, Gourin  CG.  Association between magnesium disorders and hypocalcemia following thyroidectomy.  Otolaryngol Head Neck Surg. 2016;155(3):402-410. doi:10.1177/0194599816644594PubMedGoogle ScholarCrossref
13.
Charlson  ME, Pompei  P, Ales  KL, MacKenzie  CR.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.  J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8PubMedGoogle ScholarCrossref
14.
Liu  JH, Zingmond  DS, McGory  ML,  et al.  Disparities in the utilization of high-volume hospitals for complex surgery.  JAMA. 2006;296(16):1973-1980. doi:10.1001/jama.296.16.1973PubMedGoogle ScholarCrossref
15.
Romano  PS, Roos  LL, Jollis  JG.  Adapting a clinical comorbidity index for use with ICD-9-CM administrative data: differing perspectives.  J Clin Epidemiol. 1993;46(10):1075-1079. doi:10.1016/0895-4356(93)90103-8PubMedGoogle ScholarCrossref
16.
United States Census Bureau. Metropolitan and micropolitan statistical areas. https://www.census.gov/programs-surveys/metro-micro.html. Accessed July 7, 2016.
17.
United States Census Bureau. American fact finder. https://factfinder.census.gov/faces/nav/jsf/pages/index.xhtml. Accessed July 7, 2016.
18.
Bureau of Labor Statistics, US Department of Labor. Consumer price index inflation calculator. https://www.bls.gov/data/inflation_calculator.htm. Accessed May 16, 2018.
19.
Agency for Healthcare Research and Quality. Medical expenditure panel survey. https://meps.ahrq.gov/survey_comp/hc_samplecodes_se.shtml. Accessed December 2, 2019.
20.
Costanzo  M, Marziani  A, Condorelli  F, Migliore  M, Cannizzaro  MA.  Post-thyroidectomy hypocalcemic syndrome: predictive value of early PTH: preliminary results.  Ann Ital Chir. 2010;81(4):301-305.PubMedGoogle Scholar
21.
Wilson  RB, Erskine  C, Crowe  PJ.  Hypomagnesemia and hypocalcemia after thyroidectomy: prospective study.  World J Surg. 2000;24(6):722-726. doi:10.1007/s002689910116PubMedGoogle ScholarCrossref
22.
Kazaure  HS, Sosa  JA.  Surgical hypoparathyroidism.  Endocrinol Metab Clin North Am. 2018;47(4):783-796. doi:10.1016/j.ecl.2018.07.005PubMedGoogle ScholarCrossref
23.
Kikumori  T, Imai  T, Tanaka  Y, Oiwa  M, Mase  T, Funahashi  H.  Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: long-term follow-up of grafted parathyroid function.  Surgery. 1999;125(5):504-508. doi:10.1016/S0039-6060(99)70201-1PubMedGoogle ScholarCrossref
24.
Lo  CY.  Parathyroid autotransplantation during thyroidectomy.  ANZ J Surg. 2002;72(12):902-907. doi:10.1046/j.1445-2197.2002.02580.xPubMedGoogle ScholarCrossref
25.
Lo  CY, Lam  KY.  Routine parathyroid autotransplantation during thyroidectomy.  Surgery. 2001;129(3):318-323. doi:10.1067/msy.2001.111125PubMedGoogle ScholarCrossref
26.
Smith  MA, Jarosz  H, Hessel  P, Lawrence  AM, Paloyan  E.  Parathyroid autotransplantation in total thyroidectomy.  Am Surg. 1990;56(7):404-406.PubMedGoogle Scholar
27.
Lin  YS, Hsueh  C, Wu  HY, Yu  MC, Chao  TC.  Incidental parathyroidectomy during thyroidectomy increases the risk of postoperative hypocalcemia.  Laryngoscope. 2017;127(9):2194-2200. doi:10.1002/lary.26448PubMedGoogle ScholarCrossref
28.
Kihara  M, Miyauchi  A, Kontani  K, Yamauchi  A, Yokomise  H.  Recovery of parathyroid function after total thyroidectomy: long-term follow-up study.  ANZ J Surg. 2005;75(7):532-536. doi:10.1111/j.1445-2197.2005.03435.xPubMedGoogle ScholarCrossref
29.
Lorente-Poch  L, Sancho  J, Muñoz  JL, Gallego-Otaegui  L, Martínez-Ruiz  C, Sitges-Serra  A.  Failure of fragmented parathyroid gland autotransplantation to prevent permanent hypoparathyroidism after total thyroidectomy.  Langenbecks Arch Surg. 2017;402(2):281-287. doi:10.1007/s00423-016-1548-3PubMedGoogle ScholarCrossref
30.
Sitges-Serra  A, Lorente-Poch  L, Sancho  J.  Parathyroid autotransplantation in thyroid surgery.  Langenbecks Arch Surg. 2018;403(3):309-315. doi:10.1007/s00423-018-1654-5PubMedGoogle ScholarCrossref
31.
Su  A, Gong  Y, Wu  W, Gong  R, Li  Z, Zhu  J.  Does the number of parathyroid glands autotransplanted affect the incidence of hypoparathyroidism and recovery of parathyroid function?  [published online February 2, 2018].  Surgery. doi:10.1016/j.surg.2017.12.025PubMedGoogle Scholar
32.
Xing  T, Hu  Y, Wang  B, Zhu  J.  Role of oral calcium supplementation alone or with vitamin D in preventing post-thyroidectomy hypocalcaemia: a meta-analysis.  Medicine (Baltimore). 2019;98(8):e14455. doi:10.1097/MD.0000000000014455PubMedGoogle Scholar
33.
Al Khadem  MG, Rettig  EM, Dhillon  VK, Russell  JO, Tufano  RP.  Postoperative IPTH compared with IPTH gradient as predictors of post-thyroidectomy hypocalcemia.  Laryngoscope. 2018;128(3):769-774. doi:10.1002/lary.26805PubMedGoogle ScholarCrossref
34.
Alhefdhi  A, Mazeh  H, Chen  H.  Role of postoperative vitamin D and/or calcium routine supplementation in preventing hypocalcemia after thyroidectomy: a systematic review and meta-analysis.  Oncologist. 2013;18(5):533-542. doi:10.1634/theoncologist.2012-0283PubMedGoogle ScholarCrossref
35.
Landry  CS, Grubbs  EG, Hernandez  M,  et al.  Predictable criteria for selective, rather than routine, calcium supplementation following thyroidectomy.  Arch Surg. 2012;147(4):338-344. doi:10.1001/archsurg.2011.1406PubMedGoogle ScholarCrossref
36.
Lee  JW, Kim  JK, Kwon  H, Lim  W, Moon  BI, Paik  NS.  Routine low-dose calcium supplementation after thyroidectomy does not reduce the rate of symptomatic hypocalcemia: a prospective randomized trial.  Ann Surg Treat Res. 2019;96(4):177-184. doi:10.4174/astr.2019.96.4.177PubMedGoogle ScholarCrossref
37.
Nahas  ZS, Farrag  TY, Lin  FR, Belin  RM, Tufano  RP.  A safe and cost-effective short hospital stay protocol to identify patients at low risk for the development of significant hypocalcemia after total thyroidectomy.  Laryngoscope. 2006;116(6):906-910. doi:10.1097/01.mlg.0000217536.83395.37PubMedGoogle ScholarCrossref
38.
Sanabria  A, Rojas  A, Arevalo  J.  Meta-analysis of routine calcium/vitamin D3 supplementation versus serum calcium level–based strategy to prevent postoperative hypocalcaemia after thyroidectomy.  Br J Surg. 2019;106(9):1126-1137. doi:10.1002/bjs.11216PubMedGoogle ScholarCrossref
39.
Wang  TS, Cheung  K, Roman  SA, Sosa  JA.  To supplement or not to supplement: a cost-utility analysis of calcium and vitamin D repletion in patients after thyroidectomy.  Ann Surg Oncol. 2011;18(5):1293-1299. doi:10.1245/s10434-010-1437-xPubMedGoogle ScholarCrossref
40.
Aspinall  S, Oweis  D, Chadwick  D.  Effect of surgeons’ annual operative volume on the risk of permanent hypoparathyroidism, recurrent laryngeal nerve palsy and haematoma following thyroidectomy: analysis of United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS).  Langenbecks Arch Surg. 2019;404(4):421-430. doi:10.1007/s00423-019-01798-7PubMedGoogle ScholarCrossref
41.
Gourin  CG, Tufano  RP, Forastiere  AA, Koch  WM, Pawlik  TM, Bristow  RE.  Volume-based trends in thyroid surgery.  Arch Otolaryngol Head Neck Surg. 2010;136(12):1191-1198. doi:10.1001/archoto.2010.212PubMedGoogle ScholarCrossref
42.
Loyo  M, Tufano  RP, Gourin  CG.  National trends in thyroid surgery and the effect of volume on short-term outcomes.  Laryngoscope. 2013;123(8):2056-2063. doi:10.1002/lary.23923PubMedGoogle ScholarCrossref
43.
Meltzer  C, Klau  M, Gurushanthaiah  D,  et al.  Surgeon volume in thyroid surgery: surgical efficiency, outcomes, and utilization.  Laryngoscope. 2016;126(11):2630-2639. doi:10.1002/lary.26119PubMedGoogle ScholarCrossref
44.
Nouraei  SA, Virk  JS, Middleton  SE,  et al.  A national analysis of trends, outcomes and volume-outcome relationships in thyroid surgery.  Clin Otolaryngol. 2017;42(2):354-365. doi:10.1111/coa.12730PubMedGoogle ScholarCrossref
45.
Sosa  JA, Bowman  HM, Tielsch  JM, Powe  NR, Gordon  TA, Udelsman  R.  The importance of surgeon experience for clinical and economic outcomes from thyroidectomy.  Ann Surg. 1998;228(3):320-330. doi:10.1097/00000658-199809000-00005PubMedGoogle ScholarCrossref
46.
Stavrakis  AI, Ituarte  PH, Ko  CY, Yeh  MW.  Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery.  Surgery. 2007;142(6):887-899. doi:10.1016/j.surg.2007.09.003PubMedGoogle ScholarCrossref
47.
Hammerstad  SS, Norheim  I, Paulsen  T, Amlie  LM, Eriksen  EF.  Excessive decrease in serum magnesium after total thyroidectomy for Graves’ disease is related to development of permanent hypocalcemia.  World J Surg. 2013;37(2):369-375. doi:10.1007/s00268-012-1843-2PubMedGoogle ScholarCrossref
48.
Wang  W, Meng  C, Ouyang  Q, Xie  J, Li  X.  Magnesemia: an independent risk factor of hypocalcemia after thyroidectomy.  Cancer Manag Res. 2019;11:8135-8144. doi:10.2147/CMAR.S218179PubMedGoogle ScholarCrossref
49.
Fatemi  S, Ryzen  E, Flores  J, Endres  DB, Rude  RK.  Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism.  J Clin Endocrinol Metab. 1991;73(5):1067-1072. doi:10.1210/jcem-73-5-1067PubMedGoogle ScholarCrossref
50.
Allgrove  J.  Physiology of calcium, phosphate, magnesium and vitamin D.  Endocr Dev. 2015;28:7-32. doi:10.1159/000380990PubMedGoogle ScholarCrossref
51.
Clark  I.  Relation of magnesium ions to calcium and phosphate absorption.  Nature. 1965;207(5000):982-982. doi:10.1038/207982a0PubMedGoogle ScholarCrossref
52.
Paunier  L.  Effect of magnesium on phosphorus and calcium metabolism.  Monatsschr Kinderheilkd. 1992;140(9)(suppl 1):S17-S20.PubMedGoogle Scholar
53.
Reinhart  RA.  Magnesium metabolism: a review with special reference to the relationship between intracellular content and serum levels.  Arch Intern Med. 1988;148(11):2415-2420. doi:10.1001/archinte.1988.00380110065013PubMedGoogle ScholarCrossref
54.
Anast  CS, Mohs  JM, Kaplan  SL, Burns  TW.  Evidence for parathyroid failure in magnesium deficiency.  Science. 1972;177(4049):606-608. doi:10.1126/science.177.4049.606PubMedGoogle ScholarCrossref
55.
Rude  RK, Oldham  SB, Sharp  CF  Jr, Singer  FR.  Parathyroid hormone secretion in magnesium deficiency.  J Clin Endocrinol Metab. 1978;47(4):800-806. doi:10.1210/jcem-47-4-800PubMedGoogle ScholarCrossref
56.
Rodríguez-Ortiz  ME, Canalejo  A, Herencia  C,  et al.  Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration.  Nephrol Dial Transplant. 2014;29(2):282-289. doi:10.1093/ndt/gft400PubMedGoogle ScholarCrossref
57.
Quitterer  U, Hoffmann  M, Freichel  M, Lohse  MJ.  Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits.  J Biol Chem. 2001;276(9):6763-6769. doi:10.1074/jbc.M007727200PubMedGoogle ScholarCrossref
58.
Roh  JL, Park  CI.  Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy.  Am J Surg. 2006;192(5):675-678. doi:10.1016/j.amjsurg.2006.03.010PubMedGoogle ScholarCrossref
59.
Lang  BH, Chu  KK, Tsang  RK, Wong  KP, Wong  BY.  Evaluating the incidence, clinical significance and predictors for vocal cord palsy and incidental laryngopharyngeal conditions before elective thyroidectomy: is there a case for routine laryngoscopic examination?  World J Surg. 2014;38(2):385-391. doi:10.1007/s00268-013-2259-3PubMedGoogle ScholarCrossref
60.
Lang  BH, Wong  CK, Tsang  RK, Wong  KP, Wong  BY.  Evaluating the cost-effectiveness of laryngeal examination after elective total thyroidectomy.  Ann Surg Oncol. 2014;21(11):3548-3556. doi:10.1245/s10434-014-3770-yPubMedGoogle ScholarCrossref
61.
Sinclair  CF, Bumpous  JM, Haugen  BR,  et al.  Laryngeal examination in thyroid and parathyroid surgery: an American Head and Neck Society consensus statement.  Head Neck. 2016;38(6):811-819. doi:10.1002/hed.24409PubMedGoogle ScholarCrossref
62.
Zanocco  K, Kaltman  DJ, Wu  JX,  et al.  Cost effectiveness of routine laryngoscopy in the surgical treatment of differentiated thyroid cancer.  Ann Surg Oncol. 2018;25(4):949-956. doi:10.1245/s10434-018-6356-2PubMedGoogle ScholarCrossref
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    Original Investigation
    January 9, 2020

    Association of Hypocalcemia and Magnesium Disorders With Thyroidectomy in Commercially Insured Patients

    Author Affiliations
    • 1Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland
    • 2Department of Health Policy and Management, the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
    JAMA Otolaryngol Head Neck Surg. 2020;146(3):237-246. doi:10.1001/jamaoto.2019.4193
    Key Points

    Question  What factors are associated with hypocalcemia after total thyroidectomy?

    Findings  In this cross-sectional analysis of 126 766 commercially insured patients, short- and long-term hypocalcemia was significantly more likely among women, those younger than 40 years, and those with a diagnosis of thyroiditis or cancer, vitamin D deficiency, concurrent neck dissection, intraoperative parathyroid or recurrent laryngeal nerve injury, and magnesium disorders. Magnesium disorders were associated with the highest odds of postoperative hypocalcemia at 30 days and at 1 year.

    Meaning  Disorders of magnesium metabolism are a potentially modifiable target to reduce the incidence of hypocalcemia after total thyroidectomy.

    Abstract

    Importance  Hypocalcemia is a common complication of total thyroidectomy.

    Objectives  To identify factors associated with hypocalcemia after total thyroidectomy and to explore the association between hypocalcemia, magnesium disorders, and costs of care.

    Design, Setting, and Participants  A retrospective cross-sectional analysis was performed using data from the MarketScan Commercial Claim and Encounters database on 126 766 commercially insured patients younger than 65 years undergoing total thyroidectomy between January 1, 2010, and December 31, 2012. Statistical analysis was performed from January 1, 2016, to May 30, 2019.

    Main Outcomes and Measures  Short- and long-term hypocalcemia and the costs of care were examined using multivariable regression modeling.

    Results  Among the 126 766 patients in the study (81.6% women; mean age, 46.5 years [range, 18-64 years]), postoperative hypocalcemia was present in 19.1% of patients in the initial 30-day postoperative period and in 4.4% of patients at 1 year. Magnesium disorders were present in 2.1% of patients at the time of surgery. Short- and long-term hypocalcemia were significantly more likely in women (short-term: odds ratio [OR], 1.39 [95% CI, 1.29-1.50]; long-term: OR, 1.69 [95% CI, 1.52-1.89]), those younger than 40 years (short-term: OR for ages 40-64 years, 0.83 [95% CI, 0.78-0.87]; long-term: OR for ages 40-64 years, 0.73 [95% CI, 0.67-0.79]), those with a diagnosis of thyroiditis (short-term: OR, 1.48 [95% CI, 1.16-1.89]; long-term: OR, 1.60 [95% CI, 1.13-2.26]) or cancer (short-term: OR, 1.32 [95% CI, 1.05-1.67]; long-term: OR, 1.17 [95% CI, 0.83-1.63]), vitamin D deficiency (short-term: OR, 1.96 [95% CI, 1.74-2.21]; long-term: OR, 3.72 [95% CI, 3.30-4.18]), concurrent lateral neck dissection (short-term: OR, 1.51 [95% CI, 1.37-1.66]; long-term: OR, 1.95 [95% CI, 1.69-2.26]), concurrent central neck dissection (short-term: OR, 1.15 [95% CI, 1.07-1.24]; long-term: OR, 1.25 [95% CI, 1.12-1.40]), intraoperative parathyroid (short-term: OR, 1.58 [95% CI, 1.46-1.71]; and long-term: OR, 2.05 [95% CI, 1.82-2.31]) or recurrent laryngeal nerve injury (short-term: OR, 1.49 [95% CI, 1.27-1.74]; long-term: OR, 2.04 [95% CI, 1.64-2.54]), and magnesium disorders (short-term: OR, 8.40 [95% CI, 7.21-9.79]; long-term: OR, 25.23 [95% CI, 19.80-32.17]). Compared with the initial postoperative period, the odds of hypocalcemia decreased by 90.0% (OR, 0.10 [95% CI, 0.09-0.11]) at 6 months and 93.0% (OR, 0.07 [95% CI, 0.06-0.08]) at 1 year. After controlling for all other variables, magnesium disorders were associated with the highest odds of short- and long-term postoperative hypocalcemia. Hypocalcemia ($3392) and magnesium disorders ($14 314) were associated with increased mean incremental 1-year costs of care.

    Conclusions and Relevance  Hypocalcemia is common after total thyroidectomy but resolves in most patients by 1 year. Magnesium disorders are significantly independently associated with short- and long-term hypocalcemia and are associated with greater costs of care. These data suggest a potentially modifiable target to reduce the incidence and cost of long-term hypocalcemia at patient and systemic levels.

    Introduction

    Temporary hypocalcemia is the most common complication of total thyroidectomy, with a reported incidence within the literature of 1.6% to more than 50%.1,2 Although most cases of hypocalcemia resolve spontaneously, there is significant morbidity associated with hypocalcemia secondary to bronchospasm or laryngospasm, seizure, change in mental status, and cardiac dysrhythmia.3 Moreover, postoperative hypocalcemia may lead to prolonged hospital stays and may necessitate oral or intravenous calcium repletion, consequently leading to increased health care costs.4 Although rare, permanent postthyroidectomy hypocalcemia as a result of permanent hypoparathyroidism is an independent risk factor for mortality.5 As such, there is significant value in identifying modifiable risk factors for postthyroidectomy hypocalcemia.

    Previous studies of postthyroidectomy hypocalcemia have identified female sex, preoperative hypocalcemia, preoperative hypovitaminosis D, large goiters, thyroid cancer with or without neck dissection, and reoperation as factors associated with transient hypocalcemia.2,6 A subset of these risk factors (namely, concomitant neck dissection, reoperation for bleeding, Grave disease, and larger thyroid specimens) were associated with permanent hypocalcemia.6,7 Recently, abnormal serum magnesium levels and, by extension, magnesium metabolism disorders have been implicated in postoperative hypocalcemia.8-12 The serum magnesium level has been observed to mimic calcium levels postoperatively and potentially provides a modifiable risk factor in the development of surgical hypocalcemia.8,9

    To our knowledge, there has been no large database study examining the factors associated with and consequences of long-term hypocalcemia in patients after thyroidectomy. We sought to identify risk factors associated with both short- and long-term hypocalcemia after total thyroidectomy and to explore the association between hypocalcemia, magnesium disorders, and costs of care using claims data on young (<65 years) commercially insured patients.

    Methods
    Selection and Description of Study Patients

    A cross-sectional analysis of patients undergoing total thyroidectomy was performed using data from the MarketScan Commercial Claims and Encounters database and the MarketScan Lab database (Truven Health Analytics). This large US-based, employment-based database contains individual-level inpatient and outpatient insurance billing claims for employees and their dependents from approximately 45 large employers covered by more than 100 commercial payers. MarketScan allows longitudinal tracking of patients across different sites of care over multiple years and contains information regarding inpatient and outpatient treatment, demographic data, primary and secondary diagnoses and procedures, and costs. This protocol was reviewed by the Johns Hopkins Medical Institutions Institutional Review Board and approved as exempt because all data were deidentified and publicly available.

    Treatment was ascertained using all inpatient, outpatient, facility, and pharmaceutical claims files and using International Classification of Diseases, Ninth Revision (ICD-9) codes, Current Procedural Terminology codes, and Healthcare Common Procedure Coding System (HCPCS) codes for treatment. Adult patients (≥18 years of age) who underwent total thyroidectomy for benign or malignant disease between January 1, 2010, and December 31, 2012, comprised the study cohort (eTable 1 in the Supplement). Additional surgical procedures performed at the time of total thyroidectomy, including concurrent neck dissection (central or lateral), parathyroid reimplantation, and recurrent laryngeal nerve (RLN) repair, were defined by claims on the day of or within 30 days of thyroidectomy. Hypocalcemia was defined by a diagnosis of hypocalcemia or hypoparathyroidism, and RLN injury was defined by codes for RLN injury or repair (eTable 2 in the Supplement). Hypocalcemia or RLN injury was defined as present when they occurred in claims for care; when absent, we defined these conditions as resolved. Additional variables were derived from codes for disorders of magnesium metabolism, disorders of phosphate metabolism, vitamin D deficiency, and menopause or ovarian dysfunction, including codes for calcium and magnesium supplementation. Comorbidity was graded using the Romano adaptation of the Charlson Comorbidity Index, excluding ICD-9 codes for the index cancer diagnosis from the solid tumor category.13-15 Patients were followed up from the index surgery date for 12 months or until death, termination of health insurance, or end of database availability.

    Data Collection

    The MarketScan Commercial Claims and Encounters database includes only commercially insured individuals; thus, patients 65 years or older, patients receiving Medicare or Medicaid, and uninsured patients are not included. Data on race/ethnicity, educational level, income, hospital characteristics and identifiers, American Joint Commission on Cancer tumor stage, tumor grade, histologic subtype, and survival after hospital discharge are not available from the MarketScan database. Metropolitan statistical area (MSA) is provided in MarketScan and is defined as a geographical region that contains a core population of 50 000 individuals or more, consisting of 1 or more counties that have a high degree of social and economic integration.16 The Census MSA-level median household income for the year of diagnosis was determined as an approximate measure of socioeconomic status via linkage to the US Census Bureau and was divided into quintiles.17

    The MSA was also used to derive a surrogate for treatment volume. The mean annual number of total thyroidectomy cases performed per year of surgical activity was obtained by calculating the mean of the number of cases performed each year for each individual MSA, for the years in which at least 1 total thyroidectomy was performed within that MSA. We examined the distribution of the number of cases per MSA and stratified MSA volume by tertiles, which resulted in cutoff values for annual case volumes of 46 or fewer cases, 47 to 122 cases, and 123 cases or more, which were used to classify MSAs as low, intermediate, and high volume.

    Postoperative hypocalcemia and overall costs of care were examined as dependent variables. Magnesium and phosphate metabolism disorders, vitamin D deficiency, and menopause or ovarian disorder were examined as independent variables and included diagnoses codes in claims as well as claims for magnesium, calcium, and vitamin D supplementation. These variables were defined as short-term when they occurred during the initial treatment period using claims dating from the date of total thyroidectomy up to 30 days after surgery, whereas long-term outcomes were defined as those occurring in claims occurring from 3 months to 12 months after surgery.

    Secondary independent variables were age, sex, region, payer source (commercial, health maintenance organization, preferred provider organization, point of service, or other including consumer-driven health plans and high-deductible health plans), comorbidity, site (inpatient or outpatient), Census MSA-level median income quintile, MSA case volume, additional surgical procedures, RLN injury, and diagnosis. Costs were evaluated using all paid amounts from all standard analytic files, including inpatient, outpatient, facility, and pharmaceutical claims files. Costs were categorized as inpatient, outpatient, and other and combined into overall costs that were used in this analysis. Costs differ from charges in that costs reflect only the amount paid for care rendered. Costs were adjusted for inflation with results converted to 2018 US dollars.18

    Statistical Analysis

    Statistical analysis was performed from January 1, 2016, to May 30, 2019. Data were analyzed using Stata, version 12 (StataCorp). Associations between variables were analyzed using cross-tabulations and multivariable regression analysis. Data were structured as panel data for the analysis of outcomes or conditions that were measured over time. National projections of case volumes in the commercially insured population were extrapolated using a proprietary method developed by MarketScan, using sampling weights derived from similar subpopulations in the Medical Expenditure Panel Survey19 and corrected for changes in sampling over time. Variables with missing data for more than 10% of the population were coded with a dummy variable to represent the missing data in regression analysis. The primary clinical end point of hypocalcemia was evaluated using multivariable logistic regression analysis. Generalized linear regression modeling with a log link was used to analyze total costs for the 30-day initial treatment period as well as overall total costs at 1 year after surgery.

    Results

    A total of 126 766 cases met study criteria (Table 1). The mean patient age was 46.5 years (range, 18-64 years). Most patients were female (81.6%), 40 years of age or older (70.6%), with no comorbidity (93.0%), and had surgery in the southern United States (39.4%) and as outpatients (66.2%). The most common indication for surgery was malignant neoplasm (50.2%), followed by goiter (37.8%). Concurrent central neck dissection was performed in 15.9% of cases, and lateral neck dissection was performed in 6.9% of cases. Recurrent laryngeal nerve injury occurred in 2.2% of patients, with RLN repair performed in 0.8% of patients. Overall, vitamin D deficiency was recorded in 3.7% of cases, a magnesium disorder in 2.1%, phosphate disorder in 0.3%, and menopause or an ovarian disorder in 0.9% of cases. Hungry bone syndrome was present in less than 0.1% of cases and was excluded from analysis. Readmission within 30 days occurred in 3.9% of cases.

    Presence of Hypocalcemia

    Hypocalcemia was present in 19.1% of patients in the initial 30-day postoperative period and was significantly more common in women than men (85.1% vs 80.8%), younger (18-39 years) patients than older patients (33.8% vs 28.4%), and in patients with thyroiditis (11.8% vs 10.2%), thyroid cancer (53.9% vs 49.3%), comorbidities (8.2% vs 6.7%), vitamin D deficiency (6.4% vs 3.1%), and disorders of magnesium (7.4% vs 0.8%) or phosphate (1.2% vs 0.1%) metabolism. Hypocalcemia was also more common in patients who underwent central neck dissection (19.1% vs 15.1%) or lateral neck dissection (10.1% vs 6.2%) and who sustained an RLN injury (3.2% vs 2.0%) compared with those who did not. Parathyroid reimplantation at the time of surgery was performed in 10.1% of cases and was more commonly performed for patients who developed hypocalcemia than for those who did not (14.5% vs 9.0%). Readmission within 30 days was more common among patients with hypocalcemia than among patients without hypocalcemia (11.1% vs 2.3%).

    The prevalence of hypocalcemia decreased to 5.3% at 6 months and 4.4% at 12 months after surgery. Because of the low numbers of patients, phosphate disorders were excluded from multivariable analysis. Multivariable random-effect regression analysis controlling for time-invariant and time-variant variables demonstrated that, compared with the initial postoperative period, the odds of hypocalcemia decreased by 90.0% (odds ratio [OR], 0.10 [95% CI, 0.09-0.11]) at 6 months and decreased by 93.0% (OR, 0.07 [95% CI, 0.06-0.08]) at 1 year. The short- and long-term odds of hypocalcemia were significantly higher for women (short-term: OR, 1.39 [95% CI, 1.29-1.50]; and long-term: OR, 1.69 [95% CI, 1.52-1.89]) and for patients who underwent surgery for a malignant neoplasm (short-term: OR, 1.32 [95% CI, 1.05-1.67]; long-term: OR, 1.17 [95% CI, 0.83-1.63]) or thyroiditis (short-term: OR, 1.48 [95% CI, 1.16-1.89]; long-term: OR, 1.60 [95% CI, 1.13-2.26]), were younger than 40 years (short-term: OR for ages 40-64 years, 0.83 [95% CI, 0.78-0.87]; long-term: OR for ages 40-64 years, 0.73 [95% CI, 0.67-0.79]), and who had comorbid conditions (short-term for ≥2 comorbidities: OR, 1.42 [95% CI, 1.11-1.80]; long-term: OR, 1.63 [95% CI, 1.14-2.34]) (Table 2). Central neck dissection (short-term: OR, 1.15 [95% CI, 1.07-1.24]; long-term: OR, 1.25 [95% CI, 1.12-1.40]) or lateral neck dissection (short-term: OR, 1.51 [95% CI, 1.37-1.66]; long-term: OR, 1.95 [95% CI, 1.69-2.26]), intraoperative parathyroid injury (short-term: OR, 1.58 [95% CI, 1.46-1.71]; long-term: OR, 2.05 [95% CI, 1.82-2.31]), and RLN injury (short-term: OR, 1.49 [95% CI, 1.27-1.74]; long-term: OR, 2.04 [95% CI, 1.64-2.54]) were associated with increased odds of both short- and long-term hypocalcemia. Vitamin D deficiency (short-term: OR, 1.96 [95% CI, 1.74-2.21]; long-term: OR, 3.72 [95% CI, 3.30-4.18]) and magnesium disorders (short-term: OR, 8.40 [95% CI, 7.21-9.79]; and long-term: OR, 25.23 [95% CI, 19.80-32.17]) were associated with significantly increased odds of short- and long-term hypocalcemia, whereas menopause was associated with an increased odds of long-term hypocalcemia (OR, 1.66 [95% CI, 1.36-2.04). Magnesium disorders were associated with the highest odds of both short- and long-term hypocalcemia.

    Costs of Care

    Multivariable generalized linear regression analysis of independent variables associated with overall costs in the 30-day initial treatment period and at 1 year is shown in Table 3 and Table 4. After controlling for all other variables, we found that comorbidity was associated with the greatest increases in both short-term and 1-year costs (short-term for comorbidity score of ≥2, $8332; long-term for comorbidity score of ≥2, $27 936), followed by extent of surgery (short-term for lateral neck dissection, $6618; long-term for lateral neck dissection, $10 342) and RLN injury (short-term, $6309; long-term, $13 286). The 1-year costs of care were highest for patients with comorbidity, cancer-related treatment with neck dissection, postoperative radiotherapy ($14 522), postoperative radioactive iodine ($7137), RLN injury, and magnesium disorders ($14 314). A statistically significant association was observed between hypocalcemia and increased mean incremental costs of care. Magnesium disorders were significantly associated with even greater mean incremental costs of care, exceeded only by the costs associated with advanced comorbidity. High-volume MSA care was associated with lower short-term (–$1882) and long-term costs (–$1647), whereas the high median income quintile was associated with greater short-term ($1713) and long-term costs ($2831) of care.

    Discussion

    These data demonstrate that postoperative hypocalcemia is common among commercially insured patients after total thyroidectomy, documented in 19.1% of patients, but it resolves in most patients by 1 year after surgery. Similar to other reports, we found that a diagnosis of thyroiditis or cancer, vitamin D deficiency, concurrent neck dissection, intraoperative parathyroid or RLN injury, and magnesium disorders were associated with an increased risk of both perioperative and permanent hypocalcemia. In this study, magnesium disorders were associated with the highest odds of postoperative hypocalcemia at 30 days and 1 year after total thyroidectomy and were associated with increased costs of care.1,2,6-12,20,21 These observations are important at a time when outcomes are increasingly important factors in discussions of value and reimbursement, and they suggest that magnesium disorders may be a potentially modifiable risk factor that can be targeted to reduce the likelihood of postthyroidectomy hypocalcemia.

    Current recommendations to reduce the risk of postoperative hypocalcemia include prompt recognition of devascularized or inadvertently removed parathyroid glands with prompt autotransplantation and the use of routine postoperative calcium supplementation.22-26 Incidental parathyroidectomy, defined as the presence of parathyroid tissue within the surgical specimen, has previously been associated with higher incidences of postoperative hypocalcemia.27 Although parathyroid autotransplantation is considered standard practice, the success rates are variable.28-31 In addition, the practice of routine postoperative oral calcium supplementation has been observed to mitigate the rate of short-term hypocalcemia in some series.22,32-38 Others have proposed selective calcium supplementation based on postoperative parathyroid hormone (PTH) and calcium levels, the postoperative calcium trend, or PTH gradient (between preoperative and 1-hour postoperative levels).33,37 Selective supplementation, although shown to be associated with higher quality of life, comes at a higher cost per patient than routine supplementation.35,36,39 Oral calcium supplementation is not reflected in HCPCS or ICD-9 codes from administrative data, limiting evaluation of this practice in this study.

    An association between high-volume surgical care and reduced postoperative hypocalcemia has been reported by several authors.40-46 More important, surgeon case volume, rather than hospital case volume, has been significantly associated with surgical outcomes. Surgeons with a high volume of cases, typically defined as those who perform more than 25 to 100 thyroid surgical procedures per year, were associated with lower overall complication rates, with lower rates of permanent hypoparathyroidism and RLN palsy, shorter operative times, and decreased length of hospital stay.41-46 We did not find an association between MSA volume and hypocalcemia in our study; however, MSA volume is neither hospital or surgeon specific but rather refers to geographical volumes, which can encompass a range of hospital and surgeon volumes within a particular MSA.

    In recent years, several studies have demonstrated hypomagnesemia as a risk factor for the development of postthyroidectomy hypocalcemia.8-12,21,47 Nellis et al12 found that the odds of developing hypocalcemia was the greatest for patients with magnesium metabolism disorders. We found similar results in our study, which suggests the hypothesis that selective magnesium supplementation may be an effective prophylaxis against surgical hypocalcemia. Furthermore, postoperative magnesium levels have been observed to mimic calcium levels, with the magnitude of decline, as well as the absolute magnesium level on postoperative day 1 and 2, directly associated with the incidence of both temporary and permanent hypocalcemia.8-10,47 A recent study by Wang et al48 found that the risk of postthyroidectomy hypocalcemia in patients with concurrent hypomagnesemia was 4.6 times higher than in patients with normomagnesemia and that the decrease in serum calcium level was more significant in patients who also had a severe decrease in serum magnesium level compared with preoperative levels. Although, to our knowledge, no randomized clinical trials exist to establish causality between hypomagnesemia and hypocalcemia, Fatemi et al49 were able to show a significant decrease in serum calcium levels in a group of healthy men subjected to a 3-week low-magnesium diet. These clinical observations regarding the importance of the magnesium level in postoperative hypocalcemia corroborate the large body of basic science research documenting the interdependent association between serum calcium and magnesium.50-53 The direct binding of calcium or magnesium ions activates calcium-sensing receptors present on parathyroid cells, leading to calcium-dependent inhibition of PTH secretion. The corollary is that a low magnesium level reduces calcium-sensing receptor activation, promoting PTH release and increasing the level of serum calcium.50 However, the paradoxical block of PTH secretion in the setting of severe hypomagnesemia, specifically in patients with magnesium concentrations less than 0.5mM, has been observed clinically and replicated in in vitro and in vivo models.52,54 This secondary hypocalcemia is resistant to calcium substitution and is restored by magnesium replacement alone.49,54,55 Some have hypothesized that this is an adaptive phenomenon in chronic hypomagnesemia to prevent the development of secondary hyperparathyroidism.56 Quitterer et al57 have implicated the increased activity of Gα subunits in the paradoxical block of PTH in vitro, suggesting that patients with magnesium disorders may carry G-protein subunit variations that confer additional susceptibility to PTH blunting in the setting of hypomagnesemia. Taken together, these data suggest that targeting magnesium levels may be efficacious in reducing postthyroidectomy hypocalcemia in some patients.

    Limitations

    There are several limitations to the use of claims databases in risk adjustment and documentation that may affect our findings. MarketScan contains no information on stage of disease, grade, subtype, race/ethnicity, socioeconomic variables, or survival. Although comorbidity scores were used for risk classification, the ability to adequately control for case mix is limited when discharge diagnoses from claims data are used. Poor outcomes may reflect lower quality or may reflect unobserved patient severity. Metropolitan statistical area–based median income level and volumes may be an imprecise surrogate for true income and hospital volumes. There are limitations to the use of claims data in the identification of postoperative complications because information on outcomes is not collected, and the presence or absence of disease states in claims data may reflect coding practices rather than care provided. Although HCPCS codes for magnesium administration were used to define magnesium deficiency, ICD-9 codes for magnesium and phosphate disorders do not distinguish between deficiency and excess states, and these disorders may be underreported, as may the incidence of vitamin D deficiency and menopause. Laboratory data are not available from claims data. The incidence of complications may be underreported because complications pertaining to hypoparathyroidism may not be evident until after hospital discharge, and many surgeons routinely discharge patients with prophylactic over-the-counter calcium supplementation; in such patients, hypocalcemia may not appear in claims data and thus may be underestimated.1,2,58 Similarly, low calcium levels in patients with hypocalcemia may prompt additional laboratory tests, such as magnesium levels. In such a setting, hypocalcemia may result in the overidentification of baseline hypomagnesemia in some patients in whom this would have otherwise been asymptomatic. Furthermore, a laryngoscopic examination may not be routinely performed, and RLN injury may be underestimated.59-62

    Nevertheless, these data demonstrate a strong association between the extent of thyroid disease and surgery with postoperative hypocalcemia, and they confirm an association between magnesium disorders and short- and long-term hypocalcemia that is associated with significant increases in costs. These observations suggest that early identification and treatment of magnesium disorders may provide a potentially modifiable target to reduce the incidence and morbidity of long-term hypocalcemia after total thyroidectomy.

    Conclusions

    Hypocalcemia is a common complication after total or completion thyroidectomy, but it resolves in most patients within 1 year. Magnesium disorders appear to be an independent factor significantly associated with short- and long-term hypocalcemia and are associated with greater costs of care. This study suggests the hypothesis that perioperative magnesium supplementation after thyroid surgery may potentially improve health care value by reducing the incidence of hypocalcemia and its attendant costs.

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    Article Information

    Accepted for Publication: November 9, 2019.

    Corresponding Author: Jonathon O. Russell, MD, Department of Otolaryngology–Head and Neck Surgery, The Johns Hopkins School of Medicine. Johns Hopkins Outpatient Center, 601 N Caroline St, Ste 6260, Baltimore, MD 21287 (jrusse41@jhmi.edu).

    Published Online: January 9, 2020. doi:10.1001/jamaoto.2019.4193

    Author Contributions: Dr Russell had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Razavi, Chang, Tufano, Gourin, Russell.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Liu, Razavi, Gourin, Russell.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Razavi, Chang, Gourin.

    Obtained funding: Gourin.

    Administrative, technical, or material support: Chang, Tufano, Eisele, Gourin, Russell.

    Supervision: Tufano, Gourin, Russell.

    Conflict of Interest Disclosures: Dr Tufano reported receiving personal fees from Medtronic and Hemostatix outside the submitted work. No other disclosures were reported.

    References
    1.
    Pattou  F, Combemale  F, Fabre  S,  et al.  Hypocalcemia following thyroid surgery: incidence and prediction of outcome.  World J Surg. 1998;22(7):718-724. doi:10.1007/s002689900459PubMedGoogle ScholarCrossref
    2.
    Puzziello  A, Rosato  L, Innaro  N,  et al.  Hypocalcemia following thyroid surgery: incidence and risk factors: a longitudinal multicenter study comprising 2,631 patients.  Endocrine. 2014;47(2):537-542. doi:10.1007/s12020-014-0209-yPubMedGoogle ScholarCrossref
    3.
    Stack  BC  Jr, Bimston  DN, Bodenner  DL,  et al.  American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: postoperative hypoparathyroidism—definitions and management  [published correction appears in Endocr Pract. 2015;21(10):1187].  Endocr Pract. 2015;21(6):674-685. doi:10.4158/EP14462.DSCPubMedGoogle ScholarCrossref
    4.
    Reeve  T, Thompson  NW.  Complications of thyroid surgery: how to avoid them, how to manage them, and observations on their possible effect on the whole patient.  World J Surg. 2000;24(8):971-975. doi:10.1007/s002680010160PubMedGoogle ScholarCrossref
    5.
    Almquist  M, Ivarsson  K, Nordenström  E, Bergenfelz  A.  Mortality in patients with permanent hypoparathyroidism after total thyroidectomy.  Br J Surg. 2018;105(10):1313-1318. doi:10.1002/bjs.10843PubMedGoogle ScholarCrossref
    6.
    Edafe  O, Antakia  R, Laskar  N, Uttley  L, Balasubramanian  SP.  Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia.  Br J Surg. 2014;101(4):307-320. doi:10.1002/bjs.9384PubMedGoogle ScholarCrossref
    7.
    Chadwick  DR.  Hypocalcaemia and permanent hypoparathyroidism after total/bilateral thyroidectomy in the BAETS Registry.  Gland Surg. 2017;6(suppl 1):S69-S74. doi:10.21037/gs.2017.09.14PubMedGoogle ScholarCrossref
    8.
    Brophy  C, Woods  R, Murphy  MS, Sheahan  P.  Perioperative magnesium levels in total thyroidectomy and relationship to hypocalcemia.  Head Neck. 2019;41(6):1713-1718. doi:10.1002/hed.25644PubMedGoogle ScholarCrossref
    9.
    Cherian  AJ, Gowri  M, Ramakant  P, Paul  TV, Abraham  DT, Paul  MJ.  The role of magnesium in post-thyroidectomy hypocalcemia.  World J Surg. 2016;40(4):881-888. doi:10.1007/s00268-015-3347-3PubMedGoogle ScholarCrossref
    10.
    Garrahy  A, Murphy  MS, Sheahan  P.  Impact of postoperative magnesium levels on early hypocalcemia and permanent hypoparathyroidism after thyroidectomy.  Head Neck. 2016;38(4):613-619. doi:10.1002/hed.23937PubMedGoogle ScholarCrossref
    11.
    Luo  H, Yang  H, Zhao  W,  et al.  Hypomagnesemia predicts postoperative biochemical hypocalcemia after thyroidectomy.  BMC Surg. 2017;17(1):62. doi:10.1186/s12893-017-0258-2PubMedGoogle ScholarCrossref
    12.
    Nellis  JC, Tufano  RP, Gourin  CG.  Association between magnesium disorders and hypocalcemia following thyroidectomy.  Otolaryngol Head Neck Surg. 2016;155(3):402-410. doi:10.1177/0194599816644594PubMedGoogle ScholarCrossref
    13.
    Charlson  ME, Pompei  P, Ales  KL, MacKenzie  CR.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.  J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8PubMedGoogle ScholarCrossref
    14.
    Liu  JH, Zingmond  DS, McGory  ML,  et al.  Disparities in the utilization of high-volume hospitals for complex surgery.  JAMA. 2006;296(16):1973-1980. doi:10.1001/jama.296.16.1973PubMedGoogle ScholarCrossref
    15.
    Romano  PS, Roos  LL, Jollis  JG.  Adapting a clinical comorbidity index for use with ICD-9-CM administrative data: differing perspectives.  J Clin Epidemiol. 1993;46(10):1075-1079. doi:10.1016/0895-4356(93)90103-8PubMedGoogle ScholarCrossref
    16.
    United States Census Bureau. Metropolitan and micropolitan statistical areas. https://www.census.gov/programs-surveys/metro-micro.html. Accessed July 7, 2016.
    17.
    United States Census Bureau. American fact finder. https://factfinder.census.gov/faces/nav/jsf/pages/index.xhtml. Accessed July 7, 2016.
    18.
    Bureau of Labor Statistics, US Department of Labor. Consumer price index inflation calculator. https://www.bls.gov/data/inflation_calculator.htm. Accessed May 16, 2018.
    19.
    Agency for Healthcare Research and Quality. Medical expenditure panel survey. https://meps.ahrq.gov/survey_comp/hc_samplecodes_se.shtml. Accessed December 2, 2019.
    20.
    Costanzo  M, Marziani  A, Condorelli  F, Migliore  M, Cannizzaro  MA.  Post-thyroidectomy hypocalcemic syndrome: predictive value of early PTH: preliminary results.  Ann Ital Chir. 2010;81(4):301-305.PubMedGoogle Scholar
    21.
    Wilson  RB, Erskine  C, Crowe  PJ.  Hypomagnesemia and hypocalcemia after thyroidectomy: prospective study.  World J Surg. 2000;24(6):722-726. doi:10.1007/s002689910116PubMedGoogle ScholarCrossref
    22.
    Kazaure  HS, Sosa  JA.  Surgical hypoparathyroidism.  Endocrinol Metab Clin North Am. 2018;47(4):783-796. doi:10.1016/j.ecl.2018.07.005PubMedGoogle ScholarCrossref
    23.
    Kikumori  T, Imai  T, Tanaka  Y, Oiwa  M, Mase  T, Funahashi  H.  Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: long-term follow-up of grafted parathyroid function.  Surgery. 1999;125(5):504-508. doi:10.1016/S0039-6060(99)70201-1PubMedGoogle ScholarCrossref
    24.
    Lo  CY.  Parathyroid autotransplantation during thyroidectomy.  ANZ J Surg. 2002;72(12):902-907. doi:10.1046/j.1445-2197.2002.02580.xPubMedGoogle ScholarCrossref
    25.
    Lo  CY, Lam  KY.  Routine parathyroid autotransplantation during thyroidectomy.  Surgery. 2001;129(3):318-323. doi:10.1067/msy.2001.111125PubMedGoogle ScholarCrossref
    26.
    Smith  MA, Jarosz  H, Hessel  P, Lawrence  AM, Paloyan  E.  Parathyroid autotransplantation in total thyroidectomy.  Am Surg. 1990;56(7):404-406.PubMedGoogle Scholar
    27.
    Lin  YS, Hsueh  C, Wu  HY, Yu  MC, Chao  TC.  Incidental parathyroidectomy during thyroidectomy increases the risk of postoperative hypocalcemia.  Laryngoscope. 2017;127(9):2194-2200. doi:10.1002/lary.26448PubMedGoogle ScholarCrossref
    28.
    Kihara  M, Miyauchi  A, Kontani  K, Yamauchi  A, Yokomise  H.  Recovery of parathyroid function after total thyroidectomy: long-term follow-up study.  ANZ J Surg. 2005;75(7):532-536. doi:10.1111/j.1445-2197.2005.03435.xPubMedGoogle ScholarCrossref
    29.
    Lorente-Poch  L, Sancho  J, Muñoz  JL, Gallego-Otaegui  L, Martínez-Ruiz  C, Sitges-Serra  A.  Failure of fragmented parathyroid gland autotransplantation to prevent permanent hypoparathyroidism after total thyroidectomy.  Langenbecks Arch Surg. 2017;402(2):281-287. doi:10.1007/s00423-016-1548-3PubMedGoogle ScholarCrossref
    30.
    Sitges-Serra  A, Lorente-Poch  L, Sancho  J.  Parathyroid autotransplantation in thyroid surgery.  Langenbecks Arch Surg. 2018;403(3):309-315. doi:10.1007/s00423-018-1654-5PubMedGoogle ScholarCrossref
    31.
    Su  A, Gong  Y, Wu  W, Gong  R, Li  Z, Zhu  J.  Does the number of parathyroid glands autotransplanted affect the incidence of hypoparathyroidism and recovery of parathyroid function?  [published online February 2, 2018].  Surgery. doi:10.1016/j.surg.2017.12.025PubMedGoogle Scholar
    32.
    Xing  T, Hu  Y, Wang  B, Zhu  J.  Role of oral calcium supplementation alone or with vitamin D in preventing post-thyroidectomy hypocalcaemia: a meta-analysis.  Medicine (Baltimore). 2019;98(8):e14455. doi:10.1097/MD.0000000000014455PubMedGoogle Scholar
    33.
    Al Khadem  MG, Rettig  EM, Dhillon  VK, Russell  JO, Tufano  RP.  Postoperative IPTH compared with IPTH gradient as predictors of post-thyroidectomy hypocalcemia.  Laryngoscope. 2018;128(3):769-774. doi:10.1002/lary.26805PubMedGoogle ScholarCrossref
    34.
    Alhefdhi  A, Mazeh  H, Chen  H.  Role of postoperative vitamin D and/or calcium routine supplementation in preventing hypocalcemia after thyroidectomy: a systematic review and meta-analysis.  Oncologist. 2013;18(5):533-542. doi:10.1634/theoncologist.2012-0283PubMedGoogle ScholarCrossref
    35.
    Landry  CS, Grubbs  EG, Hernandez  M,  et al.  Predictable criteria for selective, rather than routine, calcium supplementation following thyroidectomy.  Arch Surg. 2012;147(4):338-344. doi:10.1001/archsurg.2011.1406PubMedGoogle ScholarCrossref
    36.
    Lee  JW, Kim  JK, Kwon  H, Lim  W, Moon  BI, Paik  NS.  Routine low-dose calcium supplementation after thyroidectomy does not reduce the rate of symptomatic hypocalcemia: a prospective randomized trial.  Ann Surg Treat Res. 2019;96(4):177-184. doi:10.4174/astr.2019.96.4.177PubMedGoogle ScholarCrossref
    37.
    Nahas  ZS, Farrag  TY, Lin  FR, Belin  RM, Tufano  RP.  A safe and cost-effective short hospital stay protocol to identify patients at low risk for the development of significant hypocalcemia after total thyroidectomy.  Laryngoscope. 2006;116(6):906-910. doi:10.1097/01.mlg.0000217536.83395.37PubMedGoogle ScholarCrossref
    38.
    Sanabria  A, Rojas  A, Arevalo  J.  Meta-analysis of routine calcium/vitamin D3 supplementation versus serum calcium level–based strategy to prevent postoperative hypocalcaemia after thyroidectomy.  Br J Surg. 2019;106(9):1126-1137. doi:10.1002/bjs.11216PubMedGoogle ScholarCrossref
    39.
    Wang  TS, Cheung  K, Roman  SA, Sosa  JA.  To supplement or not to supplement: a cost-utility analysis of calcium and vitamin D repletion in patients after thyroidectomy.  Ann Surg Oncol. 2011;18(5):1293-1299. doi:10.1245/s10434-010-1437-xPubMedGoogle ScholarCrossref
    40.
    Aspinall  S, Oweis  D, Chadwick  D.  Effect of surgeons’ annual operative volume on the risk of permanent hypoparathyroidism, recurrent laryngeal nerve palsy and haematoma following thyroidectomy: analysis of United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS).  Langenbecks Arch Surg. 2019;404(4):421-430. doi:10.1007/s00423-019-01798-7PubMedGoogle ScholarCrossref
    41.
    Gourin  CG, Tufano  RP, Forastiere  AA, Koch  WM, Pawlik  TM, Bristow  RE.  Volume-based trends in thyroid surgery.  Arch Otolaryngol Head Neck Surg. 2010;136(12):1191-1198. doi:10.1001/archoto.2010.212PubMedGoogle ScholarCrossref
    42.
    Loyo  M, Tufano  RP, Gourin  CG.  National trends in thyroid surgery and the effect of volume on short-term outcomes.  Laryngoscope. 2013;123(8):2056-2063. doi:10.1002/lary.23923PubMedGoogle ScholarCrossref
    43.
    Meltzer  C, Klau  M, Gurushanthaiah  D,  et al.  Surgeon volume in thyroid surgery: surgical efficiency, outcomes, and utilization.  Laryngoscope. 2016;126(11):2630-2639. doi:10.1002/lary.26119PubMedGoogle ScholarCrossref
    44.
    Nouraei  SA, Virk  JS, Middleton  SE,  et al.  A national analysis of trends, outcomes and volume-outcome relationships in thyroid surgery.  Clin Otolaryngol. 2017;42(2):354-365. doi:10.1111/coa.12730PubMedGoogle ScholarCrossref
    45.
    Sosa  JA, Bowman  HM, Tielsch  JM, Powe  NR, Gordon  TA, Udelsman  R.  The importance of surgeon experience for clinical and economic outcomes from thyroidectomy.  Ann Surg. 1998;228(3):320-330. doi:10.1097/00000658-199809000-00005PubMedGoogle ScholarCrossref
    46.
    Stavrakis  AI, Ituarte  PH, Ko  CY, Yeh  MW.  Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery.  Surgery. 2007;142(6):887-899. doi:10.1016/j.surg.2007.09.003PubMedGoogle ScholarCrossref
    47.
    Hammerstad  SS, Norheim  I, Paulsen  T, Amlie  LM, Eriksen  EF.  Excessive decrease in serum magnesium after total thyroidectomy for Graves’ disease is related to development of permanent hypocalcemia.  World J Surg. 2013;37(2):369-375. doi:10.1007/s00268-012-1843-2PubMedGoogle ScholarCrossref
    48.
    Wang  W, Meng  C, Ouyang  Q, Xie  J, Li  X.  Magnesemia: an independent risk factor of hypocalcemia after thyroidectomy.  Cancer Manag Res. 2019;11:8135-8144. doi:10.2147/CMAR.S218179PubMedGoogle ScholarCrossref
    49.
    Fatemi  S, Ryzen  E, Flores  J, Endres  DB, Rude  RK.  Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism.  J Clin Endocrinol Metab. 1991;73(5):1067-1072. doi:10.1210/jcem-73-5-1067PubMedGoogle ScholarCrossref
    50.
    Allgrove  J.  Physiology of calcium, phosphate, magnesium and vitamin D.  Endocr Dev. 2015;28:7-32. doi:10.1159/000380990PubMedGoogle ScholarCrossref
    51.
    Clark  I.  Relation of magnesium ions to calcium and phosphate absorption.  Nature. 1965;207(5000):982-982. doi:10.1038/207982a0PubMedGoogle ScholarCrossref
    52.
    Paunier  L.  Effect of magnesium on phosphorus and calcium metabolism.  Monatsschr Kinderheilkd. 1992;140(9)(suppl 1):S17-S20.PubMedGoogle Scholar
    53.
    Reinhart  RA.  Magnesium metabolism: a review with special reference to the relationship between intracellular content and serum levels.  Arch Intern Med. 1988;148(11):2415-2420. doi:10.1001/archinte.1988.00380110065013PubMedGoogle ScholarCrossref
    54.
    Anast  CS, Mohs  JM, Kaplan  SL, Burns  TW.  Evidence for parathyroid failure in magnesium deficiency.  Science. 1972;177(4049):606-608. doi:10.1126/science.177.4049.606PubMedGoogle ScholarCrossref
    55.
    Rude  RK, Oldham  SB, Sharp  CF  Jr, Singer  FR.  Parathyroid hormone secretion in magnesium deficiency.  J Clin Endocrinol Metab. 1978;47(4):800-806. doi:10.1210/jcem-47-4-800PubMedGoogle ScholarCrossref
    56.
    Rodríguez-Ortiz  ME, Canalejo  A, Herencia  C,  et al.  Magnesium modulates parathyroid hormone secretion and upregulates parathyroid receptor expression at moderately low calcium concentration.  Nephrol Dial Transplant. 2014;29(2):282-289. doi:10.1093/ndt/gft400PubMedGoogle ScholarCrossref
    57.
    Quitterer  U, Hoffmann  M, Freichel  M, Lohse  MJ.  Paradoxical block of parathormone secretion is mediated by increased activity of G alpha subunits.  J Biol Chem. 2001;276(9):6763-6769. doi:10.1074/jbc.M007727200PubMedGoogle ScholarCrossref
    58.
    Roh  JL, Park  CI.  Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy.  Am J Surg. 2006;192(5):675-678. doi:10.1016/j.amjsurg.2006.03.010PubMedGoogle ScholarCrossref
    59.
    Lang  BH, Chu  KK, Tsang  RK, Wong  KP, Wong  BY.  Evaluating the incidence, clinical significance and predictors for vocal cord palsy and incidental laryngopharyngeal conditions before elective thyroidectomy: is there a case for routine laryngoscopic examination?  World J Surg. 2014;38(2):385-391. doi:10.1007/s00268-013-2259-3PubMedGoogle ScholarCrossref
    60.
    Lang  BH, Wong  CK, Tsang  RK, Wong  KP, Wong  BY.  Evaluating the cost-effectiveness of laryngeal examination after elective total thyroidectomy.  Ann Surg Oncol. 2014;21(11):3548-3556. doi:10.1245/s10434-014-3770-yPubMedGoogle ScholarCrossref
    61.
    Sinclair  CF, Bumpous  JM, Haugen  BR,  et al.  Laryngeal examination in thyroid and parathyroid surgery: an American Head and Neck Society consensus statement.  Head Neck. 2016;38(6):811-819. doi:10.1002/hed.24409PubMedGoogle ScholarCrossref
    62.
    Zanocco  K, Kaltman  DJ, Wu  JX,  et al.  Cost effectiveness of routine laryngoscopy in the surgical treatment of differentiated thyroid cancer.  Ann Surg Oncol. 2018;25(4):949-956. doi:10.1245/s10434-018-6356-2PubMedGoogle ScholarCrossref
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