Perioperative indicators of hypocalcemia in total thyroidectomy: the role of vitamin D and parathyroid hormone

Transcription

1 The American Journal of Surgery (2013) 206, Southwestern Surgical Congress Perioperative indicators of hypocalcemia in total thyroidectomy: the role of vitamin D and parathyroid hormone Eric M. Salinger, M.D.*, John T. Moore, M.D., F.A.C.S. Department of Graduate Medical Education, Exempla Saint Joseph Hospital, 1835 Franklin Street, Denver, CO 80218, USA KEYWORDS: Prospective trial; Total thyroidectomy; Completion thyroidectomy; Postoperative parathyroid hormone levels; Vitamin D; Postoperative hypocalcemia Abstract BACKGROUND: Hypocalcemia is a common complication of thyroidectomy. The aim of this study was to identify risk factors for this problem. METHODS: This prospective analysis included 111 patients undergoing total or completion thyroidectomy. Preoperative vitamin D levels and postoperative day 1 parathyroid hormone levels were analyzed for their predictive effects on postoperative hypocalcemia. RESULTS: Patients with ionized calcium,4.4 mg/dl had significantly lower mean parathyroid hormone levels than normocalcemic patients (13.0 vs 28.4 pg/ml, P,.001). Parathyroid hormone levels were also significantly lower in symptomatic patients (11.0 vs 28.4 pg/ml, P,.001). Preoperative vitamin D level, body mass index, gender, and pathologic findings were not associated with low calcium levels or symptoms of hypocalcemia. CONCLUSIONS: Younger age and low postoperative parathyroid hormone levels are predictive of symptomatic hypocalcemia. A parathyroid hormone level outside of the reference range may indicate a need for more aggressive postoperative calcium supplementation and treatment with activated vitamin D. Older patients with normal postoperative parathyroid hormone levels may be safely discharged with appropriate calcium supplementation. Ó 2013 Elsevier Inc. All rights reserved. Hypocalcemia is a well-defined complication of total thyroidectomy. 1,2 Low postoperative serum calcium has been attributed to transient hypoparathyroidism due to intraoperative injury to the adjacent parathyroid tissue or its blood supply. 3 Vitamin D also plays an integral role in calcium metabolism. Early studies of patients undergoing hemithyroidectomy revealed that changes in vitamin D metabolism can occur even in the absence of total thyroidectomy. 4 Although hospital readmission is rare after The authors declare no conflicts of interest. * Corresponding author. Tel.: ; fax: address: eric.salinger@gmail.com Manuscript received March 16, 2013; revised June 26, 2013 thyroidectomy, hypocalcemia remains the most common reason for readmission. 5,6 The ability to predict which patients will develop hypocalcemia has been challenging. Traditionally, serum or ionized calcium levels are evaluated on the evening of surgery and again on postoperative day 1 to evaluate for low calcium. However, symptomatic hypocalcemia can frequently occur 48 to 72 hours after discharge. 7 Discharging patients on calcium supplementation has been endorsed as a means to reduce symptomatic hypocalcemia Although treating all patients with oral calcium reduces the overall risk for hypocalcemia, small populations of patients remain hypocalcemic even with calcium supplementation. Recently published studies have attempted to refine risk /$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.

2 E.M. Salinger and J.T. Moore Perioperative Indicators of Hypocalcemia 877 stratification for postoperative hypocalcemia in thyroidectomy patients, with varying results The focus of these studies has been to identify perioperative markers of hypocalcemia. In this study, we attempted to discern if preoperative vitamin D 3 levels and postoperative parathyroid hormone levels are predictive of postoperative hypocalcemia after total or completion thyroidectomy. Additionally, age, sex, body mass index (BMI), and pathologic findings were also evaluated as potential risk factors for symptomatic hypocalcemia. An identifiable risk factor would allow surgeons to identify those patients who are safe for early discharge. Additionally, patients requiring supplemental calcium, and closer monitoring to prevent symptoms, could be identified earlier. Methods From March 2010 to July 2012, 111 consecutive patients undergoing total thyroidectomy or completion thyroidectomy at Exempla Saint Joseph Hospital by a single surgeon were enrolled in this prospective study. Patients with end-stage renal disease, as determined from the medical record, were excluded. The study was approved by the Exempla Saint Joseph Hospital institutional review board. Verbal and written informed consent was obtained for all participants in the study at the time of enrollment. Each patient underwent preoperative evaluation of serum 25-hydroxyvitamin D (vitamin D 3 ). Normal vitamin D levels were defined as.30 ng/dl, insufficient levels as 20 to 29 ng/dl, and deficient levels as,20 ng/dl. Thyroidectomy was undertaken through a cervical incision. In each procedure, the attending surgeon attempted to identify all parathyroid glands and assess their individual viability. Marginally viable glands were autotransplanted in the sternocleidomastoid muscle using well-established techniques Therapeutic central lymph node dissection was performed at the discretion of the surgeon; prophylactic lymph node dissections were not performed. Serum ionized calcium was checked at 8 pm on the day of surgery. Serum parathyroid hormone and ionized calcium were analyzed in the morning on postoperative day 1. Hypoparathyroidism was considered to be any value below the lower limit of the reference range (14 pg/ml). Any value within the reference range was considered to be normal. Hypocalcemia was defined as serum ionized calcium,4.4 mg/dl. Patients with symptomatic hypocalcemia were those with reported paresthesia, perioral numbness, and cramping. Throughout the hospitalization, patients were checked for signs and symptoms of hypocalcemia. Any patients with signs or symptoms of hypocalcemia, as well as those patients with serum ionized calcium,4.40 mg/dl, were treated with intravenous calcium gluconate replacement. Patients were started on twice-daily oral calcium citrate 1,200 mg with vitamin D 500 IU on postoperative day 1 and continued on this supplementation at discharge until outpatient follow-up. Patients with asymptomatic hypocalcemia were maintained on oral therapy alone. Initial outpatient follow-up was conducted 10 to 14 days after operation. All 111 patients were classified according to age, sex, and BMI. Pathologic findings for each patient were also recorded. Specifically, the classification of benign versus malignant thyroid disease and presence of parathyroid tissue within the specimen were recorded. Statistical analysis of continuous data was performed using paired t tests. Categorical data were analyzed using either Fisher s exact tests or chi-square tests as appropriate. P values,.05 were considered statistically significant. Results In this study, women constituted 86% of the population (n 5 95) and men 14% of the population (n 5 16). The mean age was years, and the mean BMI was kg/m 2. Within the cohort, 92 patients had preoperative vitamin D 3 levels analyzed; the mean level was ng/ml. (Values for vitamin D 3 for the remaining 19 patients were unavailable at the time of analysis because of unavailable results or failure of specimen collection.) Forty-nine of 92 patients (53.2%) had normal levels, 21 (22.8%) had insufficient levels, and 22 (23.9%) had deficient levels. The mean postoperative parathyroid hormone level in the cohort (n 5 103) was pg/ml (reference range, 14 to 72 pg/ml). (Eight patients did not have parathyroid hormone values drawn because of lab error.) Pathologic analysis revealed that 62 of 111 patients (55.9%) had benign thyroid disease, and 49 (44.1%) had malignant pathology (Table 1). Of the patients with benign disease, 17 of 49 (34.7%) had hyperthyroidism. In this subgroup, 4 of 17 developed hypoparathyroidism (23.5%), 4 had hypocalcemia (1 of these had a normal parathyroid hormone level), and 1 developed symptoms. Sixteen of 111 patients (14.4%) had parathyroid glands found within the resected specimens. In this group, 9 of 16 (56.3%) developed hypoparathyroidism. All 9 developed hypocalcemia, but only 4 (44%) developed symptoms. Nine of 111 patients (8.1%) underwent central neck dissection. In the cohort, 19 of 111 patients (17.1%) had metastatic nodal disease. Parathyroid autotransplantation was performed in 16 of 111 (14.4%). Seven of these 16 had hypoparathyroidism (43.8%); 4 of these 7 had hypocalcemia (25%), but only 1 (6.2%) had symptoms. There were no hospital readmissions or visits to the emergency department for the cohort. There were no cases of permanent hypocalcemia. Comparisons of patients with and without postoperative hypocalcemia and symptoms are presented in Tables 2 and 3. For patient BMI, vitamin D 3, gender, type of pathology, or presence of parathyroid gland in the specimen, there was no statistically significant difference between symptomatic and asymptomatic patients, nor was there a difference between the hypocalcemic and normocalcemic

3 878 The American Journal of Surgery, Vol 206, No 6, December 2013 Table 1 Pathologic diagnosis of thyroidectomy specimens Diagnosis n Benign Multinodular goiter 27 Follicular adenoma 14 Graves disease 11 Toxic multinodular goiter 6 Recurrent thyroid mass 1 Thyroiditis 1 Hurthle cell adenoma 1 Adenomatoid nodule 1 Malignant Papillary carcinoma 40 Follicular carcinoma 6 Hurthle cell carcinoma 3 patients for any of the above variables. Postoperative parathyroid hormone levels were significantly lower in those patients who had hypocalcemia and symptoms. Patients with hypocalcemia had a mean parathyroid hormone level of pg/ml, while normocalcemic patients had a mean parathyroid hormone level of pg/ml (P,.001). Similarly, symptomatic patients had a mean parathyroid hormone level of pg/ml compared with pg/ml in the asymptomatic group (P,.001). Patient age was the other significantly associated variable in this cohort. Hypocalcemic patients had a mean age of years, compared with years in their normocalcemic counterparts (P,.001). Patients with symptoms were also significantly younger than those without ( vs years, P 5.019). Using the lower limit of the reference range (14 pg/ml) as a cutoff, the sensitivity and specificity of parathyroid hormone in the prediction of symptoms were 71.4% and 73.2%, respectively. The positive predictive and negative predictive values for parathyroid hormone in the prediction of symptoms were 40.5% and 90.9%, respectively. When analyzing parathyroid hormone as a predictor of hypocalcemia, sensitivity and specificity were 73.1% and 80.3%. The positive and negative predictive values were 57.6% and 89.1%. Each of the aforementioned values was highly significant (P,.0001). Comments One of the authors (J.T.M.) experiences was the impetus for carrying out this study. Before the study, the most common reason for patients to seek urgent medical attention after hospitalization was symptoms of hypocalcemia despite prophylactic calcium and vitamin D replacement. Measuring postoperative calcium levels was helpful but not always effective in identifying patients who would later develop symptomatic hypocalcemia. In addition, the referral pattern for these patients was such that they would frequently seek attention at hospital emergency departments remote from the home institution. This often resulted in a fractionated approach, with frequent delays in appropriate therapy and high patient dissatisfaction. Understanding the physiology of calcium metabolism is paramount to the understanding of hypocalcemia in thyroidectomy patients. The primary focus of this study centers on the complex interaction of parathyroid hormone and its relationship with vitamin D levels. Parathyroid hormone acts throughout the body to increase serum ionized calcium. It increases gastrointestinal absorption through activation of 25-hydroxyvitamin D to 1,25-hydroxyvitamin (activated) vitamin D, which increases gut absorption of dietary calcium. It also increases calcium reabsorption in the kidneys and bone. Serum ionized calcium acts as a feedback mechanism, inhibiting the release of parathyroid hormone at elevated levels. Additionally, activated vitamin D inhibits the production of parathyroid hormone at the nuclear level within the parathyroid gland. If the parathyroid glands have been injured, they may not respond appropriately to low ionized calcium. Vitamin D is a steroid hormone that acts at the intracellular level to change gene expression. Pre vitamin Table 2 Variable Differences in continuous variables between patients with and without hypocalcemia Hypocalcemia (ica, 4.44 mg/dl) (n 5 28) Normocalcemia (ica R 4.44 mg/dl) (n 5 75) P Age (y) ,.001* BMI (kg/m 2 ) Vitamin D (ng/ml) Postoperative PTH (pg/ml) ,.001* Symptomatic (n 5 22) Asymptomatic (n 5 89) Age (y) * BMI (kg/m 2 ) Vitamin D (ng/ml) Postoperative PTH (pg/ml) ,.001* BMI 5 body mass index; ica 5 ionized calcium; PTH 5 parathyroid hormone. *Statistically significant.

4 E.M. Salinger and J.T. Moore Perioperative Indicators of Hypocalcemia 879 Table 3 Variable Differences in categorical variables between patients with and without hypocalcemia Hypocalcemia (ica, 4.44 mg/dl) (n 5 28) Normocalcemia (ica R 4.44 mg/dl) (n 5 75) P Gender Male 5 (18%) 11 (15%).762 Female 23 (82%) 64 (85%) Inpatient symptoms Yes 9 (32%) 2 (3%),.001* No 19 (68%) 73 (97%) Outpatient symptoms Yes 5 (19%) 7 (11%).325 No 22 (81%) 58 (89%) Cancer Yes 14 (50%) 30 (41%).389 No 14 (50%) 44 (59%) Parathyroid on pathology Yes 6 (21%) 10 (13%).363 No 22 (79%) 65 (87%) Symptomatic (n 5 22) Asymptomatic (n 5 89) Gender Male 4 (18%) 13 (15%).742 Female 18 (82%) 76 (85%) Cancer Yes 10 (45%) 30 (41%).848 No 12 (55%) 44 (59%) Parathyroid on pathology Yes 5 (23%) 12 (13%).323 No 17 (77%) 77 (87%) ica 5 ionized calcium. D is created from cholesterol molecules within the skin via exposure to ultraviolet light. It is then converted into cholecalciferol (vitamin D 3 ), which is hydroxylated in the liver to become 25-hydroxyvitamin D. The body does not stringently regulate this process. In the kidney, 1a-hydroxylase then converts 25-hydroxyvitamin D into 1,25-hydroxyvitamin D, which is the active form. This step is stimulated by parathyroid hormone and is inhibited by high phosphate levels. Activated vitamin D induces the expression of proteins that lead to an increase in total body calcium levels. Calbindin-D is one such protein that increases the movement of calcium across the intestinal epithelium. Although the exact mechanism of action is unknown, there is evidence that it increases the production of a calcium-proton adenosine triphosphatase. 18 Vitamin D also increases bone storage of calcium. A disruption in this physiologic pathway will clearly increase the risk for hypocalcemia. The logical effect of an injury to the parathyroid glands during thyroidectomy would be an inability to respond to low serum ionized calcium. We would expect that hypocalcemia would result. As such, checking a postoperative parathyroid hormone level might be predictive of hypocalcemia. Similarly, if vitamin D levels were low enough, the body would have insufficient stores to create enough activated vitamin D, despite an appropriate parathyroid response. Because 25-hydroxyvitamin D is not regulated by the body and is at a fairly steady state, preoperative evaluation is an appropriate time for evaluation. In our patient population, low postoperative parathyroid hormone was predictive of both hypocalcemia and symptoms. This is in concordance with several other studies. 12,19 25 The sensitivity and specificity in our cohort were not as high as in some of the other studies. However, the negative predictive value of 90% in patients with normal parathyroid hormone suggests that patients with normal parathyroid hormone levels can likely be discharged early with low risk for outpatient complications. In prior studies, the sensitivity and specificity of parathyroid hormone to predict hypocalcemia often approached 100%. 19,20,22,25 Although our data do not support this degree of sensitivity and specificity, we suspect that a larger cohort of patients may have achieved similar results. There is much variability in the timing of the laboratory assessment of parathyroid hormone levels in the literature. 25 Intraoperative, immediate postoperative, and more remote testing all are predictive of hypocalcemia. We opted to check postoperative day 1 because we routinely observe our patients overnight. This is largely because many of the patients are referred from remote locations. As such, the surgeon preferred to observe them overnight rather than send them to remote locations. On the basis of the

5 880 The American Journal of Surgery, Vol 206, No 6, December 2013 literature, a surgeon who otherwise felt compelled to discharge patients on the day of surgery could probably safely do so given a normal parathyroid hormone level. Overall, this study is in concordance with the existing literature. Our attempt to risk-stratify patients for postoperative hypocalcemia demonstrates that parathyroid hormone remains the best single test for identification of patients at risk for postoperative hypocalcemia. Normal or near normal levels can be used to justify early discharge of patients. Conversely, early intervention (calcium and activated vitamin D supplementation) should be strongly considered for patients with low parathyroid hormone levels. Determination of the optimal treatment for the atrisk population remains challenging. This has been addressed in previously reported retrospective and prospective trials, 12,13,26 but an optimal algorithm has not been clearly elucidated. Additional prospective analyses are needed to derive the most effective regimen to prevent outpatient complications and hospital readmissions while minimizing the cost and adverse effects of aggressive calcitriol supplementation. On the basis of the findings of this study, we have begun treating patients with postoperative hypoparathyroidism using.5 mg of calcitriol twice daily in addition to routine calcium supplementation. Prior reports coincide with our finding suggesting that younger patient age may be a significant risk factor for postoperative hypocalcemia. 2,12 Conversely, other studies have found older age to be a risk factor. 23,27 The reason for this is unclear from a physiologic standpoint. In our study, there was no clear age cutoff for the development of hypocalcemia. It is difficult to draw conclusions on the basis of this conflicting data. However, in our cohort, younger age did appear to place patients at increased risk for postoperative hypocalcemia. It is incumbent upon surgeons to be aware of this risk factor and incorporate it into the decision-making process when evaluating the timing of discharge and the need for more aggressive calcium and vitamin D supplementation. Another finding that is notable in our study is the overall levels of vitamin D in the population. Although the mean value of vitamin D3 in our cohort was within the reference range, nearly half of the patients (46%) were below normal, and almost one fourth of all patients were deficient in vitamin D. Although low vitamin D levels did not correlate with hypocalcemia in this trial, they have shown a correlation in several others. 23,27,28 Additionally, vitamin D deficiency has been linked to several other health problems 29 and has a high prevalence in the United States. 30 The selection of factors for evaluation was driven largely by previously published studies. It was our intent to identify risk factors that might be easily identified by a community surgeon to improve the safety of patients being discharged after thyroidectomy. As previously mentioned, young patient age, preoperative vitamin D level, and parathyroid hormone level had previously been identified as predictors. BMI was included because it had not been a point of focus in previous studies, and obese patients are a cohort that is at risk for vitamin D deficiency. In other studies, thyroid pathology, extent of neck dissection, and patient sex were not predictive of hypocalcemia, and our findings are in concordance with that. Patients with positive metastatic lymph nodes, and those undergoing central neck dissections, may warrant analysis for increased risk for hypoparathyroidism and hypocalcemia. In this cohort, the number of central neck dissections (9 of 111) was not large enough to reach statistical significance. Patients with positive nodes represented a larger percentage of the cohort (17.1%), and this population could be considered for retrospective analysis. An additional subgroup that was not analyzed separately was patients with hyperthyroidism. This group of patients has been identified as having an increased risk for hypocalcemia postoperatively, in theory because these patients can develop bone hunger. 31 We felt it appropriate to include this group of patients, because our primary interest was the relationship between postoperative parathyroid hormone, preoperative vitamin D level, and the development of symptomatic hypocalcemia. We felt that if the rate of hypocalcemia and the rate of postoperative hypoparathyroidism were greater in patients with hyperthyroidism, this would be identified in the subset analysis and potentially excluded. In addition, our patients generally were returned to and maintained in a euthyroid condition with blocking agents for a considerable time before surgical intervention, thereby reducing the prevalence of postoperative bone hunger. The data in this study confirmed that this group did not have higher rates of hypocalcemia. One of the limitations of this trial was that it was not blinded. The surgeons had access to individual patient results. As it became clear that low parathyroid hormone levels were predictive of hypocalcemia, patients with postoperative hypoparathyroidism were preemptively treated with calcitriol. It is possible that this prevented emergency department visits and rehospitalizations. There also is a diminished value in the preoperative vitamin D findings because of the 19 patients with unavailable values. Missing this many patients may have prevented the achievement of statistical significance. There were fewer missing values for parathyroid hormone results, but this too may have had an impact on the sensitivity, specificity, and negative and positive predictive values. Finally, including additional subgroup analysis for metastatic lymph nodes, central neck dissection, hyperthyroid disease, and parathyroid autotransplantation would likely have been of benefit. Conclusions Symptomatic hypocalcemia is a well-known complication of total thyroidectomy that represents the most common reason for hospital readmission after surgery. In our study, we identified postoperative parathyroid hormone level as a strong predictor of symptomatic hypocalcemia. A normal parathyroid hormone level on postoperative day 1 can be used to identify patients who may be safely

6 E.M. Salinger and J.T. Moore Perioperative Indicators of Hypocalcemia 881 discharged with minimal risk for hypocalcemia. Low parathyroid hormone on postoperative day 1 indicates the need for more aggressive therapy, likely with activated vitamin D and increased calcium supplementation. Additionally, younger patients may be at increased risk for developing symptomatic hypocalcemia. Surgeons need to be aware of this and use their best judgment when discharging patients. References 1. Efremidou EI, Papageorgiou MS, Liratzopoulos N, et al. The efficacy and safety of total thyroidectomy in the management of benign thyroid disease: a review of 932 cases. Can J Surgery 2009;52: Bhattacharyya N, Fried MP. Assessment of the morbidity and complications of total thyroidectomy. Arch Otolaryngol Head Neck Surg 2002;128: Yamashita H, Murakami T, Noguchi S, et al. Postoperative tetany in Graves disease: important role of vitamin D metabolites. Ann Surg 1999;229: Bergenfelz A, Ahrén B. Calcium metabolism after hemithyroidectomy. Horm Res 1993;39: Hessman C, Fields J, Schuman E. Outpatient thyroidectomy: is it a safe and reasonable option? Am J Surg 2011;201: Snyder SK, Hamid KS, Roberson CR, et al. Outpatient thyroidectomy is safe and reasonable: experience with more than 1,000 planned outpatient procedures. J Am Coll Surg 2010;210: McHenry CR, Speroff T, Wentworth D, et al. Risk factors for postthyroidectomy hypocalcemia. Surgery 1994;116: Roh JL, Park CI. Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy. Am J Surg Nov 2006;192: Bellantone R, Lombardi CP, Raffaelli M, et al. Is routine supplementation therapy (calcium and vitamin D) useful after total thyroidectomy? Surgery 2002;132: Wang TS, Roman SA, Sosa JA. Postoperative calcium supplementation in patients undergoing thyroidectomy. Curr Opin Oncol 2012; 24: Roh JL, Park JY, Park CI. 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Autotransplantation of parathyroid glands in thyroid carcinoma surgery and their postoperative function [article in Japanese]. Nihon Geka Gakkai Zasshi 1989;90: Barrett K, Barman S, Boitano S, et al. Hormonal control of calcium & phosphate metabolism & the physiology of bone. In: Ganong s review of medical physiology. 24th ed. New York: McGraw-Hill; Asari R, Passler C, Kaczirek K, et al. Hypoparathyroidism after total thyroidectomy: a prospective study. Arch Surg 2008;143: Bozec A, Guevara N, Bailleux S, et al. [Early PTH assay after total thyroidectomy: predictive factor for post operative hypocalcemia? [article in French]. Rev Laryngol Otol Rhinol (Bord) 2006;127: Chia SH, Weisman RA, Tieu D, et al. Prospective study of perioperative factors predicting hypocalcemia after thyroid and parathyroid surgery. Arch Otolaryngol Head Neck Surg 2006;132: Cote V, Sands N, Hier MP, et al. Cost savings associated with postthyroidectomy parathyroid hormone levels. Otolaryngol Head Neck Surg 2008;138: Erbil Y, Bozbora A, Ozbey N, et al. Predictive value of age and serum parathormone and vitamin D 3 levels for postoperative hypocalcemia after total thyroidectomy for nontoxic multinodular goiter. Arch Surg 2007;142: Grodski S, Serpell J. Evidence for the role of perioperative PTH measurement after total thyroidectomy as a predictor of hypocalcemia. World J Surg 2008;32: AES Guidelines 06/01 Group. Australian Endocrine Surgeons Guidelines AES06/01. Postoperative parathyroid hormone measurement and early discharge after total thyroidectomy: analysis of Australian data and management recommendations. ANZ J Surg 2007;77: Youngwirth L, Benavidez J, Sippel R, et al. Postoperative parathyroid hormone testing decreases symptomatic hypocalcemia and associated emergency room visits after total thyroidectomy. Surgery 2010;148: Erbil Y, Barbaros U, Temel B, et al. The impact of age, vitamin D 3 level, and incidental parathyroidectomy on postoperative hypocalcemia after total or near total thyroidectomy. Am J Surg 2009;197: Díez M, Vera C, Ratia T, et al. Effect of vitamin D deficiency on hypocalcaemia after total thyroidectomy due to benign goitre [article in Spanish]. Cir Esp. Nov 2013;91: Schöttker B, Haug U, Schomburg L, et al. Strong associations of 25- hydroxyvitamin D concentrations with all-cause, cardiovascular, cancer, and respiratory disease mortality in a large cohort study. Am J Clin Nutr 2013;97: Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res 2011;31: Pesce CE, Shiue Z, Tsai HL, et al. Postoperative hypocalcemia after thyroidectomy for Graves disease. Thyroid 2010;20: Discussion Maria Albuja-Cruz, M.D. (Aurora, CO): Thank you Dr Salinger for a very nice presentation. This study tried to address 1 of the most common postoperative complications after total thyroidectomy which commonly results in the need for additional medications, increased length in hospital stay and readmissions, all of which are inconvenient and costly to the patient and the health care system. For all these reasons, the identification of preoperative or postoperative risk factors that could be modified or identify those who are at risk of these complication would be of great benefit. This study contributes to the existing literature in 2 aspects: First, it supports the arm of existing data that had found that low vitamin D is not a predictive factor of postoperative hypocalcaemia and second, it confirms which has been previously described in the sense of PTH being 1 of the stronger predictors of post thyroidectomy hypocalcaemia. These are my questions for you: What was the rationale to check PTH levels on POD#1 and not do it at an earlier postoperative time when it be

7 882 The American Journal of Surgery, Vol 206, No 6, December 2013 used as a criterion for discharge on the same day of surgery or to initiate a more aggressive therapy at an earlier time? Also, interestingly in your surgical series, 15% of the study population underwent thyroidectomy for Graves disease and toxic multinodular goiter, all these known to carry a 20 fold increase in postoperative hypocalcaemia secondary to thyrotoxic osteodystrophy or hungry bone syndrome. Will you be able to explain to us what was the rationale of including this subset of patients in your study? Did you find in this subset of patients a higher risk of biochemical or symptomatic hypocalcaemia? And lastly, how did the result of your study change your practice regarding the supplementation of vitamin D and calcium or early discharge? Thank you. Eric Salinger, M.D. (Denver, CO): Thanks for your questions. Regarding the first question, in terms of the timing of our evaluation, it is routine in our institution for us to keep all of our patients undergoing total thyroidectomy for overnight observation, for concern for hematoma. While it is possible that patients being discharged after that can develop a hematoma, most of them occur within the first 24 hours. So we felt that waiting the additional overnight period wouldn t have an impact on our findings and would potentially allow for a little bit more stabilization of their parathyroid hormone levels. Secondly, regarding Graves and toxic multinodular goiter, we did not opt to separate them out from the remainder of our study, largely because we felt with their increased risk factor that their parathyroid hormone level would still probably be indicative. Unfortunately we did not have a subset analysis to look and see if there are any differences. In looking at several different subsets, there wasn t a large enough population in our study. I think it would have been underpowered; I don t think the data would have achieved any sort of significance. And finally, regarding the calcium and vitamin D supplementation, and how it is going to change our practice: I think 1 thing that it is going to do is patients who do have a low parathyroid hormone level will be treated with activated vitamin D empirically without waiting for them to develop symptoms. And I think that that is going to be the biggest paradigm change for us. I think it may allow us to consider discharging patients earlier, meaning after a short observation period, discharging them on postoperative day 0, knowing that our hematoma rate in our hospital is quite low and it will be something to consider. We will continue to keep all patients on a dose of oral calcium and potentially cholecalciferol, but certainly at the addition of activated vitamin D to patients who are hypoparathyroid will be a change in our practice. Anees Chagpar, M.D. (New Haven, CT): How will you use this practically? When do you get that PTH level and at what level would you implement supplementation? Dr Salinger: We currently check it with morning labs usually around 5 in the morning on postoperative day 1, and at our hospital the result is usually back within an hour or 2, so it allows us to identify patients who are low. In our institution, 14 is the lower limit of normal and that correlated quite well with our patients who developed symptoms. So we are using a low value outside of the reference range to initiate treatment. There are a few studies that have looked at stratifying patients who are extremely low and not quite as low and then closer to reference range to decide on dosing. We did not certainly have enough patients to evaluate that to attempt to figure out. That would be a question to another study, I think.