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Routine postoperative administration of vitamin D and calcium after total thyroidectomy: a meta-analysis
International Journal of Surgery 9 (2011) 46e51
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.theijs.com
Routine postoperative administration of vitamin D and calcium after total thyroidectomy: a meta-analysisq Alvaro Sanabria*, Luis C. Dominguez, Valentin Vega, Camilo Osorio, Daniel Duarte Department of Surgery, School of Medicine, Universidad de La Sabana, Bogota, Campus Puente del Comun, Km 21 Autopista Norte, Chia, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2010 Accepted 15 August 2010 Available online 8 September 2010
Background: Temporary hypocalcemia is a frequent complication after total thyroidectomy. Routine postoperative administration of vitamin D and calcium can reduce the incidence of symptomatic postoperative hypocalcemia. We undertook a systematic review to assess the effectiveness of this intervention. Methods: We identified randomized controlled trials comparing the administration of vitamin D or metabolites to oral calcium or no treatment in patients after total thyroidectomy in MEDLINE, EMBASE and LILACS databases. Results: Four studies with 706 patients were included: 346 in the calcitriol group, 288 in the oral calcium group and 72 in the control group. The rates of hypocalcemia symptoms were 4%, 19% and 31%, respectively. The OR value for the comparison between calcitriol þ calcium as compared to no treatment and to exclusive calcium treatment groups was 0.32 (95% CI, 0.13e0.79) and 0.31 (95% CI, 0.14e0.70), respectively. Conclusion: The prophylactic treatment with vitamin D or metabolites þ calcium is effective to decrease the incidence of symptoms of temporary hypocalcemia. Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid neoplasm Thyroidectomy Hypocalcemia
1. Introduction Thyroidectomy is the most common surgical procedure performed in the neck by surgeons. Hypocalcemia is the most frequent complication after total thyroidectomy, and it is the main cause of prolonged hospital stay.1e3 Hypocalcemia can occur from the immediate postoperative period up to five days after surgery, and it is described as one of the most unpleasant experiences because of symptoms of tingling, spasm and chest oppression in severe cases. The rate of symptomatic postoperative hypocalcemia ranges from 5 to 50%,4 but only 1e3% of cases is definitive. Treatment of postoperative hypocalcemia depends on its severity. For mild cases, oral vitamin D and calcium supplements are enough to relieve symptoms and return serum calcium values to normal levels. In cases of severe hypocalcemia, emergency admission to the hospital is necessary, which involves periodic serum calcium measurements, administration of intravenous calcium gluconate and supplementation with high doses of oral vitamin D and calcium. Based on the extent of tissue involved, thyroidectomy could be classified as an intermediate procedure, necessitating an outpatient
procedure in the majority of cases.5,6 However, symptoms of hypocalcemia limit the use of thyroidectomy as an outpatient procedure due to the high frequency of symptoms, general unpleasantness of them, and the risk of severe consequences such as cardiorespiratory arrest. To address these issues, some authors have suggested that routine measurements of serum calcium and parathyroid hormone could predict the development of hypocalcemia, allowing doctors to treat patients before symptoms appear.7 However, this strategy has not been successful because symptomatic hypocalcemia is a multifactorial condition. Others have suggested the routine prophylactic administration of oral vitamin D and calcium in the postoperative period to reduce the rate of symptomatic hypocalcemia.8e12 However, the number of studies and patients included in individual studies are low and do not offer clear evidence of the benefits of this therapy. In this case, a meta-analysis could offer a more precise evaluation of the effectiveness of treatment. The aim of this study was assess the effectiveness of prophylactic administration of vitamin D or metabolites and calcium in patients who underwent total thyroidectomy. 2. Materials and methods
q Presented at the World Congress of Thyroid Cancer. Toronto, Canada. August 9, 2009. * Corresponding author. Tel./fax: þ57 8615555. E-mail address: [email protected] (A. Sanabria).
We performed a bibliography search on the MEDLINE, EMBASE and LILACS databases for studies published from January 1980 to April 2008 using the MESH and free terms “thyroidectomy”, “thyroid surgery”, “calcitriol” and “vitamin D”. An expanded search was used using Boolean operators. References were explored to
1743-9191/$ e see front matter Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2010.08.006
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51
47
QUORUM diagram Potentially relevant RCTs identified and screened for retrieval n = 12
RCTs retrieved for more detailed evaluation n=5
RCTs excluded n = 7 List reasons n = 7 non randomized design
RCTs excluded n = 0
Potentially appropriate RCTs to be included in the meta-analysis n=5 RCTs excluded from meta-analysis n = 0 List reasons n = RCTs included in meta-analysis n=5 RCTs withdrawn, by outcome, n = 1 List reasons n = 1 without data about main outcome RCTs with usable information, by outcome, n=4 Fig. 1. Quorum DIAGRAM.
identify other articles. We included studies published in any language. All abstracts were reviewed, and those which dealt with the use of vitamin D or metabolites after thyroidectomy as a therapy to avoid postoperative hypocalcemia were selected for further analysis. We assumed bioequivalence of vitamin D (cholecalciferol) and its direct metabolite, calcitriol, because the first is the precursor of the second, have the same pharmacological properties and offer a similar mechanism of action and clinical effect. Criteria for inclusion of studies were as follows: randomized controlled trial (RCT) comparing the administration of oral vitamin D or metabolites associated or not with oral calcium or other medication to nothing, placebo or oral calcium administration in patients submitted for total thyroidectomy with or without central neck dissection for any cause, with postoperative clinical evaluation of hypocalcemia symptoms and postoperative evaluation of blood calcium. Patients with a history of neck surgery or radiotherapy or extensive surgical procedures and those operated on due to concurrent parathyroid disease were excluded. Patients undergoing lateral neck dissection were not excluded, assuming that hypoparathyroidism is not more common when lateral neck dissections are performed simultaneously with total thyroidectomy.13 The main outcomes assessed were clinical symptoms of hypocalcemia, defined as circumoral tingling and Chvostek and Trousseau signs based on the principles of outcomes research, where patient-centered outcomes offer more relevant evidence for physicians who have to take clinical decisions. Two independent investigators acquired data about the risk of bias (generation of the allocation sequence, allocation concealment, blinding and follow up) according to the recommendations of the Cochrane Collaboration.14 We also recorded the inclusion and exclusion criteria in each trial. The following details were extracted: (1) details of the administration of vitamin D or metabolites with or without other medications; (2) number and characteristics of randomized patients; (3) number of patients not randomized and reasons; (4) exclusion after randomization; (5) drop-outs; and (6) ‘intention-to-treat’ analysis. Authors were contacted in cases of missing data. Datarelated conflicts were solved by consensus. The statistical package Stata 8.0 (Stata Corporation, TX, USA) was used. For dichotomous outcomes, the impact of the intervention was expressed as an odds ratio with 95% confidence intervals. In the analysis of continuous variables, we employed means with standard deviations. We used a random-effects model. The chi-squared test for heterogeneity was used to provide an indication of between-study heterogeneity. Furthermore, we explored the causes of heterogeneity using a meta-regression. We used a funnel plot to provide a visual assessment and used the adjusted rank correlation test (Begg test) to assess funnel plot asymmetry. The number needed to treat was calculated using Cates method.
3. Results The primary search with the selected terms identified 776 articles. From this sample, 12 studies were identified as candidates,
but only four of these studies satisfied the inclusion criteria.4,9,10,15 The reasons for excluding the other studies were a non-randomized design8,12,16e20 and a preoperative intervention with no postoperative hypocalcemia data.11 (Fig. 1) Study characteristics and quality evaluation are shown in Tables 1 and 2. The kappa-weighted coefficient was 0.76. Regarding methodological quality, any study used placebo. Bellantone9 and Roh10 studies offered no treatment as control group and Tartaglia15 and Pisaniello4 offered calcium without Vitamin D or metabolites as control group. Blinding evaluation was satisfactory only in Pisaniello trial4 and unclear in the others. Authors were contacted to clear this data, but only Roh10 and Tartaglia15 answered the requests. The lack of a placebo arm and weakness of blinding are important factors that could bias the results in favor of treatment. A study by Bellantone9 showed no difference in serum calcium or parathyroid hormone levels at day 7. Furthermore, patients treated with vitamin D or metabolites and oral calcium developed milder symptoms of hypocalcemia in comparison with patients in the control group. Therapy with vitamin D or metabolites and calcium was suspended in 85% of patients at postoperative day 7 and in 97% at postoperative day 30. Pisaniello4 reported differences in serum calcium levels at postoperative days 1, 2 and 3; calcium levels were higher in the group treated with vitamin D or metabolites. There is no information available regarding the time when treatment was suspended. The only adverse event reported in patients who received vitamin D or metabolites was gastric pyrosis. There is no information about the rate of permanent hypoparathyroidism. Tartaglia15 showed differences in serum calcium, only on the first postoperative day. They reported that treatment for all patients was suspended at day 15 postoperatively, with a progressive decrease of doses (0.5 mg of calcitriol and 125 mg of calcium every 3e5 days). At six months postoperatively, 3% of patients in the 0.5 mg calcitriol group, 2% of patients in the 1 mg calcitriol group and 4% of patients in the control group had permanent hypoparathyroidism. There was no difference when the outcome analyzed was the frequency of
48
Table 1 Included study descriptions.
COUNTRY PATIENTS
Roh Korea
Pisaniello Italy
Tartaglia Italy
Total thyroidectomy, excluding: 1. previous thyroid or neck operation or irradiation, 2. substernal goiter, 3. Concomitant central or lateral neck dissection, 4. Concomitant parathyroid disease, 5. Video-assisted thyroidectomy Malignancy rate 22%; Hyperthyroidism rate 8% Two groups: 1. oral calcium carbonate 1 g every 8 hours and rescue therapy for symptomatic patients with calcitriol 0.5 mg every 12 hours; 2. oral calcium carbonate 1 g every 8 hours plus calcitriol 0.5 mg every 12 hours. Intraoperative parathyroid gland management not stated.
Total thyroidectomy, excluding: 1. previous thyroid or neck operation or irradiation, 2. Abnormal renal function Malignancy rate 83%; Hyperthyroidism rate 5%
Total thyroidectomy, excluding: 1. hypercalcemia; 2. chronic renal failure. Malignancy rate 8.5% Hyperthyroidism rate not reported
Total thyroidectomy, excluding: 1. previous surgery; 2. concomitant lymph dissection; 3. hyperparathyroidism. Malignancy rate 20.6%; Hyperthyroidism rate 13.1%
oral calcium carbonate 1 g every 8 hours plus vitamin D 0.5 g every 12 hours until postoperative day 14. Intraoperative parathyroid gland management: carefully preservation and transplantation.
oral calcium carbonate 1500 mg per day, vitamin D 400 IU per day. All patients receive thyroid hormone on postoperative day 1. Intraoperative parathyroid gland management not stated.
No treatment, rescue therapy for symptomatic patients with oral calcium 1 g every 8 hours plus vitamin D 0.5 g every 12 hours Serum calcium and parathyroid hormone levels on postoperative day 1, 2, 3, 7. Hypocalcemia defined as ionized calcium <1.0 mmol/L and serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “perioral tingling and numbness to carpopedal spasms and tetany”
Oral calcium carbonate 3000 mg per day, rescue therapy for symptomatic patients with intravenous calcium. All patients receive thyroid hormone on postoperative day 1. Serum calcium levels on postoperative day 1, 2, 3, 30, 60, 90, 120. Hypocalcemia defined as serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “perioral tingling, muscle cramp, Chvostek’s and Trousseau’s signs”
Two groups: 1. Oral calcium carbonate 500 mg every 8 hours þ calcitriol 0.5 mg twice per day; 2. Oral calcium carbonate 500 mg every 8 hours þ calcitriol 1 mg twice per day. Intraoperative parathyroid gland management: carefully preservation a. No transplantation 1. Oral calcium carbonate 1500 mg per day
CONTROL
No treatment, rescue therapy for symptomatic patients with oral calcium 1 g every 8 hours plus calcitriol 0.5 mg every 12 hours
OUTCOME
Serum calcium and parathyroid hormone levels in postoperative day 1, 2, 3, 7. Hypocalcemia defined as serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “signs of hypocalcemia and evaluation of Chvostek’s sign”
Serum calcium levels on postoperative day 1, 2, 3, 30, 60, 90, 120. Hypocalcemia defined as serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “paresthesias and tetany; .as spontaneous masseter muscle contraction and carpal spasm.presence of serious and widespread paresthesias with positive Trousseau’s sign.”
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51
INTERVENTION
Bellantone Italy
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51 Table 2 Risk of bias evaluation.
Sequence generation Allocation concealment Blind evaluation Incomplete outcome data Intention-to-treat analyses Statistical methods description Intervention criteria description
49 Odds ratio (95% CI)
Study
Bellantone Pisaniello Tartaglia
Roh
Yes UNCLEAR UNCLEAR No Yes Yes Yes
Yes UNCLEAR UNCLEAR No Yes Yes Yes
Yes UNCLEAR Yes No Yes Yes Yes
No UNCLEAR UNCLEAR No Yes Yes Yes
postoperative paresthesia. Roh10 showed statistical differences in serum calcium but not in parathyroid hormone on postoperative days 1, 2 and 7. Patients treated with vitamin D or metabolites and oral calcium developed milder symptoms of hypocalcemia in comparison with patients in the control group. There is no information about the rate of permanent hypoparathyroidism. The RCTs selected included 706 patients: 346 in the vitamin D or metabolites group, 288 in the oral calcium group and 72 in the control group (Table 3). The rate of hypocalcemia symptoms was 13/346 (4%, 1e23%) patients in the vitamin D or metabolites group, 28/288 (19%, 7e35%) in the oral calcium group and 22/72 (31%, 24e41%) in the control group. The OR value for the comparison between calcitriol þ calcium as compared to no treatment was 0.32 (95% CI, 0.13e0.79). Statistical heterogeneity was not identified (P ¼ 0.45) (Fig. 2). The number needed to treat was six (95% CI, 4e12). The OR value was 0.31 (95% CI, 0.14e0.70) for the comparison between the vitamin D or metabolites and exclusive calcium treatment groups. Statistical heterogeneity was not identified (P ¼ 0.40) (Fig. 3). The number needed to treat was six (95% CI, 4e19). The funnel plot for the comparison between vitamin D or metabolites and oral calcium did not show asymmetry. The Begg test showed a P-value of 0.56. As malignancy and hyperthyroidism rates could be a source of heterogeneity between studies, we used these variables to make a meta-regression. A meta-regression is a statistical method which assesses the effect of a covariable on the final result of the metaanalysis. The results of this regression did not show a statistically significant difference (p > 0.05), but its statistical power is low in reviews with few trials. For the case of intraoperative management of parathyroid glands, the heterogeneity of the data did not allow any adjustment.
4. Discussion Postoperative hypocalcemia is a common problem after thyroidectomy, due to its high frequency and the decrease in quality of life for patients who suffer from severe symptoms.1,2 Furthermore, postoperative hypocalcemia has increased the length of stay and discouraged the widespread use of thyroidectomy as an outpatient procedure.3,5,6
% Weight
Bellantone
0.44 (0.13,1.44)
56.3
Roh
0.22 (0.06,0.86)
43.7
Overall (95% CI)
0.32 (0.13,0.79)
.1
1
10 Odds ratio
Fig. 2. Forrest plot for comparison between vitamin D or metabolites þ calcium vs. no treatment.
Some authors have tried to assess the utility of serum calcium and parathyroid hormone measurements in the postoperative period as a way to predict which patients will develop hypocalcemia. Selecting the most recent articles published on MEDLINE was expected to elucidate the efficacy of this approach. Toniato et al.7 assessed pre- and postoperative measurement of PTH and found a specificity and positive predictive value of 96% and 93%, respectively. However, sensitivity was low. Cavicchi et al.21 found a sensitivity of 100% with a specificity ranging from 46 to 85%. Erbil et al.22 found a 16-fold increase in the risk of hypocalcemia with PTH levels under 10 pg/ml. If we assume a specificity of 95% similar to the other studies, the expected sensitivity is approximately 80%. These results show that even in the best hands and with the availability of modern serum tests, it is not easy to predict with certainty which patients are going to develop postoperative hypocalcemia. Other authors suggested the use of routine prophylactic vitamin D or metabolites þ calcium or exclusive calcium as an alternative strategy to decrease the rate of hypocalcemia, based on the principle that offering prophylaxis to all patients will help all susceptible patients, even those that are not detected by serum tests. This approach would avoid the routine measurement of serum calcium and in cases of symptomatic hypocalcemia; the crisis will be less severe and easy to treat in comparison with patients who do not receive any prophylaxis.8e12 On the other hand, based on the philosophy of patient-centered outcomes, levels of calcium or PTH do not necessarily represent the most important final clinical outcome for the patients: the symptoms of hypocalcemia. Only four studies assessed the effectiveness of this therapy under the demanding conditions of an RCT. However, although individually the trials showed a statistically significant difference, the sample size of each one was too small to allow reliable conclusions and does not offer a precise estimate. Our meta-analysis with more than 700 patients showed a decrease of almost 70% in the rate of
Table 3 Patients and outcomes data. AUTHOR
VITAMIN D GROUP
Hypocalcemia symptoms (%)
Roh Bellantone Pisaniello Tartaglia
45 26 60 104a 111b 215
3 6 1 3 0 3
a b
Vitamin D group 0.5 mg. Vitamin D group 1 mg.
(6.6) (23.0) (1.6) (2.8) (0) (1.4)
ORAL CALCIUM GROUP
Hypocalcemia symptoms (%)
26 60 202
9 (34.6) 4 (6.6) 15 (7.4)
NO INTERVENTION GROUP
Hypocalcemia symptoms (%)
PATIENTS TOTAL
Hypocalcemia TOTAL (%)
45 27
11 (24.4) 11 (40.7)
90 79 120 417
14 26 5 94
(15.5) (36.7) (4.2) (22.5)
50
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51 Odds ratio (95% CI)
Study
% Weight
Tartaglia
0.18 (0.05,0.62)
42.0
Pisaniello
0.24 (0.03,2.19)
13.4
Bellantone
0.57 (0.17,1.92)
44.6
Overall (95% CI)
0.31 (0.14,0.70)
.1
1
10 Odds ratio
Fig. 3. Forrest plot for comparison between vitamin D or metabolites þ calcium vs. exclusive calcium.
symptomatic postoperative hypocalcemia between the group treated with vitamin D or metabolites þ calcium as compared to no prophylaxis or exclusive calcium groups. These results showed that vitamin D or metabolites þ calcium is the most effective strategy. However, the confidence intervals are too wide to consider the results obtained to be precise estimates. The studies showed a significant range of variability in patients’ characteristics. The rate of hyperthyroidism varied from 0 to 13%. In the Tartaglia study15 where the rate of hyperthyroidism was higher, the OR of the individual study was lower, which supports the idea that in cases of high risk, a larger protective effect is expected. Also, the malignancy rate varied from 8 to 83% and the same phenomenon occurs for the case of Roh study10 where the malignancy rate was higher. The same argument could be used to support the inclusion of patients with radical neck dissection as occurred in the Roh study10 (19%). Recent data from an RCT made by Roh in patients who underwent total thyroidectomy and central neck dissection confirmed these assumptions.23 Even more, the randomized design of the studies compensates for different types of surgery (as neck dissection and methods to identify or manage the parathyroid glands) and variations in the definitions of hypocalcemia. The main principle of randomization is balancing between groups, known and unknown variables that could affect the final outcome. As the rate of permanent hypoparathyroidism was similar between studies it is not expected that variability in the intraoperative management of the parathyroid glands could have an important effect on the results of the study. However, some elements related to methodological quality such as the blind evaluation of results and allocation concealment are weak in this analysis. This diminished the quality of the trials, but this may be an effect of inadequate reporting because the trials did not include all of the elements suggested by the CONSORT statement.24 It is important to note that a lack of blind evaluation and adequate allocation concealment may have biased the results of these studies. One factor to consider is the method of clinical detection of symptoms and the definition of clinically relevant hypocalcemia. Up to date, only one instrument has been specifically designed and statistically validated to assess the symptoms of postoperative hypoparathyroidism, but this scale is not widely applied in trials assessing complications of thyroidectomy.25 Therefore, the detection of the symptom could be biased. However, we consider that a careful collection of data in a previously designed format could compensate the risk of bias derived from this lack of homogeneity in the definition of hypocalcemia. One probable advantage not included in this analysis is the avoidance of routine serum calcium measurements. If the
prophylaxis is administered, symptoms of hypocalcemia are the markers of an adequate level of serum calcium. Furthermore, some patients present low serum calcium levels but never suffer symptoms, which could potentially lead to the administration of calcium or to extended hospital stays unnecessarily. Another advantage is the ability to offer thyroidectomy as an outpatient procedure, because the risk of hypocalcemia decreases to very low levels that allow more confident ambulatory control. Although some concerns exist about the possibility of developing a temporary state of hypercalcemia, these data could not be obtained from the primary trials. Furthermore, the potential adverse vents derived from the treatment in all patients, such as gastric symptoms or constipation, were not adequately assessed in the studies and could represent an increase in costs not considered in the analysis. In conclusion, the use of prophylaxis for hypocalcemia comprising vitamin D or metabolites þ calcium or exclusive calcium is effective to decrease the incidence of symptoms of temporary hypocalcemia. Funding Universidad de La Sabana. Conflict of interest The authors do not have any conflict of interest. Ethical approval This is a systematic review and do not include patients. The approval was made by the School of Medicine, Universidad de La Sabana. References 1. Falk SA, Birken EA, Baran DT. Temporary postthyroidectomy hypocalcemia. Arch Otolaryngol Head Neck Surg 1988;114:168e74. 2. Rao RS, Jog VB, Baluja CA, Damle SR. Risk of hypoparathyroidism after surgery for carcinoma of the thyroid. Head Neck 1990;12:321e5. 3. Chia SH, Weisman RA, Tieu D, Kelly C, Dillmann WH, Orloff LA. Prospective study of perioperative factors predicting hypocalcemia after thyroid and parathyroid surgery. Arch Otolaryngol Head Neck Surg 2006;132:41e5. 4. Pisaniello D, Parmeggiani D, Piatto A, Avenia N, d’Ajello M, Monacelli M, et al. Which therapy to prevent post-thyroidectomy hypocalcemia? G Chir 2005;26:357e61. 5. Mishra AK, Agarwal A. Same-day discharge after total thyroidectomy: the value of 6-hour serum parathyroid hormone and calcium levels. Head Neck 2005;27:1112e3. 6. Payne RJ, Hier MP, Tamilia M, Mac NE, Young J, Black MJ. Same-day discharge after total thyroidectomy: the value of 6-hour serum parathyroid hormone and calcium levels. Head Neck 2005;27:1e7. 7. Toniato A, Boschin IM, Piotto A, Pelizzo M, Sartori P. Thyroidectomy and parathyroid hormone: tracing hypocalcemia-prone patients. Am J Surg 2008;196:285e8. 8. Moore Jr FD. Oral calcium supplements to enhance early hospital discharge after bilateral surgical treatment of the thyroid gland or exploration of the parathyroid glands. J Am Coll Surg 1994;178:11e6. 9. Bellantone R, Lombardi CP, Raffaelli M, Boscherini M, Alesina PF, De Crea C, et al. Is routine supplementation therapy (calcium and vitamin D) useful after total thyroidectomy? Surgery 2002;132:1109e12. 10. Roh JL, Park CI. Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy. Am J Surg 2006;192:675e8. 11. Testa A, Fant V, De Rosa A, Fiore GF, Grieco V, Castaldi P, et al. Calcitriol plus hydrochlorothiazide prevents transient post-thyroidectomy hypocalcemia. Horm Metab Res 2006;38:821e6. 12. Uruno T, Miyauchi A, Shimizu K, Tomoda C, Takamura Y, Ito Y, et al. A prophylactic infusion of calcium solution reduces the risk of symptomatic hypocalcemia in patients after total thyroidectomy. World J Surg 2006;30:304e8. 13. Cheah WK, Arici C, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Complications of neck dissection for thyroid cancer. World J Surg 2002;26:1013e6. 14. Higgins J, Green S. Cochrane Handbook for systematic reviews of interventions Version 5.0.0. Chichester, UK: John Wiley & Sons; 2008. 15. Tartaglia F, Giuliani A, Sgueglia M, Biancari F, Juvonen T, Campana FP. Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am J Surg 2005;190:424e9. 16. Bove A, Bongarzoni G, Dragani G, Serafini F, Di Iorio A, Palone G, et al. Should female patients undergoing parathyroid-sparing total thyroidectomy receive routine prophylaxis for transient hypocalcemia? Am Surg 2004;70:533e6.
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51 17. Mittendorf EA, Merlino JI, McHenry CR. Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management. Am Surg 2004;70:114e9. 18. 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;116:906e10. 19. Payne RJ, Hier MP, Tamilia M, Young J, MacNamara E, Black MJ. Postoperative parathyroid hormone level as a predictor of post-thyroidectomy hypocalcemia. J Otolaryngol 2003;32:362e7. 20. Kurukahvecioglu O, Karamercan A, Akin M, Tezel E, Ege B, Taneri F, et al. Potential benefit of oral calcium/vitamin D administration for prevention of symptomatic hypocalcemia after total thyroidectomy. Endocr Regul 2007;41:35e9. 21. Cavicchi O, Piccin O, Caliceti U, Fernandez IJ, Bordonaro C, Saggese D, et al. Accuracy of PTH assay and corrected calcium in early prediction of
22.
23.
24. 25.
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hypoparathyroidism after thyroid surgery. Otolaryngol Head Neck Surg 2008;138:594e600. Erbil Y, Bozbora A, Ozbey N, Issever H, Aral F, Ozarmagan S, et al. Predictive value of age and serum parathormone and vitamin d3 levels for postoperative hypocalcemia after total thyroidectomy for nontoxic multinodular goiter. Arch Surg 2007;142:1182e7. Roh JL, Park JY, Park CI. Prevention of postoperative hypocalcemia with routine oral calcium and vitamin D supplements in patients with differentiated papillary thyroid carcinoma undergoing total thyroidectomy plus central neck dissection. Cancer 2009;115:251e8. Kessler KM. The CONSORT statement: explanation and elaboration. Consolidated standards of reporting trials. Ann Intern Med 2002;136:926e7. Bohrer T, Fleischmann P, Tersteegen A, Hasse C. [The farmost unknown disease of postoperative permanent hypoparathyroidismefeasibility and validation of an innovative questionnaire instrument]. Zentralbl Chir 2005;130:440e8.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.theijs.com
Routine postoperative administration of vitamin D and calcium after total thyroidectomy: a meta-analysisq Alvaro Sanabria*, Luis C. Dominguez, Valentin Vega, Camilo Osorio, Daniel Duarte Department of Surgery, School of Medicine, Universidad de La Sabana, Bogota, Campus Puente del Comun, Km 21 Autopista Norte, Chia, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history: Received 14 July 2010 Accepted 15 August 2010 Available online 8 September 2010
Background: Temporary hypocalcemia is a frequent complication after total thyroidectomy. Routine postoperative administration of vitamin D and calcium can reduce the incidence of symptomatic postoperative hypocalcemia. We undertook a systematic review to assess the effectiveness of this intervention. Methods: We identified randomized controlled trials comparing the administration of vitamin D or metabolites to oral calcium or no treatment in patients after total thyroidectomy in MEDLINE, EMBASE and LILACS databases. Results: Four studies with 706 patients were included: 346 in the calcitriol group, 288 in the oral calcium group and 72 in the control group. The rates of hypocalcemia symptoms were 4%, 19% and 31%, respectively. The OR value for the comparison between calcitriol þ calcium as compared to no treatment and to exclusive calcium treatment groups was 0.32 (95% CI, 0.13e0.79) and 0.31 (95% CI, 0.14e0.70), respectively. Conclusion: The prophylactic treatment with vitamin D or metabolites þ calcium is effective to decrease the incidence of symptoms of temporary hypocalcemia. Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid neoplasm Thyroidectomy Hypocalcemia
1. Introduction Thyroidectomy is the most common surgical procedure performed in the neck by surgeons. Hypocalcemia is the most frequent complication after total thyroidectomy, and it is the main cause of prolonged hospital stay.1e3 Hypocalcemia can occur from the immediate postoperative period up to five days after surgery, and it is described as one of the most unpleasant experiences because of symptoms of tingling, spasm and chest oppression in severe cases. The rate of symptomatic postoperative hypocalcemia ranges from 5 to 50%,4 but only 1e3% of cases is definitive. Treatment of postoperative hypocalcemia depends on its severity. For mild cases, oral vitamin D and calcium supplements are enough to relieve symptoms and return serum calcium values to normal levels. In cases of severe hypocalcemia, emergency admission to the hospital is necessary, which involves periodic serum calcium measurements, administration of intravenous calcium gluconate and supplementation with high doses of oral vitamin D and calcium. Based on the extent of tissue involved, thyroidectomy could be classified as an intermediate procedure, necessitating an outpatient
procedure in the majority of cases.5,6 However, symptoms of hypocalcemia limit the use of thyroidectomy as an outpatient procedure due to the high frequency of symptoms, general unpleasantness of them, and the risk of severe consequences such as cardiorespiratory arrest. To address these issues, some authors have suggested that routine measurements of serum calcium and parathyroid hormone could predict the development of hypocalcemia, allowing doctors to treat patients before symptoms appear.7 However, this strategy has not been successful because symptomatic hypocalcemia is a multifactorial condition. Others have suggested the routine prophylactic administration of oral vitamin D and calcium in the postoperative period to reduce the rate of symptomatic hypocalcemia.8e12 However, the number of studies and patients included in individual studies are low and do not offer clear evidence of the benefits of this therapy. In this case, a meta-analysis could offer a more precise evaluation of the effectiveness of treatment. The aim of this study was assess the effectiveness of prophylactic administration of vitamin D or metabolites and calcium in patients who underwent total thyroidectomy. 2. Materials and methods
q Presented at the World Congress of Thyroid Cancer. Toronto, Canada. August 9, 2009. * Corresponding author. Tel./fax: þ57 8615555. E-mail address: [email protected] (A. Sanabria).
We performed a bibliography search on the MEDLINE, EMBASE and LILACS databases for studies published from January 1980 to April 2008 using the MESH and free terms “thyroidectomy”, “thyroid surgery”, “calcitriol” and “vitamin D”. An expanded search was used using Boolean operators. References were explored to
1743-9191/$ e see front matter Ó 2010 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijsu.2010.08.006
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51
47
QUORUM diagram Potentially relevant RCTs identified and screened for retrieval n = 12
RCTs retrieved for more detailed evaluation n=5
RCTs excluded n = 7 List reasons n = 7 non randomized design
RCTs excluded n = 0
Potentially appropriate RCTs to be included in the meta-analysis n=5 RCTs excluded from meta-analysis n = 0 List reasons n = RCTs included in meta-analysis n=5 RCTs withdrawn, by outcome, n = 1 List reasons n = 1 without data about main outcome RCTs with usable information, by outcome, n=4 Fig. 1. Quorum DIAGRAM.
identify other articles. We included studies published in any language. All abstracts were reviewed, and those which dealt with the use of vitamin D or metabolites after thyroidectomy as a therapy to avoid postoperative hypocalcemia were selected for further analysis. We assumed bioequivalence of vitamin D (cholecalciferol) and its direct metabolite, calcitriol, because the first is the precursor of the second, have the same pharmacological properties and offer a similar mechanism of action and clinical effect. Criteria for inclusion of studies were as follows: randomized controlled trial (RCT) comparing the administration of oral vitamin D or metabolites associated or not with oral calcium or other medication to nothing, placebo or oral calcium administration in patients submitted for total thyroidectomy with or without central neck dissection for any cause, with postoperative clinical evaluation of hypocalcemia symptoms and postoperative evaluation of blood calcium. Patients with a history of neck surgery or radiotherapy or extensive surgical procedures and those operated on due to concurrent parathyroid disease were excluded. Patients undergoing lateral neck dissection were not excluded, assuming that hypoparathyroidism is not more common when lateral neck dissections are performed simultaneously with total thyroidectomy.13 The main outcomes assessed were clinical symptoms of hypocalcemia, defined as circumoral tingling and Chvostek and Trousseau signs based on the principles of outcomes research, where patient-centered outcomes offer more relevant evidence for physicians who have to take clinical decisions. Two independent investigators acquired data about the risk of bias (generation of the allocation sequence, allocation concealment, blinding and follow up) according to the recommendations of the Cochrane Collaboration.14 We also recorded the inclusion and exclusion criteria in each trial. The following details were extracted: (1) details of the administration of vitamin D or metabolites with or without other medications; (2) number and characteristics of randomized patients; (3) number of patients not randomized and reasons; (4) exclusion after randomization; (5) drop-outs; and (6) ‘intention-to-treat’ analysis. Authors were contacted in cases of missing data. Datarelated conflicts were solved by consensus. The statistical package Stata 8.0 (Stata Corporation, TX, USA) was used. For dichotomous outcomes, the impact of the intervention was expressed as an odds ratio with 95% confidence intervals. In the analysis of continuous variables, we employed means with standard deviations. We used a random-effects model. The chi-squared test for heterogeneity was used to provide an indication of between-study heterogeneity. Furthermore, we explored the causes of heterogeneity using a meta-regression. We used a funnel plot to provide a visual assessment and used the adjusted rank correlation test (Begg test) to assess funnel plot asymmetry. The number needed to treat was calculated using Cates method.
3. Results The primary search with the selected terms identified 776 articles. From this sample, 12 studies were identified as candidates,
but only four of these studies satisfied the inclusion criteria.4,9,10,15 The reasons for excluding the other studies were a non-randomized design8,12,16e20 and a preoperative intervention with no postoperative hypocalcemia data.11 (Fig. 1) Study characteristics and quality evaluation are shown in Tables 1 and 2. The kappa-weighted coefficient was 0.76. Regarding methodological quality, any study used placebo. Bellantone9 and Roh10 studies offered no treatment as control group and Tartaglia15 and Pisaniello4 offered calcium without Vitamin D or metabolites as control group. Blinding evaluation was satisfactory only in Pisaniello trial4 and unclear in the others. Authors were contacted to clear this data, but only Roh10 and Tartaglia15 answered the requests. The lack of a placebo arm and weakness of blinding are important factors that could bias the results in favor of treatment. A study by Bellantone9 showed no difference in serum calcium or parathyroid hormone levels at day 7. Furthermore, patients treated with vitamin D or metabolites and oral calcium developed milder symptoms of hypocalcemia in comparison with patients in the control group. Therapy with vitamin D or metabolites and calcium was suspended in 85% of patients at postoperative day 7 and in 97% at postoperative day 30. Pisaniello4 reported differences in serum calcium levels at postoperative days 1, 2 and 3; calcium levels were higher in the group treated with vitamin D or metabolites. There is no information available regarding the time when treatment was suspended. The only adverse event reported in patients who received vitamin D or metabolites was gastric pyrosis. There is no information about the rate of permanent hypoparathyroidism. Tartaglia15 showed differences in serum calcium, only on the first postoperative day. They reported that treatment for all patients was suspended at day 15 postoperatively, with a progressive decrease of doses (0.5 mg of calcitriol and 125 mg of calcium every 3e5 days). At six months postoperatively, 3% of patients in the 0.5 mg calcitriol group, 2% of patients in the 1 mg calcitriol group and 4% of patients in the control group had permanent hypoparathyroidism. There was no difference when the outcome analyzed was the frequency of
48
Table 1 Included study descriptions.
COUNTRY PATIENTS
Roh Korea
Pisaniello Italy
Tartaglia Italy
Total thyroidectomy, excluding: 1. previous thyroid or neck operation or irradiation, 2. substernal goiter, 3. Concomitant central or lateral neck dissection, 4. Concomitant parathyroid disease, 5. Video-assisted thyroidectomy Malignancy rate 22%; Hyperthyroidism rate 8% Two groups: 1. oral calcium carbonate 1 g every 8 hours and rescue therapy for symptomatic patients with calcitriol 0.5 mg every 12 hours; 2. oral calcium carbonate 1 g every 8 hours plus calcitriol 0.5 mg every 12 hours. Intraoperative parathyroid gland management not stated.
Total thyroidectomy, excluding: 1. previous thyroid or neck operation or irradiation, 2. Abnormal renal function Malignancy rate 83%; Hyperthyroidism rate 5%
Total thyroidectomy, excluding: 1. hypercalcemia; 2. chronic renal failure. Malignancy rate 8.5% Hyperthyroidism rate not reported
Total thyroidectomy, excluding: 1. previous surgery; 2. concomitant lymph dissection; 3. hyperparathyroidism. Malignancy rate 20.6%; Hyperthyroidism rate 13.1%
oral calcium carbonate 1 g every 8 hours plus vitamin D 0.5 g every 12 hours until postoperative day 14. Intraoperative parathyroid gland management: carefully preservation and transplantation.
oral calcium carbonate 1500 mg per day, vitamin D 400 IU per day. All patients receive thyroid hormone on postoperative day 1. Intraoperative parathyroid gland management not stated.
No treatment, rescue therapy for symptomatic patients with oral calcium 1 g every 8 hours plus vitamin D 0.5 g every 12 hours Serum calcium and parathyroid hormone levels on postoperative day 1, 2, 3, 7. Hypocalcemia defined as ionized calcium <1.0 mmol/L and serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “perioral tingling and numbness to carpopedal spasms and tetany”
Oral calcium carbonate 3000 mg per day, rescue therapy for symptomatic patients with intravenous calcium. All patients receive thyroid hormone on postoperative day 1. Serum calcium levels on postoperative day 1, 2, 3, 30, 60, 90, 120. Hypocalcemia defined as serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “perioral tingling, muscle cramp, Chvostek’s and Trousseau’s signs”
Two groups: 1. Oral calcium carbonate 500 mg every 8 hours þ calcitriol 0.5 mg twice per day; 2. Oral calcium carbonate 500 mg every 8 hours þ calcitriol 1 mg twice per day. Intraoperative parathyroid gland management: carefully preservation a. No transplantation 1. Oral calcium carbonate 1500 mg per day
CONTROL
No treatment, rescue therapy for symptomatic patients with oral calcium 1 g every 8 hours plus calcitriol 0.5 mg every 12 hours
OUTCOME
Serum calcium and parathyroid hormone levels in postoperative day 1, 2, 3, 7. Hypocalcemia defined as serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “signs of hypocalcemia and evaluation of Chvostek’s sign”
Serum calcium levels on postoperative day 1, 2, 3, 30, 60, 90, 120. Hypocalcemia defined as serum calcium <8.0 mg/dl Clinical assessment of hypocalcemia “paresthesias and tetany; .as spontaneous masseter muscle contraction and carpal spasm.presence of serious and widespread paresthesias with positive Trousseau’s sign.”
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51
INTERVENTION
Bellantone Italy
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51 Table 2 Risk of bias evaluation.
Sequence generation Allocation concealment Blind evaluation Incomplete outcome data Intention-to-treat analyses Statistical methods description Intervention criteria description
49 Odds ratio (95% CI)
Study
Bellantone Pisaniello Tartaglia
Roh
Yes UNCLEAR UNCLEAR No Yes Yes Yes
Yes UNCLEAR UNCLEAR No Yes Yes Yes
Yes UNCLEAR Yes No Yes Yes Yes
No UNCLEAR UNCLEAR No Yes Yes Yes
postoperative paresthesia. Roh10 showed statistical differences in serum calcium but not in parathyroid hormone on postoperative days 1, 2 and 7. Patients treated with vitamin D or metabolites and oral calcium developed milder symptoms of hypocalcemia in comparison with patients in the control group. There is no information about the rate of permanent hypoparathyroidism. The RCTs selected included 706 patients: 346 in the vitamin D or metabolites group, 288 in the oral calcium group and 72 in the control group (Table 3). The rate of hypocalcemia symptoms was 13/346 (4%, 1e23%) patients in the vitamin D or metabolites group, 28/288 (19%, 7e35%) in the oral calcium group and 22/72 (31%, 24e41%) in the control group. The OR value for the comparison between calcitriol þ calcium as compared to no treatment was 0.32 (95% CI, 0.13e0.79). Statistical heterogeneity was not identified (P ¼ 0.45) (Fig. 2). The number needed to treat was six (95% CI, 4e12). The OR value was 0.31 (95% CI, 0.14e0.70) for the comparison between the vitamin D or metabolites and exclusive calcium treatment groups. Statistical heterogeneity was not identified (P ¼ 0.40) (Fig. 3). The number needed to treat was six (95% CI, 4e19). The funnel plot for the comparison between vitamin D or metabolites and oral calcium did not show asymmetry. The Begg test showed a P-value of 0.56. As malignancy and hyperthyroidism rates could be a source of heterogeneity between studies, we used these variables to make a meta-regression. A meta-regression is a statistical method which assesses the effect of a covariable on the final result of the metaanalysis. The results of this regression did not show a statistically significant difference (p > 0.05), but its statistical power is low in reviews with few trials. For the case of intraoperative management of parathyroid glands, the heterogeneity of the data did not allow any adjustment.
4. Discussion Postoperative hypocalcemia is a common problem after thyroidectomy, due to its high frequency and the decrease in quality of life for patients who suffer from severe symptoms.1,2 Furthermore, postoperative hypocalcemia has increased the length of stay and discouraged the widespread use of thyroidectomy as an outpatient procedure.3,5,6
% Weight
Bellantone
0.44 (0.13,1.44)
56.3
Roh
0.22 (0.06,0.86)
43.7
Overall (95% CI)
0.32 (0.13,0.79)
.1
1
10 Odds ratio
Fig. 2. Forrest plot for comparison between vitamin D or metabolites þ calcium vs. no treatment.
Some authors have tried to assess the utility of serum calcium and parathyroid hormone measurements in the postoperative period as a way to predict which patients will develop hypocalcemia. Selecting the most recent articles published on MEDLINE was expected to elucidate the efficacy of this approach. Toniato et al.7 assessed pre- and postoperative measurement of PTH and found a specificity and positive predictive value of 96% and 93%, respectively. However, sensitivity was low. Cavicchi et al.21 found a sensitivity of 100% with a specificity ranging from 46 to 85%. Erbil et al.22 found a 16-fold increase in the risk of hypocalcemia with PTH levels under 10 pg/ml. If we assume a specificity of 95% similar to the other studies, the expected sensitivity is approximately 80%. These results show that even in the best hands and with the availability of modern serum tests, it is not easy to predict with certainty which patients are going to develop postoperative hypocalcemia. Other authors suggested the use of routine prophylactic vitamin D or metabolites þ calcium or exclusive calcium as an alternative strategy to decrease the rate of hypocalcemia, based on the principle that offering prophylaxis to all patients will help all susceptible patients, even those that are not detected by serum tests. This approach would avoid the routine measurement of serum calcium and in cases of symptomatic hypocalcemia; the crisis will be less severe and easy to treat in comparison with patients who do not receive any prophylaxis.8e12 On the other hand, based on the philosophy of patient-centered outcomes, levels of calcium or PTH do not necessarily represent the most important final clinical outcome for the patients: the symptoms of hypocalcemia. Only four studies assessed the effectiveness of this therapy under the demanding conditions of an RCT. However, although individually the trials showed a statistically significant difference, the sample size of each one was too small to allow reliable conclusions and does not offer a precise estimate. Our meta-analysis with more than 700 patients showed a decrease of almost 70% in the rate of
Table 3 Patients and outcomes data. AUTHOR
VITAMIN D GROUP
Hypocalcemia symptoms (%)
Roh Bellantone Pisaniello Tartaglia
45 26 60 104a 111b 215
3 6 1 3 0 3
a b
Vitamin D group 0.5 mg. Vitamin D group 1 mg.
(6.6) (23.0) (1.6) (2.8) (0) (1.4)
ORAL CALCIUM GROUP
Hypocalcemia symptoms (%)
26 60 202
9 (34.6) 4 (6.6) 15 (7.4)
NO INTERVENTION GROUP
Hypocalcemia symptoms (%)
PATIENTS TOTAL
Hypocalcemia TOTAL (%)
45 27
11 (24.4) 11 (40.7)
90 79 120 417
14 26 5 94
(15.5) (36.7) (4.2) (22.5)
50
A. Sanabria et al. / International Journal of Surgery 9 (2011) 46e51 Odds ratio (95% CI)
Study
% Weight
Tartaglia
0.18 (0.05,0.62)
42.0
Pisaniello
0.24 (0.03,2.19)
13.4
Bellantone
0.57 (0.17,1.92)
44.6
Overall (95% CI)
0.31 (0.14,0.70)
.1
1
10 Odds ratio
Fig. 3. Forrest plot for comparison between vitamin D or metabolites þ calcium vs. exclusive calcium.
symptomatic postoperative hypocalcemia between the group treated with vitamin D or metabolites þ calcium as compared to no prophylaxis or exclusive calcium groups. These results showed that vitamin D or metabolites þ calcium is the most effective strategy. However, the confidence intervals are too wide to consider the results obtained to be precise estimates. The studies showed a significant range of variability in patients’ characteristics. The rate of hyperthyroidism varied from 0 to 13%. In the Tartaglia study15 where the rate of hyperthyroidism was higher, the OR of the individual study was lower, which supports the idea that in cases of high risk, a larger protective effect is expected. Also, the malignancy rate varied from 8 to 83% and the same phenomenon occurs for the case of Roh study10 where the malignancy rate was higher. The same argument could be used to support the inclusion of patients with radical neck dissection as occurred in the Roh study10 (19%). Recent data from an RCT made by Roh in patients who underwent total thyroidectomy and central neck dissection confirmed these assumptions.23 Even more, the randomized design of the studies compensates for different types of surgery (as neck dissection and methods to identify or manage the parathyroid glands) and variations in the definitions of hypocalcemia. The main principle of randomization is balancing between groups, known and unknown variables that could affect the final outcome. As the rate of permanent hypoparathyroidism was similar between studies it is not expected that variability in the intraoperative management of the parathyroid glands could have an important effect on the results of the study. However, some elements related to methodological quality such as the blind evaluation of results and allocation concealment are weak in this analysis. This diminished the quality of the trials, but this may be an effect of inadequate reporting because the trials did not include all of the elements suggested by the CONSORT statement.24 It is important to note that a lack of blind evaluation and adequate allocation concealment may have biased the results of these studies. One factor to consider is the method of clinical detection of symptoms and the definition of clinically relevant hypocalcemia. Up to date, only one instrument has been specifically designed and statistically validated to assess the symptoms of postoperative hypoparathyroidism, but this scale is not widely applied in trials assessing complications of thyroidectomy.25 Therefore, the detection of the symptom could be biased. However, we consider that a careful collection of data in a previously designed format could compensate the risk of bias derived from this lack of homogeneity in the definition of hypocalcemia. One probable advantage not included in this analysis is the avoidance of routine serum calcium measurements. If the
prophylaxis is administered, symptoms of hypocalcemia are the markers of an adequate level of serum calcium. Furthermore, some patients present low serum calcium levels but never suffer symptoms, which could potentially lead to the administration of calcium or to extended hospital stays unnecessarily. Another advantage is the ability to offer thyroidectomy as an outpatient procedure, because the risk of hypocalcemia decreases to very low levels that allow more confident ambulatory control. Although some concerns exist about the possibility of developing a temporary state of hypercalcemia, these data could not be obtained from the primary trials. Furthermore, the potential adverse vents derived from the treatment in all patients, such as gastric symptoms or constipation, were not adequately assessed in the studies and could represent an increase in costs not considered in the analysis. In conclusion, the use of prophylaxis for hypocalcemia comprising vitamin D or metabolites þ calcium or exclusive calcium is effective to decrease the incidence of symptoms of temporary hypocalcemia. Funding Universidad de La Sabana. Conflict of interest The authors do not have any conflict of interest. Ethical approval This is a systematic review and do not include patients. The approval was made by the School of Medicine, Universidad de La Sabana. References 1. Falk SA, Birken EA, Baran DT. Temporary postthyroidectomy hypocalcemia. Arch Otolaryngol Head Neck Surg 1988;114:168e74. 2. Rao RS, Jog VB, Baluja CA, Damle SR. Risk of hypoparathyroidism after surgery for carcinoma of the thyroid. Head Neck 1990;12:321e5. 3. Chia SH, Weisman RA, Tieu D, Kelly C, Dillmann WH, Orloff LA. Prospective study of perioperative factors predicting hypocalcemia after thyroid and parathyroid surgery. Arch Otolaryngol Head Neck Surg 2006;132:41e5. 4. Pisaniello D, Parmeggiani D, Piatto A, Avenia N, d’Ajello M, Monacelli M, et al. Which therapy to prevent post-thyroidectomy hypocalcemia? G Chir 2005;26:357e61. 5. Mishra AK, Agarwal A. Same-day discharge after total thyroidectomy: the value of 6-hour serum parathyroid hormone and calcium levels. Head Neck 2005;27:1112e3. 6. Payne RJ, Hier MP, Tamilia M, Mac NE, Young J, Black MJ. Same-day discharge after total thyroidectomy: the value of 6-hour serum parathyroid hormone and calcium levels. Head Neck 2005;27:1e7. 7. Toniato A, Boschin IM, Piotto A, Pelizzo M, Sartori P. Thyroidectomy and parathyroid hormone: tracing hypocalcemia-prone patients. Am J Surg 2008;196:285e8. 8. Moore Jr FD. Oral calcium supplements to enhance early hospital discharge after bilateral surgical treatment of the thyroid gland or exploration of the parathyroid glands. J Am Coll Surg 1994;178:11e6. 9. Bellantone R, Lombardi CP, Raffaelli M, Boscherini M, Alesina PF, De Crea C, et al. Is routine supplementation therapy (calcium and vitamin D) useful after total thyroidectomy? Surgery 2002;132:1109e12. 10. Roh JL, Park CI. Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy. Am J Surg 2006;192:675e8. 11. Testa A, Fant V, De Rosa A, Fiore GF, Grieco V, Castaldi P, et al. Calcitriol plus hydrochlorothiazide prevents transient post-thyroidectomy hypocalcemia. Horm Metab Res 2006;38:821e6. 12. Uruno T, Miyauchi A, Shimizu K, Tomoda C, Takamura Y, Ito Y, et al. A prophylactic infusion of calcium solution reduces the risk of symptomatic hypocalcemia in patients after total thyroidectomy. World J Surg 2006;30:304e8. 13. Cheah WK, Arici C, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Complications of neck dissection for thyroid cancer. World J Surg 2002;26:1013e6. 14. Higgins J, Green S. Cochrane Handbook for systematic reviews of interventions Version 5.0.0. Chichester, UK: John Wiley & Sons; 2008. 15. Tartaglia F, Giuliani A, Sgueglia M, Biancari F, Juvonen T, Campana FP. Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am J Surg 2005;190:424e9. 16. Bove A, Bongarzoni G, Dragani G, Serafini F, Di Iorio A, Palone G, et al. Should female patients undergoing parathyroid-sparing total thyroidectomy receive routine prophylaxis for transient hypocalcemia? Am Surg 2004;70:533e6.
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