Perioperative versus postoperative calcium and vitamin D supplementation to prevent symptomatic hypocalcemia after total thyroidectomy: a randomized placebo controlled trial

Background:

Hypocalcemia is the most common complication following total thyroidectomy. This study aimed to evaluate the efficacy of perioperative combined calcium and vitamin D supplementation compared to postoperative combined calcium and vitamin D supplementation in reducing symptomatic hypocalcemia.

Materials and methods:

A prospective randomized placebo-controlled trial was carried out in patients undergoing total or completion thyroidectomy from June 2017 to May 2022. Eligible patients were assigned to receive either calcium carbonate and alfacalcidol or placebo 3 days before surgery, and both groups were given calcium carbonate and alfacalcidol for 14 days after surgery. Clinical outcomes (signs and symptoms of hypocalcemia, requirement of intravenous calcium, and medication-induced hypercalcemia) and laboratory results (calcium and parathyroid hormone levels) were compared between the two groups.

Results:

One hundred and thirty-four patients were included in the analysis, 68 were in perioperative oral calcium and vitamin D supplementation group, and 66 were in postoperative oral calcium and vitamin D supplementation group. Symptomatic hypocalcemia rates were significantly lower in the perioperative group than in the postoperative group (8.8 and 22.7%, respectively, P=0.033). All symptomatic hypocalcemia cases in the perioperative group occurred in the first 24 hours after surgery. Mean calcium levels were significantly higher in the perioperative group at 24 and 48 hours after surgery. Intravenous calcium requirement rate was lower in the perioperative group but the difference was insignificant (2.9 and 12.1%, P=0.053). Mean parathyroid hormone levels were within the normal range and did not differ between groups. No medication-induced hypercalcemia was detected in either group.

Conclusion:

Perioperative oral calcium and vitamin D supplementation significantly decreased the risks of symptomatic and biochemical hypocalcemia compared to postoperative oral calcium and vitamin D supplementation. The perioperative supplementation also shortened the recovery period of symptomatic hypocalcemia to within 24 hours.

Highlights

• Hypocalcemia is the most common complication after total or completion thyroidectomy.

• Perioperative calcium and vitamin D effectively reduced postoperative hypocalcemia.

• Perioperative supplementation was more effective than postoperative supplementation.

• Perioperative supplements shortened the recovery period of symptomatic hypocalcemia.

• Perioperative supplementation could be more beneficial in central neck dissection.

Introduction

Hypocalcemia due to hypoparathyroidism is a common complication following total or completion thyroidectomy, which results from inadvertent direct injury, devascularization, or removal of the parathyroid glands. Transient biochemical hypocalcemia, resolving within 6 months after surgery, has a reported rate of 0.3–49%. In contrast, permanent hypocalcemia, persisting after 6 months, has a rate of 0–13%1,2.

On the other hand, symptomatic hypocalcemia has been found in 1.6–50% of patients, usually in the early postoperative period within 24–72 hours when serum calcium is below 8.0 mg/dl1,3,4. Mild and moderate symptoms of hypocalcemia, presenting with perioral or acral paresthesia, tingling, and carpopedal spasm can be treated with oral calcium and/or vitamin D. However, severe hypocalcemia with a serum calcium level less than 7 mg/dl, presenting with seizures, laryngospasm, or cardiac arrhythmias should be managed immediately with an intravenous infusion of calcium and intensive monitoring which is a major cause of prolonged hospital stay1,3–5.

The management of postoperative hypocalcemia remains a challenging issue. Some practitioners closely monitor serum calcium levels and symptoms of hypocalcemia in the postoperative period and immediately treat with oral calcium with or without a vitamin D supplement or intravenous calcium infusion, depending on the severity of the condition. In contrast, some clinicians routinely manage with preoperative, postoperative, or perioperative supplementation to prevent transient hypocalcemia1,3–5.

A meta-analysis of nine studies demonstrated that a routine postoperative combination of calcium and vitamin D supplementation was an effective approach in reducing the rate of symptomatic hypocalcemia compared to calcium alone, vitamin D alone, or no supplementation1. In addition, the results also showed significantly higher mean serum calcium levels in the combined calcium and vitamin D group in comparison to groups given either calcium alone or no supplementation on postoperative days 1, 2, and 71,6–14. Moreover, the efficacy of a postoperative combination of a calcium and vitamin D supplement in prevention of transient symptomatic hypocalcemia and decreasing the demand for intravenous calcium supplementation was confirmed in another meta-analysis4,6–8,11,13–18.

In a recent systematic review of perioperative supplementation, seven of the nine studies reported statistically significant reduced rates of postoperative symptomatic hypocalcemia (absolute risk reduction, 11–40%) and biochemical hypocalcemia (absolute risk reduction, 13–59%)5. However, all the studies included had varied methodologies, including intervention medications (calcium, vitamin D, or hydrochlorothiazide), dosage, duration of administration (1–14 days), control groups (different supplementation, no supplementation, or no control group), and blinding process9,19–26.

The meta-analyses and systematic review mentioned above demonstrated the benefit of routine preoperative and postoperative calcium and/or vitamin D administration in decreasing the risks of symptomatic and biochemical hypocalcemia1,4,5. However, to date, the most effective empirical prophylactic regimen has not yet been established. There was a recent randomized controlled study evaluating the efficacy of perioperative compared to postoperative combined calcium and vitamin D supplementation in reducing symptomatic hypocalcemia. No differences in both symptomatic and biochemical hypocalcemia were demonstrated. However, there are some limitations in the study, including placebo was not used, and the participants were not blinded. Only 38 participants were in the intervention arm and 44 in the control arm, which may cause the study to be underpowered. Therefore, a double-blind, randomized placebo-controlled trial with more participants should be carried out27.

The primary objective of the present study was to investigate whether perioperative calcium and vitamin D supplementation could reduce the rates of early postoperative symptomatic and biochemical hypocalcemia compared to postoperative calcium and vitamin D supplementation in patients undergoing total or completion thyroidectomy. The secondary objective was to compare the rates of requirement of intravenous calcium infusion and medication-induced hypercalcemia and postoperative length of hospital stay between the two groups.

Materials and methods

Study design

A prospective, double-blind, randomized placebo-controlled trial was conducted in compliance with the guidelines for Good Clinical Practice and the Declaration of Helsinki and approved by the institutional ethics committee. The study has been reported in line with Consolidated Standards of Reporting Trials (CONSORT) Guidelines, Supplemental Digital Content 1, http://links.lww.com/JS9/A13. Patients were recruited at the Department of Otolaryngology between June 2017 and May 2022. All patients who agreed to participate in the study signed an informed consent form before enrollment. The inclusion criteria were patients aged more than 18 years who were due to undergo open total or completion thyroidectomy. Patients were excluded from the study if they were receiving calcium, vitamin D, vitamin D analogs, or proton pump inhibitors, had abnormal serum calcium, phosphorous, magnesium, parathyroid hormone (PTH), or thyroid-stimulating hormone levels, had a history of parathyroid dysfunction, abnormal calcium metabolism, previous neck irradiation, or previous central neck surgery other than unilateral thyroid lobectomy, pregnancy, renal insufficiency, hepatic failure, or heart failure.

The sample size calculation was based on our data and previous studies with similar medications to our study14,26. The expected postoperative symptomatic hypocalcemia rate in 48 hours following thyroidectomy with postoperative calcium and vitamin D supplementation is 23%. To detect a reduction of hypocalcemia rate to 6% with the effect of perioperative calcium and vitamin D supplementation and assuming an alpha level of 5% with a power of 80%, 67 participants were required in each group. With an expected approximate dropout rate of 15%, we planned to recruit 160 participants.

Randomization and treatment

The patients were randomly included into one of two treatment groups using a computer-generated randomization code (Random Allocation Software Version 1.0) with block size 4 with an equal probability of assignment to receive either calcium carbonate 1500 mg every 8 hours and alfacalcidol 0.5 µg every 12 hours for 3 days before surgery or the same amount and duration of identically presented placebo pills. In the early postoperative period, both groups were given calcium carbonate 1500 mg every 8 hours and alfacalcidol 0.5 µg every 12 hours for 14 days. Participant recruitment and randomization were performed by an independent otolaryngologist responsible for the allocation and not involved in the other parts of this study. Participant treatment was concealed from surgeons and outcome assessors who were other independent otolaryngologists using code samples.

Symptomatic hypocalcemia was defined if the patients experienced paresthesia, numbness, and tingling of the perioral region and the fingertips, carpopedal spasm, muscle cramps, tetany, cardiac arrhythmia, or the presence of Chvostek or Trousseau’s signs. Biochemical hypocalcemia was diagnosed if the corrected serum calcium level was lower than 8 mg/dl, and hypercalcemia was defined as a corrected serum calcium level higher than 10.5 mg/dl. [corrected serum calcium=serum Ca (mg/dl)+0.8 (4−serum albumin (g/dl)].

In the early postoperative period, signs and symptoms of hypocalcemia and serum albumin and calcium levels were evaluated at the following time points: 3, 24, and 48 hours. The management guidelines of hypocalcemia in our institution are modified from the American Thyroid Association Statement on Postoperative Hypoparathyroidism3, and additional management was commenced if:

1. Corrected calcium greater than or equal to 8 mg/dl with symptomatic hypocalcemia or corrected calcium 7.5–7.9 mg/dl without symptomatic hypocalcemia, serum albumin and calcium levels and clinical hypocalcemia were reevaluated in the next 6 hours.

2. Corrected calcium 7.5–7.9 mg/dl with symptomatic hypocalcemia or corrected calcium 7.0–7.4 mg/dl without symptomatic hypocalcemia, increased calcium carbonate to 3000 mg every 8 hours, and reevaluated in the next 6 hours.

3. Correct calcium less than 7.0 mg/dl with or without symptomatic hypocalcemia or had spontaneous carpopedal spasm, tetany, or cardiac arrhythmia, infused intravenous calcium gluconate, monitor EKG, and reevaluated in the next 6 hours.

Patients were kept under observation for at least 48 hours and discharged from the hospital with the assigned dose of calcium and vitamin D supplementation if they had no signs and symptoms of hypocalcemia and normal serum calcium levels had stabilized. In addition, due to routine use of vacuum drainage at the thyroid bed and neck dissection area in our institution, the patients would be discharged after drainage tube removal.

Surgical procedure

The operations were performed by three high-volume thyroid surgeons blinded to the study group allocation. During the procedure, the surgeons meticulously dissected thyroid and parathyroid glands to avoid vascular injury or inadvertent parathyroid gland manipulation and removal. If the surgeons detected devascularization or removal of the parathyroid gland, the gland was minced into 1 mm³ pieces and autotransplanted in the ipsilateral sternocleidomastoid muscle. For patients diagnosed with thyroid cancer, additional central, and/or lateral neck dissection was done as indicated.

Clinical and laboratory assessment

The patient assessment included age, sex, underlying diseases, and diagnosis of thyroid disease. Baseline evaluation within 7 days before surgery included serum creatinine, calcium, albumin, magnesium, phosphorous, and PTH levels, thyroid function test, liver function test, electrocardiogram, vocal cord function, and symptoms and signs of hypocalcemia (Chvostek’s and Trousseau’s signs). In the postoperative period at 3, 24, and 48 hours and then 14 days on the follow-up visit, serum albumin and calcium levels, together with signs and symptoms of hypocalcemia, and PTH levels (at 3 and 24 h and 14 days) were evaluated. However, additional laboratory and clinical evaluation could be done, as mentioned in the treatment session.

Other clinical outcomes, including surgical complications, medication-induced hypercalcemia, gastrointestinal side effects of oral calcium carbonate (constipation, flatulence, and bloating), and duration of hospital stay, were recorded.

Statistical analysis

Statistical analyses were performed using SPSS, version 22 for Windows (IBM Corporation). Continuous variables were compared using Student’s t tests or Mann–Whitney U tests, and categorical variables were compared using χ ² test or Fisher’s exact test as appropriate. A linear or logistic regression model was outlined based on a stepwise forward method testing the significant variables by univariate and multivariate analysis. The risk measure was the mean difference or odds ratio (OR) and its respective 95% CI. Statistical significance was considered for P values less than 0.05.

Results

Patient characteristics

One hundred and sixty-one patients were assessed for eligibility for inclusion in the study. Patient flow through the trial is summarized in the CONSORT diagram (Fig. 1). Eleven patients were excluded: six had changes in operative procedure, two declined surgery, and three had renal function impairment. One hundred and fifty patients were eligible for inclusion and randomized. Of these, four patients in the perioperative supplementation group and five patients in the postoperative supplementation group lost to follow-up for baseline characteristics evaluation and intervention treatment after randomization. One patient in each group did not show up for surgery. One patient in the perioperative supplementation group had hemodynamic instability and abnormal EKG during induction of general anesthesia, and surgery was canceled. One patient in the perioperative supplementation group and two patients in the postoperative supplementation group were planned for total thyroidectomy. However, during the operation, the surgeons decided to do thyroid lobectomy (Supplementary Tables 1 and 2, Supplemental Digital Content 2, http://links.lww.com/JS9/A14). The remaining 134 patients were included in the analysis. There were 68 patients in the perioperative and 66 in the postoperative supplementation group.

Figure 1.

CONSORT flow diagram. FU indicates follow-up.

Baseline characteristics of the analyzed patients including mean age, sex, diagnosis of thyroid disease, operative procedure (total or completion thyroidectomy, central neck dissection, lateral neck dissection, and parathyroid autotransplantation), preoperative biochemical results (correct calcium, magnesium, phosphorous, and PTH levels), and signs and symptoms of hypocalcemia were similar for the two groups, reflecting the homogeneity of the sample of the patients (Table 1).

Table 1.

Baseline characteristics of the analyzed patients.

	Perioperative supplementation group, n=68 [n (%)]	Postoperative supplementation group, n=66 [n (%)]	P value
Age (mean±SD) (y)	47.2±13.6	48.0±13.2	0.713
Sex
Female	61 (89.7)	62 (93.9)	0.532
Male	7 (10.3)	4 (6.1)
Diagnosis of thyroid disease
Thyroid cancer	39 (57.4)	41 (62.1)	0.754
Nontoxic nodular goiter	16 (23.5)	18 (27.3)
Toxic multinodular goiter	5 (7.4)	3 (4.5)
Graves’ disease	6 (8.8)	3 (4.5)
Chronic lymphocytic thyroiditis	2 (2.9)	1 (1.5)
Operation
Total thyroidectomy	57 (83.8)	54 (81.8)	0.821
Completion thyroidectomy	11 (16.2)	12 (18.2)
Neck dissection
Central neck dissection	18 (26.5)	20 (30.3)	0.703
Lateral neck dissection	4 (5.9)	6 (9.1)	0.528
Parathyroid autotransplantation	6 (8.8)	8 (12.1)	0.583
Preoperative biochemical testing
Corrected calcium (mean±SD) (mg/dl)	9.01±0.42	8.95±0.39	0.491
Magnesium (mean±SD) (mEq/l)	1.98±0.14	2.01±0.23	0.674
Phosphorous (mean±SD) (mg/dl)	3.67±0.22	3.88±0.31	0.809
Parathyroid hormone (mean±SD) (pg/ml)	40.21+11.92	37.69±11.59	0.217
Signs or symptoms of hypocalcemia	0	0	-

Corrected calcium level: normal range=8.0–10.5 mg/dl, magnesium level: normal range=1.3–2.1 mEq/l, phosphorous level: normal range=2.8–4.5 mg/dl, parathyroid hormone level: normal range=15–65 pq/ml.

Clinical and laboratory outcomes

In the first 48 hours postoperatively, symptomatic hypocalcemia was detected significantly less frequently in the perioperative supplementation group than in the postoperative supplementation alone group (8.8 and 22.7%, respectively, OR: 0.36; 95% CI: 0.22–0.89, P=0.033). Notably, all six patients (8.8%) in the perioperative supplementation group who developed symptomatic hypocalcemia had the symptoms in the first 24 hours. In contrast, nine patients (13.6%) and three patients (4.5%) in the postoperative supplementation group still had symptomatic hypocalcemia at 48 and 72 hours, respectively. The most common presentation of symptomatic hypocalcemia was paresthesia of the perioral region and the fingertips (25%), followed by positive Trousseau’s sign (21.9%). Furthermore, no severe symptomatic hypocalcemia, including laryngospasm, tetany, or cardiac arrhythmia, was observed (Table 2).

Table 2.

Clinical outcomes in patients who received either perioperative calcium and vitamin D supplementation or postoperative calcium and vitamin D supplementation.

Outcomes	Perioperative supplementation group (n=68) [n (%)]	Postoperative supplementation group (n=66) [n (%)]	P value
Symptomatic hypocalcemia
3 hours	6 (8.8)	14 (21.2)	0.054
24 hours	3 (4.4)	15 (22.7)	0.002
48 hours	0	9 (13.6)	0.001
72 hours	0	3 (4.5)	0.117
14 d	0	0	-
Participants with at least one episode of symptomatic hypocalcemia a	6 (8.8)	15 (22.7)	0.033
Biochemical hypocalcemia b
3 hours	8 (11.8)	16 (24.2)	0.073
24 hours	4 (5.9)	17 (25.8)	0.002
48 hours	0	5 (7.6)	0.027
14 d	0	0	-
Corrected calcium (mean±SD) (mg/dl)
3 hours	8.31±0.48	8.14±0.51	0.053
24 hours	8.71±0.53	8.47±0.79	0.046
48 hours	8.79±0.56	8.56±0.70	0.039
14 days	9.14±0.57	8.98±0.49	0.068
Parathyroid hormone (mean±SD) (pg/ml)
3 hours	22.81±12.26	22.19±14.93	0.794
24 hours	17.05±7.33	16.26±10.17	0.609
14 days	21.54±9.95	22.64±12.07	0.565
Intravenous calcium infusion requirement	2 (2.9)	8 (12.1)	0.053
Additional oral calcium requirement
24 hours	3 (4.4)	7 (10.6)	0.204
48 hours	2 (2.9)	8 (12.1)	0.053
72 hours	1 (1.5)	4 (6.1)	0.205
14 days	1 (1.5)	3 (4.5)	0.362
Calcium carbonate intake (mean±SD) (mg/d)
24 hours	4698±930	4977±1369	0.175
48 hours	4632±765	5045±1479	0.044
72 hours	4566±545	4772±1081	0.163
14 days	4566±545	4704±944	0.299
Surgical complications
Vocal cord paralysis	4 (5.9)	3 (4.5)	1.000
Hematoma	1 (1.5)	2 (3)	0.617
Medication-induced hypercalcemia	0	0	-
Gastrointestinal side effects	2 (2.9)	0	0.496
Length of hospital stay (mean±SD) (d)	4.1±1.2	4.6±2.1	0.065

Bold values are statistically significant.

Corrected calcium level: normal range=8.0–10.5 mg/dl, parathyroid hormone level: normal range=15–65 pq/ml.

^a Some participants might have more than one episode of symptomatic hypocalcemia at different time points.

^b Biochemical hypocalcemia was diagnosed if the corrected serum calcium level was lower than 8 mg/dl.

Biochemical hypocalcemia also occurred less frequently in the perioperative supplementation group than in the postoperative supplementation group at 3 hours after surgery, but the difference was insignificant (11.8 and 24.2%, respectively, OR: 0.98; 95% CI: 0.41–1.59, P=0.073). However, biochemical hypocalcemia rates were significantly lower in the perioperative group than in the postoperative group at 24 hours (5.9 and 25.8%, respectively, OR: 0.58, 95% CI: 0.39–0.71, P=0.002) and at 48 hours (0 and 7.6%, respectively, OR: 0.42, 95% CI: 0.20–0.77, P=0.027).

Mean corrected calcium levels were higher in the perioperative supplementation group than in the postoperative supplementation group at 3 hours after surgery, but the difference was not significant (8.31 and 8.14 mg/dl, respectively, P=0.053). However, the differences were statistically significant at 24 hours (8.71 and 8.47 mg/dl, respectively, P=0.046), and at 48 hours (8.87 and 8.56 mg/dl, respectively, P=0.039) (Fig. 2).

Figure 2.

Mean corrected calcium levels over time between the two groups.

At the 14-day follow-up visit, no patients in either group presented with symptomatic or biochemical hypocalcemia. There were no differences in the mean corrected serum calcium levels between the two groups (Table 2).

Severe hypocalcemia requiring intravenous calcium infusion was recorded less frequently in the perioperative supplementation group than in the postoperative supplementation group, but the difference did not reach statistical significance (2.9 and 12.1%, respectively, OR: 0.66, 95% CI: 0.47–1.12, P=0.053).

Additional oral calcium carbonate was required less frequently in the perioperative supplementation group than in the postoperative supplementation group at 24, 48, 72 hours, and 14 days but the differences did not reach statistical significance. However, at 48 hours postoperatively, the mean dosage of oral calcium intake was significantly higher in the postoperative supplementation group (Table 2).

Parathyroid hormone levels were measured postoperatively at 3 and 24 hours and then 14 days. The results revealed that mean PTH levels were within the normal range and were not significantly different between groups at all time points (Table 2) (Fig. 3).

Figure 3.

Mean parathyroid hormone levels over time between the two groups.

Treatment complications and length of hospital stay

No patients in the study developed medication-induced hypercalcemia. Mild flatulence was the only gastrointestinal side effect that was detected in two patients in the perioperative group. However, the patients tolerated the condition well without the need for discontinuation of calcium carbonate. The mean length of postoperative stay was not significantly different between groups which were 4.1 days (range: 2–9 days) in the perioperative supplementation group and 4.7 days (range: 2–14 days) in the postoperative supplementation group (P=0.065). In addition, no re-admissions due to a hypocalcemic episode were recorded.

Factors affecting symptomatic hypocalcemia

Logistic regression analysis was used to evaluate possible factors affecting symptomatic hypocalcemia, including age over 60 years, female sex, thyroid cancer, central neck dissection, lateral neck dissection, and parathyroid autotransplantation. Central neck dissection and parathyroid autotransplantation were associated with the risk of symptomatic hypocalcemia in the univariate analysis (OR: 5.25, 95% CI: 1.59–7.23, P=0.006 and OR: 2.76, 95% CI: 1.06–17.19, P=0.038, respectively). However, when the multivariate analysis was applied, central neck dissection was found to be the only significant risk factor for an increase in the rate of symptomatic hypocalcemia (OR: 3.53, 95% CI: 1.32–10.57, P=0.016). We did not analyze postoperative PTH and calcium levels as predicting factors because the results could be confounded with the supplementation (Table 3).

Table 3.

Possible risks for symptomatic hypocalcemia.

Risk factors	OR (95% CI)	P value
Univariate analysis
Age >60 y	1.57 (0.55–4.48)	0.404
Female sex	1.52 (0.60–425)	0.538
Thyroid cancer	1.42 (0.53–3.80)	0.480
Central neck dissection	5.25 (1.59–7.23)	0.006
Lateral neck dissection	1.19 (0.87–6.42)	0.069
Parathyroid autotransplantation	2.76 (1.06–17.19)	0.038
Multivariate analysis
Age >60 y	0.93 (0.19–5.34)	0.873
Female sex	1.04 (0.56–4.59)	0.643
Thyroid cancer	0.87 (0.49–6.03)	0.776
Central neck dissection	3.53 (1.32–10.57)	0.016
Lateral neck dissection	1.15 (0.74–9.54)	0.557
Parathyroid autotransplantation	1.98 (0.77–8.64)	0.144

Bold values are statistically significant.

OR indicates odds ratio.

Discussion

Measurement of intraoperative and early postoperative PTH and serial calcium levels has been used to stratify for risk of postoperative symptomatic hypocalcemia development following total or completion thyroidectomy3. However, these approaches are costly, labor-intensive, and may not be available in many centers. Furthermore, the patients usually require close clinical and biochemical monitoring or education about symptoms to return to the hospital if these symptoms arise1,3,4. Therefore, routine calcium and/or vitamin D supplementation has been widely used to reduce the risk of postoperative hypocalcemia and re-admission and accelerate hospital discharge1,3,4.

Previous studies demonstrated that the rates of transient symptomatic hypocalcemia decreased from 35.6 to 42.8% with no supplementation to 13.3–23.4% with routine postoperative supplementation with a combination of calcium and vitamin D6,11,14. In addition, combined supplementation has been shown to be more effective than either calcium or vitamin D supplementation alone1,4. Furthermore, perioperative calcium and vitamin D supplementation was shown to further decrease the rate to 6–11.7% in other previous studies20,22,24,26.

Compared to postoperative calcium and vitamin D supplementation alone, our results demonstrated that perioperative calcium and vitamin D supplementation significantly decreased the rate of symptomatic hypocalcemia from 22.7 to 8.8%. All patients in the perioperative supplementation group presented with symptomatic and biochemical hypocalcemia within the first 24 hours. In contrast, some patients in the postoperative supplementation group had a more extended period of hypocalcemia to postoperative day 3. The results showed that this approach is more effective in shortening the recovery period from briefly dysfunctional parathyroid glands. Therefore, the patients can be safely discharged after close postoperative observation for 24 hours after having the perioperative supplementation.

Perioperative supplementation resulted in higher mean corrected calcium levels on postoperative days 1 and 2, and also lower rates of biochemical hypocalcemia at both time points. However, the efficacy of perioperative supplementation in reducing symptomatic and biochemical hypocalcemia did not extend to day 14 of the follow-up.

In previous studies, the rate of severe hypocalcemia requiring intravenous calcium infusion in patients with no supplementation was 17.7–26.9%, and with routine postoperative supplementation, the rate was 5.7–10.3%14,16. Our results demonstrated the rate of the need for intravenous calcium was 12.1% in the postoperative group, which was decreased to 2.9% in the perioperative group, although the difference was not statistically significant.

The long duration of calcium and vitamin D administration could raise concerns about the possible inhibition of PTH secretion28,29. However, it has been demonstrated that routine calcium and vitamin D supplementation in cases of total thyroidectomy did not decrease PTH levels6,13. Our results also showed that mean serum PTH levels were within the normal range and did not differ between groups.

Another primary concern of routine calcium and vitamin D supplementation is medication-induced hypercalcemia. However, this was not found to be a problem in the present study. Mild flatulence, a side effect of calcium carbonate, was detected in only 2 patients but was tolerated well, and there was no need to discontinue the treatment. With regard to the length of hospital stay, the mean duration was not significantly different between the two groups. However, prolonged hospitalization in thyroid cancer patients with concurrent neck dissection could affect this outcome.

Possible risk factors for postoperative hypocalcemia previously reported are old age, female sex, preoperative vitamin D deficiency, hypomagnesemia, Graves’ disease, thyroiditis, substernal goiter, thyroid cancer, having central and lateral neck dissection, and need for parathyroid autotransplantation30–32. Our results demonstrated that central neck dissection was the only factor affecting symptomatic hypocalcemia in the multivariate analysis. Therefore, perioperative calcium and vitamin D supplementation could be more beneficial in patients with planned central neck dissection.

The present study has some limitations. First, although this is a randomized controlled trial, it is a single-center study which limits the transferability of the findings. Second, we did not evaluate baseline vitamin D levels. However, the assessment of preoperative vitamin D status in predicting postoperative hypocalcemia is still controversial19,22. Third, although the leading cause of permanent hypoparathyroidism is irreversible damage to the parathyroid glands from surgical techniques, and surgeons’ experience and parathyroid vitality do not improve with medication21, longer-term follow-up for permanent hypocalcemia would be helpful to inform further studies.

Conclusion

Our results add to the body of evidence pertinent to routine supplementation in preventing hypocalcemia after total or completion thyroidectomy. We have demonstrated that perioperative calcium and vitamin D supplementation was more effective than postoperative calcium and vitamin D supplementation alone in reducing the rates of symptomatic and biochemical hypocalcemia at 24 and 48 hours postoperatively. The perioperative supplementation also shortened the recovery period of symptomatic hypocalcemia to within 24 hours. Furthermore, perioperative supplementation could be more beneficial in patients with planned central neck dissection.

Ethical approval

The study protocol was approved by the Ethics Committee of the Faculty of Medicine, Chiang Mai University. The reference identification number is ENT-2560-04636.

Sources of funding

None.

Author contribution

P.S.: conceptualization, methodology, investigation, formal analysis, and writing – original draft. D.R.: conceptualization, investigation, writing – review and editing. H.K.: investigation and methodology. T.A.: investigation and data curation. N.H.: methodology. S.B.: data curation and formal analysis. M.S.: investigation and data curation.

Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest with regard to the content of this report.

Research registration unique identifying number (UIN)

None.

Guarantor

Pichit Sittitrai.

Data statement

Due to the sensitive nature of the clinical data collected in this study, patients were assured raw data would remain confidential and would not be shared except under specific requests.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Supplementary Material

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