Abstract
Objective
The aim was to explore the effects of preoperative calcium and activated vitamin D3 supplementation on post-thyroidectomy hypocalcemia and hypo-parathyroid hormone-emia (hypo-PTHemia).
Methods
A total of 209 patients were randomly divided into control group (CG) and experimental group (EG). Oral calcium and activated vitamin D3 supplementation were preoperatively administered to EG, whereas a placebo was administered to CG. Data on serum calcium, phosphorus, and PTH concentrations before operation, on postoperative day 1 (POPD1), at postoperative week 3 (POPW3), and on the length of postoperative hospitalization were collected.
Results
The serum calcium, phosphorus, and PTH concentrations, as well as the incidence of postoperative hypocalcemia and hypo-PTHemia, did not significantly differ between EG and CG. Subgroup analysis revealed that the serum calcium concentrations of the experimental bilateral thyroidectomy subgroup (eBTS) on POPD1 and POPW3 were higher than that of the control bilateral thyroidectomy subgroup (cBTS) (P < 0.05); the reduction of serum calcium in eBTS on POPD1 and POPW3 was less than those in cBTS (P < 0.05). However, significant differences were not observed between the unilateral thyroidectomy subgroups (UTS) (P > 0.05). Moreover, the incidence of postoperative hypocalcemia in cBTS on POPD1 was significantly higher than that in eBTS (65.9% vs 41.7%) (P < 0.05). The length of hospitalization in cBTS (3.55 ± 1.89 days) was significantly longer than that (2.79 ± 1.15 days) in eBTS (P < 0.05).
Conclusion
Short-term preoperative prophylactic oral calcium and activated vitamin D3 supplementation could effectively reduce the incidence of postoperative hypocalcemia and decrease the length of postoperative hospitalization in patients who have undergone bilateral thyroidectomy.
Introduction
Thyroid cancer is one of the most common malignant tumors, and papillary thyroid carcinoma (PTC) is the most common histologic type (1). Surgery remains the most effective treatment for thyroid cancer. However, postoperative hypo-parathyroid hormone-emia (hypo-PTHemia) and/or hypocalcemia are among the most common complications of thyroid surgery, with an incidence ranging 1.2–40% (2). Patients undergoing unilateral thyroidectomy had significantly lower risk of temporary hypoparathyroidism (2.2% vs 21.3%) and permanent hypoparathyroidism (0% vs 1.8%) as compared with those who had total thyroidectomy (3). Patients with hypocalcemia may suffer from numbness, carpopedal tetany, dysphoria, and arrhythmia, thereby inducing discomfort and prolonged hospital stay (4).
The serum calcium concentration was reported to drop to the lowest 24–72 h after thyroidectomy. It is proved that post-thyroidectomy hypocalcemia can be effectively prevented by postoperative oral calcium and vitamin D3 supplementation (5, 6). Moreover, preoperative serum calcium level was indicated a risk factor for post-thyroidectomy transient hypoparathyroidism (7), whereas the effectiveness of preoperative oral calcium supplementation in preventing postoperative hypoparathyroidism and hypocalcemia remains controversial (8, 9). We lack standard specifications for the dosage or duration of preoperative calcium supplementation. Therefore, we aimed to investigate the effects of preoperative prophylactic calcium and activated vitamin D3 supplementation on postoperative hypo-PTHemia and hypocalcemia by monitoring the levels of serum calcium as well as the incidence of postoperative hypocalcemia on postoperative day 1 and postoperative week 3.
Patients and methods
This study was approved by the Ethics Committee of our hospital. All the procedures were performed in accordance with the principles of the Declaration of Helsinki.
Patients
Patients diagnosed with thyroid disease and who underwent thyroidectomy between November 8, 2019, and July 31, 2021, at our hospital were enrolled in the study. The sample size was estimated according to the formula: n = 2 × ((tα+ tβ)σ/δ)2, t0.05 = 1.645 and t0.1 = 1.282, with a result of n = 29. We estimated the expected loss rate to be 5–7% and accordingly collected at least 31 cases in each subgroup, resulting in a total of no less than 124 cases.
The eligibility criteria were as follows: patients aged 18–70 years old; patients diagnosed with or highly suspected of thyroid cancer (confirmed using fine-needle aspiration or ultrasound patterns suggest TI-RADS 4A and above) and scheduled for thyroid surgery. The exclusion criteria were as follows: patients with parathyroid disorders or those taking oral calcium or vitamin D3 supplementation for other diseases. The postoperative exclusion criteria were as follows: patients with postoperative pathological diagnosis of benign thyroid tumors or those who underwent other surgical procedures. Serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations before operation, on postoperative day 1 and postoperative week 3, and the length of hospitalization after surgery were observed.
Methods
This is a single-center, single-blind randomized study. All patients were randomly divided into the experimental and control groups using the random number table method. The numbers were put into unified envelopes which only could be opened by the doctors. The patients were unaware of their group assignments. After admission, the serum concentrations of calcium, phosphorus, and PTH were measured in all patients. The experimental group was administered oral calcium (calcium carbonate 600 mg/day) and activated vitamin D3 (alfacalcidol, 1 µg/day) for 2 days before operation, whereas the control group was administered a placebo. The placebo was consistent in appearance with calcium carbonate and alfacalcidol. The serum calcium, phosphorus, and PTH concentrations were reevaluated in all patients on the morning of postoperative day 1 (usually 18–24 h post operation) and postoperative week 3. Serum PTH was measured using IMMULITE 1000 chemiluminescence instrument (Siemens diagnostic, Germany). On the day of operation, intravenous calcium supplementation (calcium gluconate 1 g) was routinely given after surgery. If no hypocalcemia on postoperative day 1 was observed, neither intravenous nor oral calcium supplementation would be given. Patients with hypocalcemia on postoperative day 1 would be given calcium carbonate orally at a dosage of 1200 mg/day, until the serum calcium level recovered. Moreover, the dosage of calcium carbonate would be adjusted accordingly base on the blood test result. For these patients, oral administration of calcium carbonate was conducted until 3 weeks after surgery. Hypocalcemia was defined as serum calcium lower than 2.20 mmol/L, and hypo-PTHemia was defined as PTH lower than 0.742 pmol/L according to the reference range of the laboratory department in our hospital. All serum calcium indices were calibrated according to the formula: Corrected calcium (mmol/L) = measured calcium (mmol/L) + (40 – measured albumin (G /L)) × 0.02.
All procedures were performed by five chief physicians with more than 20 years of clinical experience in thyroidectomy. The experimental and control groups were divided into unilateral thyroidectomy subgroup (UTS) and bilateral thyroidectomy subgroup (BTS) according to the surgical method. Unilateral thyroidectomy combined with unilateral central lymph node dissection was performed in the UTS group. In contrast, bilateral thyroidectomy combined with unilateral or bilateral central lymph node dissection was performed in the BTS group. The primary outcomes were the reduction value of serum calcium after operation, as compared with that before surgery, the serum calcium, phosphorus, and PTH levels on postoperative day 1. The secondary outcomes were the serum calcium, phosphorus, and PTH levels on postoperative week 3 and the length of postoperative hospitalization. The study was approved by the Ethics Committee of Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine (LWEC2019006) and filed with the Chinese Clinical Trial Registry (ChiCTR2300071239).
Statistical analysis
SPSS software (version 16.0) was used for the statistical analysis. General measurement data are presented as mean ± s.d., and categorical data are presented as n (%). The level of statistical significance was set at P < 0.05. Measurement data meeting the normality and homogeneity of variance between groups were compared using t-tests or one-way ANOVA. Otherwise, the rank-sum test in nonparametric statistics was used. Categorical data were compared using the chi-squared or Fisher’s exact test.
Results
Demographics
Initially, data from 240 cases were collected, including 122 and 118 in the control group and experimental group, respectively. Ten patients in the control group and 12 in the experimental group were excluded according to the postoperative exclusion criteria. Moreover, six and three patients in the control and experimental groups were lost to follow-up. The last enrolled patient completed the 3-week postoperative follow-up on September 13, 2021. After data analysis, the study ended on March 30, 2022. Finally, we enrolled 209 participants, with 103 patients in the experimental group and 106 in the control group. Of the latter, 65 (61.3%) were assigned to the control unilateral thyroidectomy subgroup (cUTS) and 41 (38.7%) to the control bilateral thyroidectomy subgroup (cBTS). For the experimental group, 67 patients (65.0%) were enrolled in the experimental unilateral thyroidectomy subgroup (eUTS), and 36 patients (35.0%) in the experimental bilateral thyroidectomy subgroup (eBTS). Basic clinical information – including sex, age, surgical methods, number of tumors, positive or total lymph nodes (LN), parathyroid misresection, maximum tumor diameter, tumor stage, and drainage on the first day after surgery – was analyzed, and no significant difference was observed between the groups (Table 1).
Baseline characteristics of patients in each group.
| Control group | Experimental group | P | ||
|---|---|---|---|---|
| Age (years) | 45.0 ± 12.8 | 44.5 ± 12.2 | 0.762 | |
| Sex (n (%)) | Male | 20 (18.9%) | 22 (21.4%) | 0.731 |
| Female | 86 (81.1%) | 81 (78.6%) | ||
| Surgical methods (n (%)) | UTS | 65 (61.3%) | 67 (65.0%) | 0.667 |
| BTS | 41 (38.7%) | 36 (35.0%) | ||
| Central LN dissection in BTS (n (%)) | Unilateral | 13 (31.7%) | 14 (38.9%) | 0.510 |
| Bilateral | 28 (68.3%) | 22 (61.1%) | ||
| Parathyroid misresection (n (%))a | 12 (11.3%) | 12 (11.7%) | 1.000 | |
| Number of tumors (n (%)) | Unifocal | 89 (84.0%) | 83 (80.6%) | 0.588 |
| Multifocalb | 17 (16.0%) | 20 (19.4%) | ||
| Maximum tumor diameter (cm) | 0.64 ± 0.56 | 0.58 ± 0.51 | 0.407 | |
| Number of positive LN | 0.88 ± 1.84 | 1.08 ± 2.68 | 0.529 | |
| Number of total LN | 4.97 ± 5.17 | 4.83 ± 5.61 | 0.844 | |
| Tumor stage (n (%)) | Stage I | 96 (90.6%) | 100 (97.1%) | 0.083 |
| Stage II | 10 (9.4%) | 3 (2.9%) | ||
| Drainage on POPD1 (mL) | UTS | 27.84 ±14.06 | 27.16 ± 14.33 | 0.352 |
| BTS | 48.90 ± 26.95 | 43.41 ± 24.00 | ||
aParathyroid misresection, cases which parathyroid tissue was found in the pathological report postoperatively; bmultifocal, more than one tumor foci in each thyroid lobe.
BTS, bilateral thyroidectomy subgroup; LN, lymph node; POPD1, postoperative day 1; UTS, unilateral thyroidectomy subgroup.
Comparison of serum calcium, phosphorus, and PTH levels
The serum calcium, phosphorus, and PTH levels in the experimental and control groups before the operation, on postoperative day 1, and postoperative week 3 are presented in Table 2; these values did not significantly differ between the two groups. Furthermore, we observed no significant difference in each statistical value between the cUTS and eUTS (Table 3), whereas the serum calcium values of the eBTS on postoperative day 1 and postoperative week 3 were higher than those of the cBTS (P = 0.042, P = 0.020) (Table 4). These results suggest an evident decline in serum calcium concentration in the cBTS subgroup on postoperative day 1 (Fig. 1).
Serum calcium in bilateral thyroidectomy subgroups. BOP, before operation; cBTS, control bilateral thyroidectomy subgroup; eBTS, experimental bilateral thyroidectomy subgroup; POPD1, postoperative day 1; POPW3, postoperative week 3; PTH, parathyroid hormone. *P = 0.042; ∆ P = 0.020.
Citation: Endocrine Connections 13, 1; 10.1530/EC-23-0377
Serum calcium, phosphorus, and PTH values of two groups.
| Control group (n = 106) | Experimental group (n = 103) | P | ||
|---|---|---|---|---|
| BOP | Serum calcium (mmol/L) | 2.47 ± 0.09 | 2.46 ± 0.09 | 0.230 |
| Serum phosphorus (mmol/L) | 1.18 ± 0.19 | 1.17 ± 0.18 | 0.512 | |
| PTH (pmol/L) | 4.50 ± 2.18 | 4.68 ± 2.35 | 0.566 | |
| POPD1 | Serum calcium (mmol/L) | 2.31 ± 0.13 | 2.30 ± 0.17 | 0.265 |
| Serum phosphorus (mmol/L) | 1.33 ± 0.22 | 1.35 ± 0.23 | 0.444 | |
| PTH (pmol/L) | 1.57 ± 1.13 | 1.65 ± 1.74 | 0.446 | |
| POPW3 | Serum calcium (mmol/L) | 2.44 ± 0.13 | 2.45 ± 0.13 | 0.682 |
| Serum phosphorus (mmol/L) | 1.25 ± 0.22 | 1.25 ± 0.21 | 0.947 | |
| PTH (pmol/L) | 3.28 ± 1.71 | 3.25 ± 2.23 | 0.934 | |
Reference range: serum calcium 2.20–2.65 mmol/L, serum phosphorus 0.81–1.45 mmol/L, PTH 0.742–5.618 pmol/L.
BOP, before operation; POPD1, postoperative day 1; POPW3, postoperative week 3; PTH, parathyroid hormone.
Serum calcium, phosphorus, and PTH values in the unilateral thyroidectomy subgroups.
| cUTS | eUTS | P | ||
|---|---|---|---|---|
| BOP | Serum calcium (mmol/L) | 2.49 ± 0.09 | 2.46 ± 0.10 | 0.167 |
| Serum phosphorus (mmol/L) | 1.18 ± 0.19 | 1.16 ± 0.15 | 0.399 | |
| PTH (pmol/L) | 4.15 ± 1.92 | 4.68 ± 2.55 | 0.174 | |
| POPD1 | Serum calcium (mmol/L) | 2.35 ± 0.10 | 2.32 ± 0.19 | 0.129 |
| Serum phosphorus (mmol/L) | 1.31 ± 0.20 | 1.34 ± 0.20 | 0.317 | |
| PTH (pmol/L) | 1.91 ± 1.00 | 2.11 ± 1.66 | 0.879 | |
| POPW3 | Serum calcium (mmol/L) | 2.48 ± 0.11 | 2.47 ± 0.11 | 0.628 |
| Serum phosphorus (mmol/L) | 1.21 ± 0.20 | 1.18 ± 0.16 | 0.407 | |
| PTH (pmol/L) | 3.38 ± 1.65 | 3.68 ± 2.20 | 0.368 |
Reference range: serum calcium 2.20–2.65 mmol/L, serum phosphorus 0.81–1.45 mmol/L, PTH 0.742–5.618 pmol/L.
BOP, before operation; cUTS, control unilateral thyroidectomy subgroup; eUTS, experimental unilateral thyroidectomy subgroup; POPD1, postoperative day 1; POPW3, postoperative week 3; PTH, parathyroid hormone.
Serum calcium, phosphorus, and PTH values in the bilateral thyroidectomy subgroups.
| cBTS | eBTS | P | ||
|---|---|---|---|---|
| BOP | Serum calcium (mmol/L) | 2.42 ± 0.08 | 2.45 ± 0.08 | 0.249 |
| Serum phosphorus (mmol/L) | 1.18 ± 0.19 | 1.18 ± 0.21 | 0.958 | |
| PTH (pmol/L) | 5.33 ± 2.55 | 4.67 ± 2.11 | 0.218 | |
| POPD1 | Serum calcium (mmol/L) | 2.20 ± 0.15 | 2.27 ± 0.13 | 0.042 |
| Serum phosphorus (mmol/L) | 1.39 ± 0.26 | 1.37 ± 0.27 | 0.767 | |
| PTH (pmol/L) | 0.75 ± 1.00 | 1.08 ± 1.68 | 0.716 | |
| POPW3 | Serum calcium (mmol/L) | 2.36 ± 0.15 | 2.42 ± 0.15 | 0.020 |
| Serum phosphorus (mmol/L) | 1.34 ± 0.23 | 1.34 ± 0.24 | 0.869 | |
| PTH (pmol/L) | 3.02 ± 1.84 | 2.72 ± 2.17 | 0.529 |
Bold indicates statistical significance, P < 0.05. Reference range: serum calcium 2.20–2.65 mmol/L, serum phosphorus 0.81–1.45 mmol/L, PTH 0.742–5.618 pmol/L.
BOP, before operation; cBTS, control bilateral thyroidectomy subgroup; eBTS, experimental bilateral thyroidectomy subgroup; POPD1, postoperative day 1; POPW3, postoperative week 3; PTH, parathyroid hormone.
We then compared the reduction of serum calcium between cBTS and eBTS (dD1 = the serum calcium concentration before operation − the serum calcium concentration value on postoperative day 1, dW3 = the serum calcium concentration value before operation − the serum calcium concentration value on postoperative week 3). It could be seen that the reduction of serum calcium in eBTS on postoperative day 1 and postoperative week 3 was less than that in cBTS (P = 0.026, P = 0.042, respectively), while the changes of serum phosphorus and PTH were not statistically different (P > 0.05) (Table 5).
Changes of serum calcium in the bilateral thyroidectomy subgroups.
| cBTS | eBTS | P | ||
|---|---|---|---|---|
| dD1a | Serum calcium (mmol/L) | 0.17 ± 0.15 | 0.10 ± 0.11 | 0.026 |
| Serum phosphorus (mmol/L) | −0.21 ± 0.27 | −0.19 ± 0.27 | 0.651 | |
| PTH (pmol/L) | 4.58 ± 0.25 | 3.59 ± 1.86 | 0.153 | |
| dW3b | Serum calcium (mmol/L) | 0.01 ± 0.17 | −0.06 ± 0.14 | 0.042 |
| Serum phosphorus (mmol/L) | −0.17 ± 0.25 | −0.16 ± 0.21 | 0.607 | |
| PTH (pmol/L) | 2.32 ± 2.97 | 1.96 ± 2.32 | 0.876 |
Bold indicates statistical significance, P < 0.05.
adD1: the serum calcium concentration value BOP − serum calcium concentration value on POPD1. Negative values indicate that the value BOP is lower than that on POPD1; bdW3: the serum calcium concentration value BOP − serum calcium concentration value on POPW3. Negative values indicate that the value BOP is lower than that on POPW3.
cBTS, control bilateral thyroidectomy subgroup; eBTS, experimental bilateral thyroidectomy subgroup.
Comparison of incidence of postoperative hypocalcemia and hypo-PTHemia
The lower limit of the normal serum calcium and PTH were 2.2 mmol/L and 0.742 pmol/L, respectively, in our hospital. The cases in the experimental and control groups whose serum calcium and PTH levels were lower than normal values on postoperative day 1 and postoperative week 3 were counted to analyze the incidence of postoperative hypocalcemia and hypo-PTHemia (Table 6). Comparison of the incidences of hypocalcemia and hypo-PTHemia among the subgroups (Table 7) revealed 27 cases (65.9%) of hypocalcemia on postoperative day 1 in the cBTS, which was significantly higher than that in the eBTS (15 cases, 41.7%) (P = 0.041).
Incidence of postoperative hypocalcemia and hypo-PTHemia of two groups.
| Control group (n = 106) | Experimental group (n = 103) | P | |
|---|---|---|---|
| Hypocalcemiaa on POPD1, n (%) | 32 (30.2) | 21 (20.4) | 0.114 |
| Hypocalcemia on POPW3, n (%) | 5 (4.7) | 5 (4.9) | 0.963 |
| Hypo-PTHemiab on POPD1, n (%) | 25 (23.6) | 37 (30.1) | 0.051 |
| hypo-PTHemia on POPW3, n (%) | 4 (3.8) | 6 (5.8) | 0.487 |
aHypocalcemia, serum calcium <2.20 mmol/L; bHypo-PTHemia PTH <0.742 pmol/L.
POPD1, postoperative day 1; POPW3, postoperative week 3.
Incidence of postoperative hypocalcemia and hypo-PTHemia of subgroups.
| UTS | BTS | |||||
|---|---|---|---|---|---|---|
| Control | Experimental | P | Control | Experimental | P | |
| Hypocalcemiaa on POPD1, n (%) | 5 (7.7) | 6 (9.0) | 0.793 | 27 (65.9) | 15 (41.7) | 0.041 |
| Hypocalcemia on POPW3, n (%) | 0 (0.0) | 1 (1.8) | 0.432 | 5 (16.2) | 4 (8.7) | 0.319 |
| Hypo-PTHemiab on POPD1, n (%) | 7 (9.3) | 8 (14) | 0.399 | 18 (58.1) | 29 (63.0) | 0.660 |
| Hypo-PTHemia on POPW3, n (%) | 0 (0.0) | 1 (1.8) | 0.432 | 4 (12.9) | 5 (10.9) | 0.785 |
Bold indicates statistical significance, P < 0.05.
aHypocalcemia, serum calcium <2.20 mmol/L; bHypo-PTHemia, PTH <0.742 pmol/L.
BTS, bilateral thyroidectomy subgroup; POPD1, postoperative day 1; POPW3, postoperative week 3; UTS, unilateral thyroidectomy subgroup.
Postoperative hospitalization
The average length of postoperative hospitalization was 2.81 ± 1.33 and 2.58 ± 1.17 days in the control and experimental groups, respectively; however, these values were not significantly different (P = 0.151). The average postoperative hospitalization did not significantly differ between the cUTS and eUTS (2.50 ± 0.86 days vs 2.40 ± 1.16 days, respectively; P = 0.256). The average postoperative hospitalization in cBTS was 3.55 ± 1.89 days, which was significantly higher than 2.79 ± 1.15 days in eBTS (P = 0.042) (Fig. 2).
Postoperative hospitalization of subgroups. BTS, bilateral thyroidectomy subgroup; UTS, unilateral thyroidectomy subgroup. *P = 0.042.
Citation: Endocrine Connections 13, 1; 10.1530/EC-23-0377
Discussion
Postoperative hypoparathyroidism and hypocalcemia, which typically result in perioral or acral numbness and carpopedal tetany of patients, are critical complications of thyroid surgery. The evident clinical signs and symptoms cause discomfort and fear in patients, as well as result in prolonged hospitalization. In this study, the duration of preoperative administration of prophylactic oral supplementation of calcium and activated vitamin D3 was shortened to 2 days. Serum calcium levels in the eBTS group were higher than those in the cBTS group on postoperative day 1 and postoperative week 3. The reduction of serum calcium after operation in eBTS was obviously less than that of cBTS. The incidence of hypocalcemia on postoperative day 1 was significantly lower in the eBTS group than in the cBTS group. The postoperative duration of hospitalization was significantly shorter in the eBTS group than in the cBTS group. Therefore, we surmised that short-term preoperative calcium and activated vitamin D3 supplementation could effectively reduce the occurrence of postoperative hypocalcemia and length of postoperative hospitalization for patients undergoing bilateral thyroid lobectomy.
A previous study reported that the incidence of postoperative transient hypoparathyroidism in patients who underwent total thyroidectomy at our hospital was 36.1% (7). Intraoperative parathyroid injuries, including misresection, autotransplantation, and devascularization of the parathyroid gland (10), are typically believed to increase the incidence of postoperative hypocalcemia (11). Most studies have also focused on the identification and protection of the parathyroid glands during surgery, including in situ preservation of the parathyroid gland, application of carbon nanoparticles, and parathyroid autofluorescence imaging technology (12, 13, 14). However, surgeries such as bilateral thyroidectomy (15) or central group lymph node dissection are regularly performed, and the incidence of transient hypocalcemia can still reach up to 50% even if the parathyroid gland is preserved in situ. The proportion of patients with long-term postoperative hypocalcemia can also reach 6% (16). We observed that despite identifying and protecting the parathyroid gland and its vasculature during the surgery, some patients still experienced transient or permanent postoperative hypoparathyroidism.
Transient hypocalcemia is common in the early stages after thyroidectomy but does not affect the overall life of patients with appropriate intervention (4). Calcium supplementation in the early postoperative period can reduce the symptoms of hypocalcemia after total thyroidectomy (17). Prophylactic calcium supplementation may be an effective way to reduce the occurrence of postoperative hypocalcemia, but it remains undetermined. Donahue (8) et al. reported the lack of significant differences in the incidence of postoperative hypocalcemia between preoperative-to-postoperative calcium supplementation and postoperative calcium supplementation alone in patients undergoing total thyroidectomy; therefore, routine calcium supplementation before total thyroidectomy was not recommended. However, the significant differences may have been masked by the limited sample size. Khatiwada et al. (9) indicated in their review that preoperative calcium and/or vitamin D3 supplementation could reduce the incidence of postoperative hypocalcemia; therefore, preoperative calcium supplementation could be considered for patients undergoing total thyroidectomy. In our study, patients in eBTS group with preoperative prophylactic administration of calcium and activated vitamin D3 had higher postoperative serum calcium than those in cBTS, and lower incidence of postoperative hypocalcemia than cBTS; in this regard, our result was in line with Khatiwada’s findings. Interestingly, we found that although there were significant differences in serum calcium concentration between eBTS and cBTS on postoperative day 1 and postoperative week 3, no significant difference in PTH between the two groups was noticed. We further analyzed the reduction value of serum calcium and PTH in these two subgroups on postoperative day 1 and postoperative week 3, respectively. We found that the reduction of serum calcium after operation in eBTS was obviously less than that of cBTS, and there was a reduction trend of PTH in eBTS on postoperative day 1 and postoperative week 3, though no significant difference was observed. Therefore, we assumed that the reduction of PTH did not translate into significant reduction in serum calcium in eBTS due to effective preoperative oral calcium supplementation.
The duration of preoperative oral calcium supplementation is yet to be unified. Jaan (18) believed that oral calcium and vitamin D3 supplementation 1 week before surgery can reduce the incidence of hypocalcemia after bilateral thyroidectomy for thyroid cancer. Dapeng et al. (19) and Sittitrai P (20) also demonstrated that a short (2 days and 3 days, respectively) preoperative course of oral calcium and vitamin D supplementation in patients undergoing total thyroidectomy could reduce the incidence of both symptomatic and biochemical hypocalcemia, especially for those with transient hypoparathyroidism and could shorten the recovery period of symptomatic hypocalcemia.
The serum calcium and PTH on the first day after operation together (21) or the PTH concentration 3 h postoperatively (22) can predict the occurrence of postoperative hypocalcemia, which helps introduce personalized hospitalization and optimal treatment regimens. Nowadays, the effect of vitamin D in thyroid surgery has been paid more and more attention because of its close relationship with calcium absorption. Vitamin D deficiency was considered an independent contributor to transient hypocalcemia and hypoparathyroidism following parathyroidectomy (23). Saibene (24) believed that 25-hydroxy-vitamin D deficiency significantly predicted transient postoperative hypocalcemia after total thyroidectomy, while no association between preoperative vitamin D level and the development of hypocalcemia or hypoparathyroidism was found in José or Alexis Deffain’s study (25, 26). Rubin SJ (27) demonstrated that 25-hydroxy-vitamin D level <30 ng/mL was significantly associated with postoperative hypocalcemia.
Although it remains inconclusive whether preoperative vitamin D level can be used as a predictor of hypocalcemia after thyroidectomy, Ali Ramouz (28) found that vitamin D supplementation in patients with vitamin D deficiency might lead to a lower incidence of early-onset symptomatic hypocalcemia, thus requiring less calcium supplementation. Qing Hao (29) proposed supplying calcitriol if the relative decline of PTH had reached 70%. Mehreen (30) found a prophylactic vitamin D dose given in immediate preoperative period could significantly reduce acute symptomatic postoperative hypocalcemia in patients undergoing thyroid surgery. Cian Casey (31) also illustrated in her review that the use of preoperative vitamin D, with or without calcium, may provide a modest reduction in the incidence of hypocalcaemia following total thyroidectomy. As measurement of 25-OH vitamin D was not available when the study was conducted, no baseline data were obtained, which is one of the limitations of this study. We found that the preoperative serum calcium and PTH levels in the control group were slightly higher than those in the experimental group (although P > 0.05). At 3 weeks after operation, the difference of PTH between the two groups had almost recovered to the preoperative level, but the serum calcium level in the experimental group was still higher than that in the control group. Given the modulatory effect of vitamin D on calcium metabolism, we hypothesized that this difference might be the result of concomitant prophylactic vitamin D supplementation before surgery. We saw similar changes in the bilateral subgroups but unfortunately not in the unilateral subgroups, which may need to be verified in more rigorous trials.
The gradual popularization of Enhanced Recovery After Surgery (ERAS) has considerably shortened the postoperative rehabilitation time for thyroid diseases (32). Notably, the postoperative hospitalization for patients with thyroid disease is typically 2–4 days in our department. We observed that the length of postoperative hospitalization was significantly shorter in the eBTS group than in the cBTS group with short-term preoperative prophylactic calcium and activated vitamin D3 supplementation despite the lack of significant difference between the control and experimental groups. Owing to the similar surgical methods and degree of surgical trauma, the technical conditions, such as surgical drainage, affecting the length of postoperative hospitalization were similar in BTS. Therefore, we speculated that preoperative prophylactic calcium supplementation could stabilize the short-term postoperative serum calcium levels of patients in the experimental group, which may help reduce the occurrence of hypocalcemia symptoms and the need for postoperative hypocalcemia treatment. Thus, the duration of postoperative hospitalization can be shortened.
The optimal dosage of calcium supplementation remains inconclusive. Malik et al. (33) used 1000 mg/day of calcium and found that preoperative calcium and vitamin D3 supplementation could also reduce the incidence of postoperative hypocalcemia. According to Anne’s study (34), patients undergoing total thyroidectomy may benefit from the use of preoperative calcium 3000–4500 mg/day and calcitriol 0.5–1.0 µg/day supplementation, in addition to postoperative supplementation. Considering the safety of prophylactic calcium supplementation, a low dose of 600 mg calcium carbonate per day was used in this study. However, the incidence of hypocalcemia and hypo-PTHemia on postoperative day 1 and postoperative week 3 did not significantly differ between the groups. However, Grzegory et al. reported that (35) postoperative hypercalcemia or PTH inhibition did not occur even after calcium supplementation at a dose of 2000–3000 mg/day. Therefore, the dose of calcium supplementation could be increased in subsequent studies to identify the optimal prophylactic dose.
This study has a few limitations. First, the baseline vitamin D levels were not obtained, and the effects of diet and other medications on serum calcium were not included in the analysis, so the actual calcium and vitamin D intake could not be assessed precisely. Second, the number of parathyroid glands implanted in situ during surgery was not included in the analysis. Third, the number of patients who underwent unilateral thyroid lobectomy was significantly higher than those who underwent bilateral thyroid lobectomy. Although unilateral thyroid lobectomy is less invasive and may have a relatively low incidence of postoperative hypocalcemia, the results could have been biased. Moreover, we found that the clinical symptoms of hypocalcemia were relatively subjective during the preexperiment, and numbness of hands and feet could be observed in patients due to nervousness or anxiety after surgery. Consequently, we focused on more objective observation indicators, and the symptoms of hypocalcemia were not considered. Therefore, more data and a more reasonable stratified design, as well as multicenter randomized control trials, are required to further validate our findings.
Conclusions
In patients with confirmed or suspected malignant thyroid tumors who were scheduled to undergo bilateral thyroidectomy, short-term preoperative prophylactic oral calcium and activated vitamin D3 supplementation effectively reduced the incidence of postoperative hypocalcemia and decreased the length of postoperative hospitalization, which can be adopted in clinical practice for relief of postoperative discomfort.
Declaration of interest
All the authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This study was financially supported by the Shanghai Huangpu District Health Commission (grant nos. HKQ201901, HKM201906, and 2021QN03).
Ethical statement
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Ruijin Hospital Luwan Branch, Shanghai Jiaotong University School of Medicine (LWEC2019006 and ChiCTR2300071239), and informed consent was obtained from all individual participants.
Author contribution statement
Xiaoli Jin contributed to study design, medication or placebo prescription according to group assignment, data collection and analysis, manuscript writing (original draft). Jiankang Shen contributed to study design, data collection and analysis, manuscript review and editing. Conception and design: Xiaoli Jin, Jiankang Shen, Jianming Yuan. Administrative support: Tao Liu, Xunbo Huang, Tianxiang Wang, Weize Wu, Mingliang Wang. Provision of study materials or patients: Ru Zhou, Rongli Xie, Jianming Yuan. Collection and assembly of data: Ru Zhou, Rongli Xie. Data analysis and interpretation: Rongli Xie, Jianming Yuan. Manuscript writing: all authors. Final approval of manuscript: all authors.
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