Results

The search identified 5501 articles on PubMed, 6784 articles on Embase and 778 articles on Cochrane. One hundred and twenty-six articles were selected following title screening. Of these, 25 articles selected following abstract screening were examined in full.

Nine trials met the inclusion criteria (Figure 1 and Table 1).^{Reference Rowe, Arthurs, O'Neill, Hawthorne, Carroll and Wynne16–Reference Docimo, Tolone, Pasquali, Conzo, D'Alessandro and Casalino24} They included a total of 912 patients. The trials were published between 2006 and 2019, spanning 14 years. All nine trials studied adult populations in surgical in-patient departments, with follow up in out-patient clinics. Two trials were based in Italy,^{Reference Testa, Fant, De Rosa, Fiore, Grieco and Castaldi18,Reference Docimo, Tolone, Pasquali, Conzo, D'Alessandro and Casalino24} two were in Pakistan^{Reference Bhettani, Rehman, Ahmed, Altaf, Choudry and Khan17,Reference Malik, Mirza, Farooqi, Chaudhary, Waqar and Bhatti22} and the others were in India,^{Reference Jaan, Sehgal, Wani, Wani, Wani and Laway20} the USA,^{Reference Oltmann, Brekke, Schneider, Schaefer, Chen and Sippel21} Malaysia,^{Reference Lai, Zainira, Imisairi, Mazuin, Mokhzani and Ikhwan23} Australia^{Reference Rowe, Arthurs, O'Neill, Hawthorne, Carroll and Wynne16} and France.^{Reference Genser, Trésallet, Godiris-Petit, Li Sun Fui, Salepcioglu and Royer19}

Fig. 1. Flowchart of search strategy.

Table 1. Summary of included systematic reviews including rates of laboratory and symptomatic hypocalcaemia

*P-value not reported; ^†statistically significant data.

Six trials studied patients undergoing total thyroidectomy only: one included patients who had near total thyroidectomy,^{Reference Jaan, Sehgal, Wani, Wani, Wani and Laway20} where less than 1 ml of the thyroid gland is spared excision; one included patients who had completion thyroidectomy (removal of remnant thyroid tissue following less than total thyroidectomy);^{Reference Rowe, Arthurs, O'Neill, Hawthorne, Carroll and Wynne16} and one included patients undergoing near total and subtotal thyroidectomy (sparing 3–5 g of thyroid tissue).^{Reference Bhettani, Rehman, Ahmed, Altaf, Choudry and Khan17}

Indications for surgery included both malignant and benign thyroid disease in eight trials,^{Reference Rowe, Arthurs, O'Neill, Hawthorne, Carroll and Wynne16–Reference Jaan, Sehgal, Wani, Wani, Wani and Laway20,Reference Malik, Mirza, Farooqi, Chaudhary, Waqar and Bhatti22–Reference Docimo, Tolone, Pasquali, Conzo, D'Alessandro and Casalino24} whereas one trial exclusively studied patients with Graves’ disease.^{Reference Oltmann, Brekke, Schneider, Schaefer, Chen and Sippel21} Follow up ranged between 1 week to 6 months. None of the trials followed up patients for long enough to comment on permanent hypocalcaemia or hypoparathyroidism, defined as low parathyroid hormone levels or need for calcium supplementation at one-year post-surgery.

Rowe et al. treated 72 patients with a single dose of 300 000 IU cholecalciferol 7 days prior to surgery, while 78 patients received placebo.^{Reference Rowe, Arthurs, O'Neill, Hawthorne, Carroll and Wynne16} Post-operatively, both groups were treated with calcium, vitamin D or both, based on a standardised protocol. Calcium was measured at baseline, pre-operatively and post-operatively up to 180 days.

There were no statistically significant differences in the rates of hypocalcaemia between the treatment and control groups at 48 hours (22 vs 35 per cent; p = 0.09) or at any point within 180 days (29 vs 38 per cent; p = 0.23). Symptomatic hypocalcaemia rates were also not statistically significantly different (13 vs 15 per cent). There were no significant differences in hospital length of stay, nor on calcium requirement at 6 months.

Bhettani et al. studied 102 patients, 51 of whom were pre-treated with 200 000 IU of vitamin D one day before surgery.^{Reference Bhettani, Rehman, Ahmed, Altaf, Choudry and Khan17} Both treatment and control groups were given 700 mg/day of calcium carbonate for 2 days pre-operatively. Post-operatively, both groups received vitamin D and calcium for a month. Serum calcium was measured pre-operatively, post-operatively at 24 hours, on post-operative day 3 (if hypocalcaemic) and up to 4 weeks post-operatively.

Serum calcium levels were statistically significantly lower in the control group compared with the treatment group on post-operative days 1, 7 and 30. Symptomatic hypocalcaemia rate in the treatment group (11.7 per cent) was statistically significantly lower than in the control group (29.4 per cent; p < 0.05). Rates of hypocalcaemia in the treatment group were lower compared with the controls on post-operative day 1 (13.7 vs 23.5 per cent) and day 3 (2.9 vs 7.8 per cent), but the statistical significance was not reported.

Testa et al. studied 42 patients, of which 22 patients were treated with calcitriol of 1.5 mcg/day and hydrochlorothiazide of 25 mg/day for 7 days pre-operatively.^{Reference Testa, Fant, De Rosa, Fiore, Grieco and Castaldi18} In the control group, 20 patients were given placebo. Post-operatively, patients in both groups were given calcium and calcitriol. Serum calcium levels were measured at baseline, on the day before surgery and daily post-operatively.

Pre-treatment with calcitriol and hydrochlorothiazide led to a statistically significant increase in pre-operative serum calcium compared with baseline (2.44 vs 2.34 mmol/l; p < 0.05). No significant difference was seen in the control arm (2.30 vs 2.29 mmol/l). Laboratory hypocalcaemia (serum calcium less than 2.10 mmol/l) was seen in 4.5 per cent of patients in the treatment group compared with 50 per cent of controls (p < 0.01). None of the patients in the treatment group developed symptomatic hypocalcaemia compared with 20 per cent in the control arm. Hospital stay was longer in the control group (3.6 days) compared with the treatment group (2.4 days; p < 0.05).

Genser et al. studied 219 patients, of which 111 were treated with 2 ug of alfacalcidol per day from pre-operative day 1 to post-operative day 8.^{Reference Genser, Trésallet, Godiris-Petit, Li Sun Fui, Salepcioglu and Royer19} One-hundred and eight controls were not treated. Serum calcium levels were measured pre-operatively, on post-operative day 1 and daily thereafter in hypocalcaemic patients. Calcium supplementation was given to hypocalcaemic patients. Serum calcium was measured at 5 weeks and 6 months post-surgery.

Statistically significant lower calcium levels were seen in the control group (2.04 mmol/l) compared with the treatment group (2.12 mmol/l) on post-operative day 2 but not on post-operative day 1. Rates of hypocalcaemia (serum calcium less than 2 mmol/l) between the two groups on post-operative days 1 or 2 were not significantly different. However, rates of severe hypocalcaemia (serum calcium less than 1.90 mmol/l) (1 vs 6 per cent; p = 0.04) and symptomatic hypocalcaemia (11 vs 22 per cent; p = 0.02) were significantly lower in the treatment group compared with controls. Symptomatic hypocalcaemia was defined by the presence of one of the following: perioral or fingertip paraesthesia, muscle cramps, Chvostek and Trousseau signs, tetany, neuropsychiatric symptoms, and cardiovascular symptoms (not defined). Six months after surgery, hypocalcaemia persisted in four patients in the control arm compared with none in the treatment group (p = 0.04). Hospital length of stay between the two groups was not significantly different.

Jaan et al. studied 60 patients, 30 of whom were treated with 500 mg of oral calcium 4 times daily and 0.25 ug of calcitriol 4 times daily for 7 days prior to surgery and continued for 7 days post-operatively.^{Reference Jaan, Sehgal, Wani, Wani, Wani and Laway20} The control group of 30 patients received no treatment pre- or post-operatively unless they developed symptomatic hypocalcaemia. Calcium levels were measured pre-operatively and post-operatively for up to 30 days.

Pre-treatment with oral calcium and calcitriol led to no statistically significant differences in post-operative calcium levels between the control and treatment arms. At 24 hours, the rates of hypocalcaemia (serum calcium less than 2.12 mmol/l) were not significantly different between the two groups. However, at 48 hours, hypocalcaemia rate in the treatment arm (20 per cent) was significantly lower compared with controls (43.3 per cent; p = 0.04). This statistically significant difference continued at 72 hours post-operatively, but after 30 days there was no significant difference in hypocalcaemia rates between the two groups. The rate of symptomatic hypocalcaemia was significantly lower in the treatment arm (10 per cent) compared with controls (40 per cent; p < 0.01). Symptomatic hypocalcaemia was defined as the presence of one of the following: perioral or fingertip paraesthesia, neuropsychiatric manifestations, Chvostek and Trousseau signs, and prolonged QT interval on electrocardiogram.

Oltmann et al. studied 123 patients.^{Reference Oltmann, Brekke, Schneider, Schaefer, Chen and Sippel21} Of these, 45 patients undergoing total thyroidectomy for Graves’ disease were pre-treated with 1 g of calcium carbonate 3 times daily for 2 weeks prior to surgery. Thirty-eight historic controls undergoing total thyroidectomy for Graves’ disease were not pre-treated. Forty patients undergoing total thyroidectomy for a non-Graves’ pathology, who were not pre-treated, acted as procedural controls. Post-operatively, all Graves’ disease patients were routinely given calcium supplementation, whereas use of calcitriol was protocol driven. Calcium levels were measured pre-operatively. In patients staying in hospital overnight, calcium levels were also measured at 4 hours post-operatively. Calcium measurement on post-operative day 1 was at surgeon discretion.

Pre-treatment with calcium carbonate led to a symptomatic hypocalcaemia rate of 10 per cent, compared with 26 per cent in the control arm (p = 0.049). Symptomatic hypocalcaemia was defined as the presence of numbness, tingling, muscle cramping or tetany. Four-hour post-operative calcium levels were significantly higher in the pre-treated group (2.15 mmol/l) compared with controls (2.07 mmol/l; p = 0.05).

Malik et al. studied 92 patients.^{Reference Malik, Mirza, Farooqi, Chaudhary, Waqar and Bhatti22} Forty-six were treated with 200 000 IU of vitamin D and 1 g of calcium for 24 hours prior to surgery. In the control group, patients were not given anything. Post-operative treatment was not reported. In the treatment arm, 6.5 per cent developed hypocalcaemia (serum calcium <2.12 mmol/l) compared with 26.1 per cent in the control arm (p = 0.011).

Lai et al. studied 74 patients, who received either 0.5 mcg of calcitriol 3 times daily for 2 days pre-operatively or no pre-operative supplement.^{Reference Lai, Zainira, Imisairi, Mazuin, Mokhzani and Ikhwan23} Post-operatively, patients in the treatment arm were given calcitriol and oral calcium for one week. In the control arm, patients were given neither unless they were symptomatic. Calcium was measured up to 48 hours post-operatively and patients were followed up at 2 weeks and 6 months.

Rate of hypocalcaemia (serum calcium less than 2.1 mmol/l) in the treatment group was 16.7 per cent compared with 75 per cent in the control group (p = 0.000). Symptomatic hypocalcaemia was also statistically significantly lower in the treatment group (8.3 per cent) compared with the control group (48.6 per cent). Serum calcium between the two groups was significantly lower in the control group at 6 hours, 24 hours and 48 hours post-operatively. Post-operative hospital length of stay was shorter in the treatment group compared with the control group (3.92 vs 4.59 days; p = 0.001).

Docimo et al. studied 50 patients pre-treated with oral calcium of 2 g/day and vitamin D of 880 U/day for 3 days before surgery.^{Reference Docimo, Tolone, Pasquali, Conzo, D'Alessandro and Casalino24} This trial did not have a control arm. Treatment was continued until post-operative day 14. Calcium levels were measured pre-operatively, on post-operative day 1 and then every 24 hours until discharge. Laboratory hypocalcaemia (serum calcium less than 2 mmol/l) occurred in 10 per cent of patients and symptomatic hypocalcaemia in 6 per cent of patients.

Using Cochrane's risk of bias tool (version 2), one trial had low risk,^{Reference Rowe, Arthurs, O'Neill, Hawthorne, Carroll and Wynne16} four were of some concern^{Reference Bhettani, Rehman, Ahmed, Altaf, Choudry and Khan17–Reference Jaan, Sehgal, Wani, Wani, Wani and Laway20} and four had a high risk of bias.^{Reference Oltmann, Brekke, Schneider, Schaefer, Chen and Sippel21–Reference Docimo, Tolone, Pasquali, Conzo, D'Alessandro and Casalino24} Risk of bias was because of methodological issues around randomisation, concealment, blinding, analysis and reporting.