Background: Hypoparathyroidism following a thyroidectomy remains a significant clinical challenge for an endocrine surgeon. Recently, it has been proposed by some endocrine surgeons that truncal ligation may lead to a higher incidence of postoperative hypocalcemia, while others have refuted this notion by citing no long-term impact on incidence of hypoparathyroidism. This study aims to compare the effect of truncal versus branch ligation of inferior thyroid arteries on postoperative hypocalcaemia. Data Sources: Articles were identified using the MeSH, and Free Keyword searches “Thyroid”, “Truncal Ligation” and “Hypocalcaemia” in PubMed, Embase, PubMed Central, Cochrane library, Latin American and Caribbean Health Sciences Literature database and Google Scholar. Methods: Randomized and nonrandomized controlled trials of patients who underwent subtotal/total thyroidectomy, completion thyroidectomy and thyroidectomy with neck dissection were searched, and outcomes of truncal ligation vers
Postoperative hypocalcaemia is a well-established entity following a total thyroidectomy procedure
Patient related factors |
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Disease severity |
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Indication for surgery |
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Preoperative calcium levels |
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Preoperative vitamin D levels |
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Size of gland |
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Type of gland |
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Surgery related factors |
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Surgical technique |
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Surgeon’s experience |
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Injury to blood vessels |
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Different surgical strategies and innovations have been brought into practice to prevent the postoperative complication of hypocalcaemia. Some studies have used localization tools to localize the parathyroid gland, and others have used auto-transplantation to prevent postoperative hypocalcaemia
The role of ligation of inferior thyroid arteries either at truncal or branch level and its effect on incidence in post-thyroidectomy hypocalcaemia remains a matter of significant scientific debate. Sanabria et al. did a meta-analysis on 9 RCT and 11 non-RCT to demonstrate that the ligation of the inferior thyroid artery increases the risk of temporary hypocalcaemia and that the patient develops symptomatic hypocalcaemia, but the meta-analysis could not establish a risk of definite hypocalcaemia
The objective of this meta-analysis study was to compare the outcomes of truncal ligation of inferior thyroid artery versus branch ligation in postoperative patients of thyroidectomy with additional high quality RCT literature available compared to the last meta-analysis conducted and review the effect of these techniques on postoperative hypocalcaemia.
A comprehensive search of controlled trials and analytical studies was conducted on PubMed, PubMed Central, Embase, Cochrane Library and Latin American and Caribbean Health Sciences Literature database and Google Scholars, and studies were time framed from July 1965 to July 2020. The Medical Subject Heading and following term used as Free Text in the search:” Thyroid” OR “Truncal Ligation” AND “Hypocalcaemia”. Further expanded data was extracted from articles, and cited authors and references were explored. Language barriers were overcome to include relevant data.
All clinical trials which used the surgical technique of truncal ligation and branch ligation of inferior thyroid artery after bilateral subtotal/thyroidectomy were included. Studies mentioning the use of surgical method of ligation and outcome of hypocalcaemia were selected. Single arm studies/non-comparable studies, reviewers/ letters, abstract articles with no full articles were excluded. Trials and studies of unilateral lobectomies and isthmectomies, capsular dissections without definite artery ligation site, autotransplantations of parathyroid gland following inadvertent removal and studies with undefined methods of inferior thyroid artery point ligation and prophylactic preoperative calcium administration were also excluded.
Patients undergoing bilateral subtotal thyroidectomy (removal of one lobe and subtotal resection of the contralateral lobe), total thyroidectomy, completion thyroidectomy and thyroidectomy with neck dissection for benign and malignant diseases were the focus of the study. The primary outcome analyzed was postoperative hypocalcaemia. Postoperative transient and definite hypocalcaemia were included according to the author's definition. Hypocalcaemia was divided into biochemical hypocalcaemia with an asymptomatic picture, and symptomatic hypocalcaemia according to serum levels of calcium and ionized calcium. We recorded the serum calcium and parathyroid hormone levels and replacement regimen given.
Identified studies were reviewed and the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines were followed
Further full text articles were reviewed, and eligibility criteria were discussed in case of queries. All data after extraction was counterchecked before analysis. The quality of RCTs was assessed according to the Cochrane collaboration assessment tool
The quality of the RCTs and non-RCTs was reported and weaknesses further discussed. A meta-analysis was performed with comparable studies, and variability of population was prevented by using Mantel-Haenszel random effect model. Data for the individual study was obtained for risk difference calculation with chi square test 2x2 table using Review Manager 5.4 software. The meta-analysis is presented as a risk difference (RD) with a confidence interval (95% CI). Results of intervention effects were illustrated with Forrest plot and defined as subgroups of RCT and non-RCT.
Sensitive analysis was conducted by excluding each study in turn, in order to evaluate the influence on the pooled results. Cochran’s Q test was used to assess the heterogeneity, I2 test was used for the statistical analysis of the degree of heterogeneity across the studies. The heterogeneity of the individual effect of the studies was assessed with Galbraith and L’Abbe graph, and a funnel plot was constructed for the extent of publication bias. The degree of heterogeneity of interpreting the statistics was as follows: 0-40% may not be significant, 30-60% moderate heterogeneity, 50-90% substantial heterogeneity and 75-100% as considerable heterogeneity.
After an extensive literature search, 211 articles were screened, and 48 studies were assessed for eligibility. 24 studies fulfilling the criteria of the selection process were chosen after a detailed review. Rest of the articles were excluded, as shown in Fig 1.
The study included 13 RCTs
Characteristics of studies comparing the Trunk Ligation and Branch Ligation of inferior thyroid artery |
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Trunk Ligation Of ITA |
Branch Ligation of ITA |
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Non-RCT |
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|
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|
|
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Azam 2013 |
20 |
7 |
NR |
NR |
3 |
23 |
5 |
NR |
NR |
2 |
Abou-Amra 2011 |
20 |
2 |
2 |
NR |
0 |
20 |
1 |
1 |
NR |
0 |
Iqbal 2015 |
50 |
12 |
10 |
NR |
0 |
50 |
10 |
9 |
NR |
0 |
Chiad 2009 |
62 |
50 |
NR |
NR |
7 |
46 |
22 |
NR |
NR |
0 |
E Ahmed 2011 |
23 |
4 |
NR |
NR |
NR |
27 |
7 |
NR |
NR |
NR |
Cakmakli 1992 |
50 |
21 |
7 |
NR |
0 |
30 |
13 |
3 |
NR |
0 |
Khan 2008 |
50 |
11 |
NR |
NR |
NR |
50 |
13 |
NR |
NR |
NR |
Kalliomaki 1961 |
16 |
NR |
0 |
NR |
NR |
17 |
NR |
0 |
NR |
NR |
Maralcan 2010 |
104 |
15 |
15 |
NR |
0 |
126 |
3 |
3 |
NR |
0 |
Salamatullah 2012 |
30 |
4 |
2 |
NR |
NR |
30 |
3 |
0 |
NR |
NR |
Pelizzo 1995 |
10 |
3 |
0 |
NR |
NR |
10 |
5 |
1 |
NR |
NR |
RCT |
|
|
|
|
|
|
|
|
|
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Romano 2015 |
92 |
51 |
NR |
NR |
1 |
92 |
39 |
NR |
NR |
2 |
Araujo-Filho V J F 2000 |
24 |
5 |
4 |
NR |
1 |
24 |
2 |
2 |
NR |
0 |
Naseem 2015 |
50 |
NR |
14 |
NR |
NR |
50 |
NR |
2 |
NR |
NR |
Al-Kordy 2019 |
15 |
3 |
3 |
NR |
NR |
15 |
1 |
1 |
NR |
NR |
Cocchiara 2010 |
63 |
NR |
8 |
21 |
2 |
63 |
NR |
1 |
10 |
1 |
Kebsch 2015 |
42 |
12 |
1 |
NR |
NR |
39 |
22 |
0 |
NR |
NR |
Maralcan 2006 |
49 |
NR |
1 |
14 |
0 |
49 |
0 |
NR |
12 |
0 |
Nies 1994 |
50 |
38 |
10 |
15 |
1 |
50 |
37 |
12 |
16 |
1 |
Sapmaz 2020 |
68 |
38 |
22 |
NR |
?1 |
71 |
25 |
11 |
NR |
?1 |
Waseem 2020 |
157 |
36 |
36 |
NR |
0 |
162 |
5 |
5 |
NR |
0 |
Topal 2007 |
40 |
NR |
4 |
NR |
NR |
52 |
NR |
5 |
NR |
NR |
Chaudhary 2007 |
163 |
10 |
NR |
NR |
3 |
147 |
7 |
NR |
NR |
2 |
Nawrot 2000 |
19 |
8 |
NR |
NR |
0 |
18 |
7 |
NR |
NR |
0 |
The quality of non-RCTs was assessed using the Newcastle-Ottawa assessment scale and only those studies which scored seven and above, were chosen, as shown in Fig 3. Although there was mention of an adequate follow up of hypocalcaemic patients in the studies, it, unfortunately, could not be applicable for definite hypocalcaemia. RCT studies were evaluated using the Cochrane collaboration assessment scheme, which showed most of the studies were unclear or low risk as shown in Fig 4.
NRCT |
Representative |
Selection |
Ascertainment |
Outcome of interest |
Comparability |
Assessment of Outcome |
Length of follow up |
Adequacy of follow up |
Total |
Azam et al 2013 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
Abou-Amra et al 2011 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
Iqbal M et al 2015 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
Chiad et al 2009 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
E Ahmed et al 2011 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
Cakmakli et al 1992 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
Khan et al 2008 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
Kalliomaki et al 1961 |
1 |
0 |
1 |
1 |
2 |
1 |
1 |
1 |
8 |
Maralcan et al 2011 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
1 |
8 |
Salamatullah et al 2012 |
1 |
1 |
1 |
1 |
2 |
1 |
0 |
0 |
7 |
Pelizzo et al 1995 |
1 |
1 |
1 |
1 |
2 |
1 |
1 |
1 |
9 |
The number of RCT studies that reviewed postoperative biochemical hypocalcaemia were 11 and 10 were non-RCT. Pooled results of risk difference using Mantel Hansel random effect of biochemical hypocalcaemia was 10% in 1472 patients who were in the RCT group, and 6% in 831 patients in non-RCT group. Out of the 1142 patients in branch ligation group, 235 developed biochemical hypocalcaemia, while 360 patients developed hypocalcaemia out of a total of 1161 patients in truncal ligation group. This indicates a low risk of biochemical hypocalcaemia in branch ligation of inferior thyroid artery with the overall effect of P-value of 0.0005. (Fig 5). Heterogeneity of the study was further explored and by excluding Chiad et al., the heterogeneity decreased to 9% and upon further excluding Chaudhary et al., it resulted in 22% without a change in total RD level.
Symptomatic hypocalcaemia was reported in 10 RCT and 7 non-RCT studies. Risk difference reported in RCT Group was 10% (CI 95% 3-17%) while in non-RCT studies it was 7% (CI 95% 2-11%). In 1133 patients in the RCT group, 48 patients were reported to have symptoms of hypocalcaemia in branch ligation group and 116 were symptomatic in truncal group. In a total of 570 patients in the non-RCT group, 36 were identified to develop symptoms of hypocalcaemia in trunk ligation as compared to 17 patients with a P-value of 0.003. (Fig 6). Pooled results of RD were 8% in total 1703 patients with a higher risk of developing symptomatic hypocalcaemia in ligating the trunk of the inferior thyroid artery.
Definite hypocalcaemia was documented in 14 studies from both non-RCT and RCT groups, in which total 1962 patients were found. 19 cases developed permanent hypocalcaemia in the truncal group while 8 patients were found in branch ligation group with a pooled RD 0% (CI 95% -1%- +1%). Pooled RD results of non-RCT was 2% in 1703 patients while 0% in RCT group with 1361 patients showing no statistical significance as documented in the literature. Analysis of heterogeneity of the studies was further explored and excluding Chiad et al. reduced the result to 0% (CI 95% 1%-2%) with no global change in pooled results.
Further analysis done between total thyroidectomy and subtotal/total thyroidectomy studies and pooled results of biochemical hypocalcaemia shows 4% (CI 95% 2-9%, I2=28%) in subtotal thyroidectomy and 15% in total thyroidectomy (CI 95% 11-19%, P-value <0.00001, I2=0%). In symptomatic hypocalcaemia, 5% (CI 95% 0-9%, P value 0.03, I2=33%) in subtotal/total thyroidectomy and in total thyroidectomy 13% (CI 95% 7-19%, P value <0.0001, I2=38%). Analysis of total and subtotal/total thyroidectomy to evaluate the definite hypocalcaemia was 0% with no change in overall pool results.
Asymmetry of publication bias was not found in the funnel plot, as shown in fig 7.
Postoperative hypocalcaemia mainly results from an iatrogenic injury of the parathyroid gland during thyroid surgery and decreases the quality of life of the affected total/bilateral subtotal thyroidectomy patient. The incidence of temporary postoperative hypocalcaemia varies, and authors report an incidence range from 6-55% to 83%
Causes of postoperative hypocalcaemia in a previous normocalcaemic patient have been scrutinized at multiple occasions, and literature found that devascularization of the parathyroid gland due to vascular spasm during manipulation or direct injury can result in hypocalcaemia
To overcome this obstacle, it has been suggested to ligate the inferior thyroid artery close to the capsule of the thyroid gland, therefore sparing the main trunk and the preserving the vessel supplying to the parathyroid gland
Literature which compares surgical techniques in order to deduce each technique’s effect on postoperative, symptomatic biochemical and definitive hypocalcaemia and subsequent use of long-term calcium and replacement regimen, is sparse. Antakia et al
In 2017, an up-to standard meta-analysis was conducted by Sanabria et al
One of the authors of this meta-analysis conducted a study on 319 patients and included patients with malignancy and undergoing neck dissection in addition to total thyroidectomy to review the impact of truncal ligation of inferior thyroid arteries on hypocalcaemia
The quality of the studies was explored in 13 RCTs using Cochrane collaboration assessment tool and found mostly 4 points of low risk of bias with unclear bias and in 11 Cohort studies using the Newcastle-Ottawa scale criteria found to have seven or above stars indicating the good quality studies or acceptable risk of bias making it a reliable to the overall results. Though the quality of these studies was taken into consideration in terms of biochemical and symptomatic hypocalcaemia, but the adequacy of follow up and long-term follow up for definite hypocalcaemia was defined by individual studies varies. Most of the studies followed-up their patients to the extent of the patient remaining asymptomatic or recovering from transient hypocalcaemia. We used risk difference to estimate the pooled results and random effect due to the large variation of population and heterogeneity to conclude a good reliable outcome result.
Our analysis shows a lower incidence of temporary hypocalcaemia in patients who had branch ligation of inferior thyroid artery with a statistical significance of 8% in biochemical hypocalcaemia with a p value of 0.003 and 8% in symptomatic hypocalcaemia with a P value of 0.0004. For biochemical hypocalcaemia, heterogeneity of the studies decreased to 9% after excluding Chiad et al. and 22% when excluding Chaudhary et al., but the pooled result was consistent with no marked change. Although there was no change in the heterogeneity in symptomatic hypocalcaemia when individual studies were reviewed and excluded. In definite hypocalcaemia, there was no significant difference in the incidence rate in both of the groups with 0% result in agreement with the literature.
Traditionally, it is thought that postoperative hypocalcaemia is multifactorial and is caused by a disturbance in functional levels and removal or manipulation of parathyroid gland which can result in vasospasm
There were a few limitations we encountered during our research; a major limitation was the timing of the serum and ionized calcium levels checked postoperatively. Even though the pooled result did not show any difference, the authors believe it could prove a bias in the results. Similarly, the definition of permanent hypocalcaemia varied in each study and follow up period with calcium replacement regimen was not clearly defined in individual studies to recognize the effects of hypocalcaemia. Moreover, it is not clear whether asymptomatic hypocalcaemia was treated with replacement regimen or not and needs further scrutiny. The extent of surgery performed in bilateral subtotal or a near total thyroidectomy is another factor that can be a cause of heterogeneity with no clear surgical definition. Surgeon’s experience and technique on preserving the thyroid tissue can also influence the overall outcome.
In conclusion, branch ligation of inferior thyroid arteries close to its capsule can result in a decrease in the outcome of transient hypocalcaemia and early recovery of biochemical and symptomatic hypocalcaemia but not the risk of the long-term effect on permanent hypocalcaemia. Furthermore, role of truncal ligation of inferior thyroid arteries and its impact on definite hypocalcaemia in long-term follow up requires further research.