Clinical and Surgical Outcomes of Total Thyroidectomy in Basedow's Disease: the Effect of Lugol Solution (BALU)
Primary Purpose
Basedow Disease
Status
Enrolling by invitation
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Lugol -
Sponsored by
About this trial
This is an interventional treatment trial for Basedow Disease focused on measuring Lugol Solution, Total Thyroidectomy
Eligibility Criteria
Inclusion Criteria: diagnosis of Basedow disease candidate to total thyroidectomy age>18 years Exclusion Criteria: age<18 years; presence of solitary toxic nodule fine-needle aspiration biopsy result indicating cancer or suspicious cytology anticoagulant usage or coagulation disorders a previous thyroid operation pregnancy
Sites / Locations
- Azienda Università di Padova, Endocrine Surgery Unit
Arms of the Study
Arm 1
Arm 2
Arm Type
No Intervention
Active Comparator
Arm Label
Lugol -
Lugol +
Arm Description
No pre-operative Lugol Solution preparation
Pre-operative Lugol preparation (10 drops per day orally three times a day for 7 days for an amount of 10,5 ml of Lugol solution that contains 1,68 gr of Iodine).
Outcomes
Primary Outcome Measures
Intra and post-operative blood loss (mL).
Blood loss volume (mL) as the amount of blood in the suction bottle and that absorbed by gauzes used during surgery was measured (volume calculated from the difference between dry gauzes weight and soaked gauzes weight). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Secondary Outcome Measures
Post-operative laryngeal nerves palsy.
Evaluation of vocal cords disfunction. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Intra and post-operative thyrotoxicosis.
Heart rate > 120 b/min detected during surgery or during post-operative hospital days. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Post-operative hypocalcemia (hypoparathyroidism, hungry bone syndrome).
serum calcium level less than 2,00 (8 mg/dl), with serum PTH inappropriately low (<10 pg/mL). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05784792
Brief Title
Clinical and Surgical Outcomes of Total Thyroidectomy in Basedow's Disease: the Effect of Lugol Solution
Acronym
BALU
Official Title
Clinical and Surgical Outcomes of Total Thyroidectomy in Basedow's Disease: the Effect of Lugol Solution
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Enrolling by invitation
Study Start Date
February 1, 2020 (Actual)
Primary Completion Date
January 26, 2023 (Actual)
Study Completion Date
May 26, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Padova
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
Preoperative preparation of patient with Basedow's disease is crucial to avoid severe thyrotoxicosis resulting from leakage of thyroid hormone into the circulation at the time of surgery. Moreover, hyperthyroidism-related hypervascularization and tissue fragility caused by Basedow's disease thyroiditis may cause intraoperative bleeding that can reduce the visualization and preservation of parathyroid glands and laryngeal nerves with subsequent higher risk of related morbidity including neck hematoma, hypoparathyroidism and vocal cords paresis. Although some endocrine surgeons administer before surgery Lugol solution to decrease thyroid gland vascularity in Basedow's disease, there is still not an agreement on its effectiveness.
The aims of the present trial are to evaluate the impact of pre-operative short-term Lugol solution treatment (7 days) on surgical outcomes through modification of thyroid vascularity and surgical related morbidity, in patients with Basedow's disease.
Detailed Description
The study will investigate the effects of Lugol solution treatment before surgery on thyroid vascularity and tissue fragility in patients with Basedow's disease, and if these changes are associated or not with different surgical outcomes.
Hyperthyroidism is associated with hemodynamic changes, decreasing peripheral resistance that are related to both direct cardio-stimulatory effects of thyroid hormone. Preoperative preparation of the patient is crucial to avoid intra-operative or postoperative thyroid storms and to decrease the vascularity of the gland.
Inorganic iodide (Lugol solution) decreases the synthesis of thyroid hormone and release of hormone from the thyroid in the short term. Iodine also seems to reduce thyroid cellularity and vascularity and therefore is used in the preparation of patients for thyroidectomy. This effect transiently blocks thyroid hormone generation, with thyroid hormone synthesis recovering in few days.
On this matter doppler techniques seem to be the best method to evaluate blood flow in the thyroid gland.
Thyroid vascularity in Basedow's disease patients can be evaluated by monitoring CD-34 and CD-31 expression using immunohistochemistry. The vascular density of different tissues has been assessed by counting vessels labeled using immunohistochemistry with antibodies against different endothelial markers on paraffin-embedded sections. Antibodies that are most commonly used are directed against the endothelial antigens factor eight-related antigen, CD-31 (platelet endothelial cell adhesion molecule), CD-34. CD-34 is the most sensitive and specific marker currently available for the detection of angiogenesis. The use of these markers reflects total vascular density.
Moreover some authors showed that iodide inhibits vascular endothelial growth factor (VEGF) expression in cultured human thyroid follicles, and, consequently, they suggest that pro-angiogenic and anti-angiogenic factors may at least partly account for the iodide-induced decrease in thyroid blood flow. Cross-talk between angiogenesis and inflammation has also been reported. T cells can deliver VEGF to inflammatory sites and VEGF can augment pro-inflammatory T cell differentiation and promote angiogenesis.
So the detection of VEGF could be useful in the demonstration of Lugol effect on pretreated patients.
Investigators hypothesize that Lugol solution might act through different mechanisms. It probably decreases both angiogenic stimuli and blood flow in Basedow's disease. Decreased angiogenesis and blood flow resulted in a significantly decreased number of visible vessels. Therefore, it is reasonable to think that increased vascular density could reflect increased angiogenic input to this disease. Lugol solution could also act directly to vessels wall, changing arteries and veins lumen.
These modifications could cause a reduction of intra-operative bleeding that could allow better visualization and preservation of the surrounding nerves, vasculature, and parathyroid glands and so better surgical and clinical outcomes.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Basedow Disease
Keywords
Lugol Solution, Total Thyroidectomy
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Case-Control study
Masking
Care ProviderInvestigator
Allocation
Randomized
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Lugol -
Arm Type
No Intervention
Arm Description
No pre-operative Lugol Solution preparation
Arm Title
Lugol +
Arm Type
Active Comparator
Arm Description
Pre-operative Lugol preparation (10 drops per day orally three times a day for 7 days for an amount of 10,5 ml of Lugol solution that contains 1,68 gr of Iodine).
Intervention Type
Other
Intervention Name(s)
Lugol -
Intervention Description
Patients that undergo total thyroidectomy without Lugol solution pretreatment
Primary Outcome Measure Information:
Title
Intra and post-operative blood loss (mL).
Description
Blood loss volume (mL) as the amount of blood in the suction bottle and that absorbed by gauzes used during surgery was measured (volume calculated from the difference between dry gauzes weight and soaked gauzes weight). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Intra and post-operative bleeding (1st and 2nd day after surgery)
Secondary Outcome Measure Information:
Title
Post-operative laryngeal nerves palsy.
Description
Evaluation of vocal cords disfunction. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Laryngeal ultrasound on 1st and 2nd day and indirect laryngoscopy in case of dysphonia
Title
Intra and post-operative thyrotoxicosis.
Description
Heart rate > 120 b/min detected during surgery or during post-operative hospital days. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
During surgery and on 1st and 2nd day after surgery
Title
Post-operative hypocalcemia (hypoparathyroidism, hungry bone syndrome).
Description
serum calcium level less than 2,00 (8 mg/dl), with serum PTH inappropriately low (<10 pg/mL). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Blood sample on 1st and 2nd day after surgery.
Other Pre-specified Outcome Measures:
Title
Change of ultrasound thyroid vascularization: blood flow velocity (v) variation (mm/sec).
Description
US doppler of 4 thyroid arteries: blood flow velocity (v) (mm/sec) of the four main thyroid arteries, sampled near their entrance into the gland. Mean values for each artery is than calculated. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Thyroid US doppler data: 7 days before surgery and the day before surgery (after 1 week).
Title
Change of ultrasound thyroid vascularization: resistance index (RI) variation.
Description
US doppler of 4 thyroid arteries: resistance index (RI) of the four main thyroid arteries, sampled near their entrance into the gland. It is the ratio between (peack systolic velocity-end diastolic velocity)/peack systolic velocity. Mean values for each artery is than calculated. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Thyroid US doppler data: 7 days before surgery and the day before surgery (after 1 week).
Title
Change of ultrasound thyroid vascularization: pulsatility index (PI) variation
Description
US doppler of 4 thyroid arteries: pulstility index (PI) of the four main thyroid arteries, sampled near their entrance into the gland. It is the ratio between (peack systolic velocity-end diastolic velocity)/mean velocity. Mean values for each artery is than calculated. Evaluation of differences in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Thyroid US doppler data: 7 days before surgery and the day before surgery (after 1 week).
Title
Change of US thyroid volume (mL).
Description
Thyroid volume recorded through ultrasound (mL). It is also recorded directly after gland excision in the operating room (measuring the modification of the water volume inside a bowl after having dip the excised gland in the water bowl itself). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Thyroid US doppler data: 7 days before surgery and the day before surgery (after 1 week). Intra-operative thyroid volume detection (the day of surgery).
Title
Change of thyroid tissue: immunohistochemical evaluation of thyroid tissue mean vessels density.
Description
Thyroid vascularity evaluated through data recorded by hematoxylin and eosin sections and additional sections immunostained for CD-34 and CD-31. Section are scanned and mean vessels density is calculated by a specific softwear that recognizes CD31 and CD34 endothelial expression (specific colour expressed). The final count is then made by the softwear itself that through a machine learning method gives the section vessels total number and roe representative area mean vessels density. Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Post-operative pathological and immunoistochemical data recorded (in 30 days after surgery).
Title
Change of thyroid vascularization stimuli: VEGF levels variation (pg/mL).
Description
Thyroid vascularity evaluated through variation of VEGF plasmatic concentration (pg/mL) before and after Lugol solution assumption (when administrated). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Blood samples: 7 days before surgery and the day before surgery (after 1 week).
Title
Change of thyroid function and biochemical data: FT3 and FT4 variation (pmol/L).
Description
Serum FT3 and FT4 (pmol/L) levels variation before and after Lugol solution assumption (when administrated). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Blood samples: 7 days before surgery and the day before surgery (after 1 week).
Title
Change of thyroid function and biochemical data: TSH variation (mIU/L).
Description
Serum TSH (mIU/L) levels variation before and after Lugol solution assumption (when administrated). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Blood samples: 7 days before surgery and the day before surgery (after 1 week).
Title
Change of thyroid function and biochemical data: Ab anti TG, Ab anti TPO, Ab anti TSH variation (U/L).
Description
Serum Ab anti TG, Ab anti TPO, Ab anti TSH levels (U/L) variation before and after Lugol solution assumption (when administrated). Evaluation of differences (if any) in this outcome in the two groups of the study (Lugol assumption/no Lugol assumption).
Time Frame
Blood samples: 7 days before surgery and the day before surgery (after 1 week).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
diagnosis of Basedow disease candidate to total thyroidectomy
age>18 years
Exclusion Criteria:
age<18 years;
presence of solitary toxic nodule
fine-needle aspiration biopsy result indicating cancer or suspicious cytology
anticoagulant usage or coagulation disorders
a previous thyroid operation
pregnancy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maurizio Iacobone, Prof
Organizational Affiliation
University of Padova
Official's Role
Study Director
Facility Information:
Facility Name
Azienda Università di Padova, Endocrine Surgery Unit
City
Padova
State/Province
PD
ZIP/Postal Code
35121
Country
Italy
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
28611944
Citation
Hope N, Kelly A. Pre-Operative Lugol's Iodine Treatment in the Management of Patients Undergoing Thyroidectomy for Graves' Disease: A Review of the Literature. Eur Thyroid J. 2017 Feb;6(1):20-25. doi: 10.1159/000450976. Epub 2016 Nov 22.
Results Reference
result
PubMed Identifier
17389702
Citation
Erbil Y, Ozluk Y, Giris M, Salmaslioglu A, Issever H, Barbaros U, Kapran Y, Ozarmagan S, Tezelman S. Effect of lugol solution on thyroid gland blood flow and microvessel density in the patients with Graves' disease. J Clin Endocrinol Metab. 2007 Jun;92(6):2182-9. doi: 10.1210/jc.2007-0229. Epub 2007 Mar 27.
Results Reference
result
PubMed Identifier
27408715
Citation
Yilmaz Y, Kamer KE, Ureyen O, Sari E, Acar T, Karahalli O. The effect of preoperative Lugol's iodine on intraoperative bleeding in patients with hyperthyroidism. Ann Med Surg (Lond). 2016 Jun 16;9:53-7. doi: 10.1016/j.amsu.2016.06.002. eCollection 2016 Aug.
Results Reference
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PubMed Identifier
24075271
Citation
Shinall MC Jr, Broome JT, Nookala R, Shinall JB, Kiernan C, Parks L 3rd, Solorzano CC. Total thyroidectomy for Graves' disease: compliance with American Thyroid Association guidelines may not always be necessary. Surgery. 2013 Nov;154(5):1009-15. doi: 10.1016/j.surg.2013.04.064. Epub 2013 Sep 26.
Results Reference
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PubMed Identifier
26546192
Citation
Huang SM, Liao WT, Lin CF, Sun HS, Chow NH. Effectiveness and Mechanism of Preoperative Lugol Solution for Reducing Thyroid Blood Flow in Patients with Euthyroid Graves' Disease. World J Surg. 2016 Mar;40(3):505-9. doi: 10.1007/s00268-015-3298-8.
Results Reference
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PubMed Identifier
19139595
Citation
Yabuta T, Ito Y, Hirokawa M, Fukushima M, Inoue H, Tomoda C, Higashiyama T, Kihara M, Uruno T, Takamura Y, Kobayashi K, Miya A, Matsuzuka F, Miyauchi A. Preoperative administration of excess iodide increases thyroid volume of patients with Graves' disease. Endocr J. 2009;56(3):371-5. doi: 10.1507/endocrj.k08e-240. Epub 2009 Jan 9.
Results Reference
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PubMed Identifier
27797318
Citation
Smith TJ, Hegedus L. Graves' Disease. N Engl J Med. 2016 Oct 20;375(16):1552-1565. doi: 10.1056/NEJMra1510030. No abstract available.
Results Reference
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PubMed Identifier
11129808
Citation
Ansaldo GL, Pretolesi F, Varaldo E, Meola C, Minuto M, Borgonovo G, Derchi LE, Torre GC. Doppler evaluation of intrathyroid arterial resistances during preoperative treatment with Lugol's iodide solution in patients with diffuse toxic goiter. J Am Coll Surg. 2000 Dec;191(6):607-12. doi: 10.1016/s1072-7515(00)00755-9.
Results Reference
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PubMed Identifier
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Citation
Erbil Y, Giris M, Salmaslioglu A, Ozluk Y, Barbaros U, Yanik BT, Kapran Y, Abbasoglu SD, Ozarmagan S. The effect of anti-thyroid drug treatment duration on thyroid gland microvessel density and intraoperative blood loss in patients with Graves' disease. Surgery. 2008 Feb;143(2):216-25. doi: 10.1016/j.surg.2007.07.036. Epub 2007 Dec 21.
Results Reference
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Clinical and Surgical Outcomes of Total Thyroidectomy in Basedow's Disease: the Effect of Lugol Solution
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