Autofluorescence and Indocyanine Green to Avoid Hypocalcemia After Thyroidectomy

Thyroid Disease Clinical Trial

Official title:

The Use of Autofluorescence and Indocyanine Green to Avoid Hypocalcemia After Total Thyroidectomy: A Randomized Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05117853
• Other study ID #: B1262021000021
• Status: Recruiting
• Phase: Phase 3
• Start date: November 1, 2021
• Est. completion date: May 31, 2025

Study information

• Verified date: April 2024
• Source: Onze Lieve Vrouw Hospital
• Contact: Klaas Van Den Heede, MD
• Phone: 0032472893861
• Email: klaasvandenheede[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

- Hypoparathyroidism (and the resulting hypocalcemia) remains the most common morbidity after a total thyroidectomy. - The identification and preservation of parathyroid glands during neck surgery has always been challenging but is crucial to avoid postoperative hypocalcemia. - Recently, the specific autofluorescent characteristics of endogenous fluorophores in the parathyroid tissue have been used to detect and confirm parathyroid glands during thyroid surgery. - Injecting indocyanine green and using its fluorescent characteristics has the advantage of adding information about the vascular supply of the parathyroid glands. - This randomized clinical trial aims to investigate whether using autofluorescence and indocyanine green during thyroid surgery can predict or prevent postoperative hypocalcemia.

Description:

Hypoparathyroidism (and the resulting hypocalcemia) remains the most common morbidity after a total thyroidectomy. When defined as corrected serum calcium levels below 2.10 mmol/L, the temporary rates of hypocalcemia after a total thyroidectomy excluding lymph node neck dissection still easily exceed 20% (BAETS fifth national audit report, 2017). When extending the follow-up period to more than six months after surgery, late or permanent hypocalcemia is seen in over 5% of patients after a total thyroidectomy. These British numbers have been confirmed in large European and American databases. A large, Belgian, single-center analysis, including redo-surgery and lymph node neck dissections, confirmed temporary and permanent rates of hypocalcemia of 32% and 3%, respectively. While temporary hypocalcemia results in a reduced quality of life, additional medical costs to the patients and the society, and hypocalcemia-related symptoms, permanent hypocalcemia adds an increased risk of developing renal failure, basal ganglia calcifications, neuropsychiatric derangements, and infections. The identification and preservation of parathyroid glands during neck surgery has always been challenging but is crucial to avoid postoperative hypocalcemia. The visual evaluation of parathyroid gland vascularization is even more challenging, prone to subjectivity, and depending on surgical experience and surgical volume. Moreover, even experienced endocrine surgeons appear to be unreliable in using visual scores to assess the viability of parathyroid glands. Recently, the specific autofluorescent characteristics of endogenous fluorophores in the parathyroid tissue have been used to detect and confirm parathyroid glands during thyroid surgery. However, this signal does not provide any information on viability and vascularization of the parathyroid glands. Injecting indocyanine green (ICG) and using its fluorescent characteristics has the advantage of adding information about the vascular supply of the parathyroid glands. The combined technique of autofluorescent and ICG-enhanced imaging suffers from lack of standardization, optimal technique, dosage, and timing of the ICG administration, and still must prove its possible benefit in a clinical setting. Hence, this randomized clinical trial aims to investigate whether using autofluorescence (AF) and indocyanine green during thyroid surgery can predict or prevent postoperative hypocalcemia. By using parathyroid gland detection via autofluorescence imaging and verifying their viability after ICG injection, the authors aim to identify patients at risk of hypocalcemia.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: May 31, 2025
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• All adult patients undergoing a total thyroidectomy without previous neck surgery.

Exclusion Criteria:

• Children and teenagers (<18 years old)
• Patients refusing participation or unable/unwilling to sign the informed consent
• Patients with a completion thyroidectomy
• Patients with planned central and lateral neck lymph node dissections (thyroid cancer)
• Patients with previous neck surgery
• Patients with a known allergy/hypersensitivity to indocyanine green

Related Conditions & MeSH terms

• Hypocalcemia
• Hypoparathyroidism
• Hypoparathyroidism Postprocedural
• Thyroid Disease
• Thyroid Diseases

Intervention

Drug:
• Autofluorescent detection + Injection of indocyanine green
All four parathyroid glands will be actively sought for in every case selected for the use of AF/ICG, with AF verification of parathyroid tissue. The timepoints of AF will be: 1 = after lateral dissection side 1 (side 1) 2= after lateral dissection side 2 (side 2) The timepoints of ICG injection will be: 1 = after the first thyroid lobectomy (side 1) 2 = after the second thyroid lobectomy (side 2) Scoring of the viability of parathyroid glands (adapted from Vidal Fortuny et al., 2016): 1 = black = not viable/vascularized 2 = grey = moderately viably/ moderately vascularized 3 = white = viable/well-vascularized

Procedure:
• Gold standard of visual identification and evaluation of viability of the parathyroid glands.
Gold standard of visual identification and evaluation of viability of the parathyroid glands.

Locations

Country	Name	City	State
Belgium	Onze Lieve Vrouw Hospital	Aalst

Sponsors (1)

Lead Sponsor	Collaborator
Onze Lieve Vrouw Hospital

Country where clinical trial is conducted

Belgium, 

References & Publications (22)

Alander JT, Kaartinen I, Laakso A, Patila T, Spillmann T, Tuchin VV, Venermo M, Valisuo P. A review of indocyanine green fluorescent imaging in surgery. Int J Biomed Imaging. 2012;2012:940585. doi: 10.1155/2012/940585. Epub 2012 Apr 22. — View Citation

Benmiloud F, Godiris-Petit G, Gras R, Gillot JC, Turrin N, Penaranda G, Noullet S, Chereau N, Gaudart J, Chiche L, Rebaudet S. Association of Autofluorescence-Based Detection of the Parathyroid Glands During Total Thyroidectomy With Postoperative Hypocalcemia Risk: Results of the PARAFLUO Multicenter Randomized Clinical Trial. JAMA Surg. 2020 Feb 1;155(2):106-112. doi: 10.1001/jamasurg.2019.4613. — View Citation

Chen Z, Zhao Q, Du J, Wang Y, Han R, Xu C, Chen X, Shu M. Risk factors for postoperative hypocalcaemia after thyroidectomy: A systematic review and meta-analysis. J Int Med Res. 2021 Mar;49(3):300060521996911. doi: 10.1177/0300060521996911. — View Citation

Desmettre T, Devoisselle JM, Mordon S. Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Surv Ophthalmol. 2000 Jul-Aug;45(1):15-27. doi: 10.1016/s0039-6257(00)00123-5. — View Citation

Edafe O, Antakia R, Laskar N, Uttley L, Balasubramanian SP. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg. 2014 Mar;101(4):307-20. doi: 10.1002/bjs.9384. Epub 2014 Jan 9. — View Citation

Eismontas V, Slepavicius A, Janusonis V, Zeromskas P, Beisa V, Strupas K, Dambrauskas Z, Gulbinas A, Martinkenas A. Predictors of postoperative hypocalcemia occurring after a total thyroidectomy: results of prospective multicenter study. BMC Surg. 2018 Aug 9;18(1):55. doi: 10.1186/s12893-018-0387-2. — View Citation

Ji YB, Song CM, Sung ES, Jeong JH, Lee CB, Tae K. Postoperative Hypoparathyroidism and the Viability of the Parathyroid Glands During Thyroidectomy. Clin Exp Otorhinolaryngol. 2017 Sep;10(3):265-271. doi: 10.21053/ceo.2016.00724. Epub 2016 Aug 13. — View Citation

Kim J, Shin W. How to do random allocation (randomization). Clin Orthop Surg. 2014 Mar;6(1):103-9. doi: 10.4055/cios.2014.6.1.103. Epub 2014 Feb 14. — View Citation

Lorente-Poch L, Sancho JJ, Munoz-Nova JL, Sanchez-Velazquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg. 2015 Feb;4(1):82-90. doi: 10.3978/j.issn.2227-684X.2014.12.04. — View Citation

Mirallie E, Borel F, Tresallet C, Hamy A, Mathonnet M, Lifante JC, Brunaud L, Menegaux F, Hardouin JB, Blanchard C; THYRQOL Group; Ansquer C, Mourrain-Langlois E, Delemazure AS, Perrot B, Longhi M, Nomine C, Espitalier F, Drui D, Caillard C, Renaud-Moreau N, Marret O, Mucci S, Christou N. Impact of total thyroidectomy on quality of life at 6 months: the prospective ThyrQoL multicentre trial. Eur J Endocrinol. 2020 Feb;182(2):195-205. doi: 10.1530/EJE-19-0587. — View Citation

Moten AS, Thibault DP, Willis AW, Willis AI. Demographics, disparities, and outcomes in substernal goiters in the United States. Am J Surg. 2016 Apr;211(4):703-9. doi: 10.1016/j.amjsurg.2015.11.022. Epub 2016 Jan 6. — View Citation

Obana A, Miki T, Hayashi K, Takeda M, Kawamura A, Mutoh T, Harino S, Fukushima I, Komatsu H, Takaku Y, et al. Survey of complications of indocyanine green angiography in Japan. Am J Ophthalmol. 1994 Dec 15;118(6):749-53. doi: 10.1016/s0002-9394(14)72554-1. — View Citation

Reinhart MB, Huntington CR, Blair LJ, Heniford BT, Augenstein VA. Indocyanine Green: Historical Context, Current Applications, and Future Considerations. Surg Innov. 2016 Apr;23(2):166-75. doi: 10.1177/1553350615604053. Epub 2015 Sep 10. — View Citation

Riley RD, Moons KGM, Snell KIE, Ensor J, Hooft L, Altman DG, Hayden J, Collins GS, Debray TPA. A guide to systematic review and meta-analysis of prognostic factor studies. BMJ. 2019 Jan 30;364:k4597. doi: 10.1136/bmj.k4597. No abstract available. — View Citation

Sitges-Serra A. Etiology and Diagnosis of Permanent Hypoparathyroidism after Total Thyroidectomy. J Clin Med. 2021 Feb 2;10(3):543. doi: 10.3390/jcm10030543. — View Citation

Spartalis E, Ntokos G, Georgiou K, Zografos G, Tsourouflis G, Dimitroulis D, Nikiteas NI. Intraoperative Indocyanine Green (ICG) Angiography for the Identification of the Parathyroid Glands: Current Evidence and Future Perspectives. In Vivo. 2020 Jan-Feb;34(1):23-32. doi: 10.21873/invivo.11741. — View Citation

Tu C, Benn EKT. RRApp, a robust randomization app, for clinical and translational research. J Clin Transl Sci. 2017 Dec;1(6):323-327. doi: 10.1017/cts.2017.310. Epub 2018 Feb 19. — View Citation

Van Den Heede K, Tolley NS, Di Marco AN, Palazzo FF. Differentiated Thyroid Cancer: A Health Economic Review. Cancers (Basel). 2021 May 7;13(9):2253. doi: 10.3390/cancers13092253. — View Citation

Van Slycke S, Van Den Heede K, Bruggeman N, Vermeersch H, Brusselaers N. Risk factors for postoperative morbidity after thyroid surgery in a PROSPECTIVE cohort of 1500 patients. Int J Surg. 2021 Apr;88:105922. doi: 10.1016/j.ijsu.2021.105922. Epub 2021 Mar 25. — View Citation

Van Slycke S, Van Den Heede K, Brusselaers N, Vermeersch H. Feasibility of Autofluorescence for Parathyroid Glands During Thyroid Surgery and the Risk of Hypocalcemia: First Results in Belgium and Review of the Literature. Surg Innov. 2021 Aug;28(4):409-418. doi: 10.1177/1553350620980263. Epub 2020 Dec 29. — View Citation

Vidal Fortuny J, Belfontali V, Sadowski SM, Karenovics W, Guigard S, Triponez F. Parathyroid gland angiography with indocyanine green fluorescence to predict parathyroid function after thyroid surgery. Br J Surg. 2016 Apr;103(5):537-43. doi: 10.1002/bjs.10101. Epub 2016 Feb 11. — View Citation

Watt T, Cramon P, Hegedus L, Bjorner JB, Bonnema SJ, Rasmussen AK, Feldt-Rasmussen U, Groenvold M. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant treatment effects. J Clin Endocrinol Metab. 2014 Oct;99(10):3708-17. doi: 10.1210/jc.2014-1322. Epub 2014 Jul 8. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Postoperative hypocalcemia	Defined as parathyroid hormone (PTH) levels <15 pg/mL, serum calcium levels <2.10 mmol/L, or the intake of calcium or activated vitamin D supplements after total thyroidectomy.	One week after surgery
Secondary	The number of identified parathyroid glands	Visual identification and confirmation with autofluorescence	1 hour after surgery
Secondary	The number of reimplanted parathyroid glands	Visual identification and decision to re-implant after ICG	1 hour after surgery
Secondary	The presence of late or permanent hypocalcemia	Defined as persistent PTH levels <15 pg/mL, persistent serum calcium levels <2.10 mmol/L, or continued intake of calcium or activated vitamin D supplements more than six months after surgery.	Six months after surgery