Intra-operative Infra-red Fluorescent Imaging in Thyroid and Parathyroid Surgery

Development of a Clinical Protocol to Use Intra-operative Near Infra-red Fluorescent Imaging in Thyroid and Parathyroid Surgery

Reliable identification of parathyroid glands is critical to the success of thyroid and parathyroid surgery. In thyroid surgery, inadvertent injury to parathyroid glands may cause temporary or permanent hypoparathyroidism (low calcium levels needing long term treatment). In parathyroid surgery, early identification of normal and/or enlarged parathyroid glands helps in deciding on the extent of surgery and increases the chances of postoperative normal calcium levels.

Methylene Blue (Methylthioninium chloride, MB) is a dye that when given intravenously in high doses, is taken up differently by thyroid and parathyroid tissue. It is currently used during parathyroid surgery by some surgeons to help identify enlarged parathyroid glands by visual examination alone. Such visual examination is unhelpful in the identification of 'normal' parathyroid tissue. MB exhibits fluorescent properties in the near-infrared range (light just beyond the visible spectrum). This can be picked up by an appropriate imaging system. This has potential to identify and differentiate between 'normal' parathyroid, 'abnormal' parathyroid and thyroid tissue during surgery.

The investigators have established the feasibility of the intra-operative use of a near infra-red fluorescent imaging device called Fluobeam® and demonstrated the ability of this device to pick up near infra-red fluorescence from human tissue after administration of intravenous MB. Animal experiments have shown that doses as low as 0.1mg/kg of MB given intravenously enable fluorescent visualisation of thyroid and parathyroid glands.

This study will aim to optimise the dose and timing of administration of MB in human thyroid and parathyroid surgery and to develop a protocol which would then subsequently be assessed for effectiveness in a multi-centred randomized controlled setting.

Study Overview

• Status: Completed
• Conditions: Total Thyroidectomy; Bilateral Neck Exploration for Primary Hyperparathyroidism
• Intervention / Treatment: Other: MB and fluorescent imaging

Detailed Description

Around 13,000 thyroid and parathyroid operations are performed per year in England for both benign and malignant disease. Reliable identification of parathyroid glands is critical to the success of thyroid and parathyroid surgery. In thyroid surgery, inadvertent injury to parathyroid glands may cause temporary or permanent hypoparathyroidism (low calcium levels needing long term treatment); the latter is associated with significant long term problems. In parathyroid surgery, early identification of normal and/or enlarged parathyroid glands helps in deciding on the extent of surgery and increases the chances of postoperative normal calcium levels.

Methylene Blue (Methylthioninium chloride, MB) is a dye that when given intravenously in high doses, is taken up differently by thyroid and parathyroid tissue. It is currently used during parathyroid surgery by some surgeons to help identify enlarged parathyroid glands by visual examination alone. At these doses, there is a risk of adverse effects from administration of MB. Such visual examination is unhelpful in the identification of 'normal' parathyroid tissue. MB is not currently used in surgery for thyroid pathologies. MB exhibits fluorescent properties in the near-infrared range (light just beyond the visible spectrum). This can be picked up by an appropriate imaging system. This has potential to identify and differentiate between 'normal' parathyroid, 'abnormal' parathyroid and thyroid tissue during surgery.

The investigators have established the feasibility of the intra-operative use of a near infra-red fluorescent imaging device called Fluobeam® and demonstrated the ability of this device to pick up near infra-red fluorescence from human tissue after administration of intravenous MB. Animal experiments have shown that doses as low as 0.1mg/kg of MB given intravenously enable fluorescent visualisation of thyroid and parathyroid glands.

This study will aim to optimise the dose and timing of administration of MB in human thyroid and parathyroid surgery and to develop a protocol which would then subsequently be assessed for effectiveness in a multi-centred randomized controlled setting.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Department of General Surgery

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

-All patients undergoing either a total thyroidectomy or bilateral neck exploration for PHPT in Sheffield Teaching Hospitals NHS Foundation Trust

Exclusion Criteria:

• Patients undergoing re-do procedures
• Patients unable to understand spoken and written English
• Patients unable to give adequate informed consent
• Patients with a history of intolerance or sensitivity to MB
• Patients with known G6PD deficiency
• Patients on serotonin reuptake inhibitors
• Patients undergoing surgery for thyroglossal cyst and
• Patients undergoing thoracic exploration; either alone or in combination with a neck exploration

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MB and fluorescent imaging; Single arm study for the development of a protocol stipulating the optimum dose and time to peak near infra-red fluorescence from intraoperative injection of low dose Methylthioninium chloride	Other: MB and fluorescent imaging; Single arm study for the development of a protocol stipulating the optimum dose and time to peak near infra-red fluorescence from intraoperative injection of low dose Methylthioninium chloride; Other Names: Methylthioninium chloride; Fluobeam 700 near infra-red imaging device

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Optimum dose of Methylene Blue	Determine optimum dose of Methylene Blue that will enable fluorescence to be detected from the soft tissue structures in the neck	20 minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to peak fluorescence	Time to peak fluorescence at varying doses of Methylene Blue will be assessed during the observation period, which will be a maximum of twenty minutes.	20 minutes

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Postoperative calcium status		up to 12 weeks of surgery
Serious adverse event	This will include any one of the following: Death; A life-threatening adverse event; Inpatient hospitalisation or prolongation of existing hospitalisation; A disability / incapacity; A congenital anomaly in the offspring of a participant The reporting period for Serious Adverse Events will be from the time of induction of anaesthetic until 30 days after the day of surgery. Important medical events that may not result in death, be life-threatening, or require hospitalisation may be considered a serious adverse event when, based upon appropriate medical judgment, they may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. All adverse events will be assessed for seriousness, expectedness and causality.	up to 30 days after surgery

Collaborators and Investigators

• Sponsor: Sheffield Teaching Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Saba Balasubramanian, MS FRCS PhD, University of Sheffield

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: March 13, 2014
• First Submitted That Met QC Criteria: March 14, 2014
• First Posted (Estimate): March 17, 2014

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: thyroidectomy; methylene blue; parathyroid surgery; near infrared fluorescence; parathyroid identification; intraoperative imaging
• Additional Relevant MeSH Terms: Endocrine System Diseases; Parathyroid Diseases; Hyperparathyroidism; Hyperparathyroidism, Primary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Methylene Blue
• Other Study ID Numbers: STH17176