Postoperative hypoparathyroidism - Current and novel preventative methods

Background Hypocalcaemia is the most common complication following thyroid surgery. It is associated with significant short and long-term patient morbidity. Many studies have assessed and reported on risks, predictive and preventative factors for post-operative hypocalcaemia. The aims of this research were to search the literature for useful preventative measures of post-thyroidectomy hypoparathyroidism and to assess two novel modalities for their potential in the early intraoperative identification and preservation of parathyroid glands to avoid postoperative hypocalcaemia. The objectives of the study were: 1- To perform a systematic review and meta-analysis of the effectiveness of preventative and other surgical measures on post-thyroidectomy hypocalcaemia. 2- To study Methylene Blue (MB) emitted fluorescence from soft tissue structures in the rabbit neck thereby examining its potential for use in human surgery to differentiate between thyroid and parathyroid glands. 3- To determine the electrical impedance patterns of the thyroid, parathyroid and other soft tissue structure in the rabbit neck thereby examining the potential of impedance spectroscopy as an intraoperative tool for parathyroid identification. Methods Systematic review and meta-analysis: A comprehensive search of PubMed, EMBASE, and Cochrane databases was performed for studies reporting on preventative and other surgical measures and their effect on reducing post-thyroidectomy hypoparathyroidism. Quality of included papers was assessed using the Cochrane risk of bias tool or a modified Newcastle-Ottawa Scale (NOS). The results of all included studies were summarized and meta-analyses were performed where appropriate. Two animal experiments were then carried out to assess the potential role of two novel modalities, near-infrared (NIR) fluorescence imaging using intravenous (IV) MB and electrical impedance spectroscopy (EIS), in the prevention of post-operative hypocalcaemia. Near-infrared (NIR) fluorescence imaging using intravenous MB: Thyroid and external parathyroid glands (PGs) were exposed in six New Zealand White (NZW) rabbits under anaesthesia. Varying doses of MB (0.025 - 3 mg/kg) were injected through the marginal ear vein. NIR fluorescence from exposed tissues was recorded at different time intervals (0 - 74 minutes) using Fluobeam®700 device. Electrical Impedance Spectroscopy (EIS): The central neck compartment was dissected in nine freshly culled NZW rabbits. In vivo and ex vivo electrical impedance (EI) were measured from thyroid lobes, external PGs, adipose tissue and strap muscle using APX100TM device. The glands identified in these experiments were resected and sent for histological assessment. Results Systematic review and meta-analysis: This included 39 randomised controlled trials (RCTs) and 37 observational studies. Interventions studied included; haemostatic techniques, extent of thyroidectomy and central neck dissection, surgical approach, supplements (calcium, vitamin D and thiazide diuretics), parathyroid gland auto-transplantation (PGAT) and intra-operative parathyroid gland (PG) identification, truncal ligation of inferior thyroid artery (ITA), pre-operative magnesium infusion, and use of magnification loupes and surgicel. Measures associated with significantly lower rates of transient hypocalcaemia in meta-analysis were: post-operative calcium and vitamin D supplementation compared to either calcium supplements alone (odds ratio (OR) 0.66; p=0.04) or no supplements (OR 0.34; p=0.007), and bilateral subtotal thyroidectomy (BST) compared to Hartley Dunhill (HD) procedure (OR 0.35; p=0.01). Meta-analyses did not demonstrate any measure to be significantly associated with a reduction in permanent hypocalcaemia. NIR fluorescence: Thyroid and external PGs were the only neck structures to demonstrate significant fluorescence in the central neck compartment. External PGs demonstrated lower fluorescence intensities and reduced washout times at all MB doses compared to the thyroid gland. A dose of 0.1 mg/kg MB was adequate to identify fluorescence; this also delineated the blood supply of the external PGs. EIS: The impedance was higher for thyroid tissue at lower frequencies and for parathyroid tissue at higher frequencies. Ex vivo electrical impedance spectra were significantly higher compared to the in vivo spectra across all frequencies for thyroid and parathyroid tissues (p < 0.001). The ratio of low to high frequency in vivo impedance of thyroid, parathyroid and muscle was significantly different (p < 0.001), allowing for differentiation between these tissues. Histology confirmed correct identification of all excised thyroid and PGs in both experiments. Conclusions The systematic review identified post-operative calcium and vitamin D supplementation and bilateral subtotal thyroidectomy (over HD) as being effective in prevention of transient hypocalcaemia. However, the majority of RCTs were of low quality, primarily due to lack of blinding. The wide variability in study design, outcome definitions and assessment methods prevented meaningful summation of results from studies on a number of preventative measures and for permanent hypocalcemia. NIR fluorescence with IV MB helps to differentiate between thyroid and PGs in the rabbit. This has the potential to improve outcomes in thyroid and parathyroid surgery by increasing the accuracy of parathyroid identification. The use of low doses of MB may also avoid the side effects associated with currently used doses in humans (3-7mg/kg). Electrical impedance spectra of rabbit thyroid and parathyroid glands are distinct and different from each other and from skeletal muscle. If these results are replicated in human tissue, they have the potential to improve patient outcomes by achieving early identification and preservation of PGs.