Intramuscular Injection of Mashed Parathyroid Tissue Into a Forearm During Thyroid Surgery to Prevent Permanent Postoperative Parathyroid Insufficiency (IMIPAT Study)

Intramuscular Injection of Mashed Parathyroid Tissue Into a Forearm During Thyroid Surgery to Prevent Permanent Postoperative Parathyroid Insufficiency (IMIPAT Study) - a Prospective Multicentre Trial

Parathyroid insufficiency is a common complication in thyroid surgery and occurs in 6.6 to 24%. Up to 4.4% suffer from permanent hypoparathyroidism requiring life-time substitution of calcium and vitamin D in order to maintain a normal calcium homeostasis. To prevent permanent postoperative parathyroid insufficiency after thyroidectomy, devascularized parathyroid glands are re-implanted intramuscularly by standard. To achieve graft function, meticulous preparation and division of parathyroid tissue is necessary as a prerequisite for tissue nutrition by diffusion until a recapillarization of the parathyroid fragments sets in. There are persistent controversies about the optimal technique for the autotransplantation. The injection of mashed parathyroid tissue into a muscle appears to be a fast, secure and easy tech-nique to provide a sufficient parathyroid hormone (PTH) production in cases of insufficient production of the glands left in-situ. The study is based on the hypothesis that intramuscular injection of mashed parathyroid tissue is a safe procedure that enables graft survival through diffusion and allows for the subsequent production of systemically measurable levels of parathyroid hormone (PTH). The intervention consists of injecting mashed parathyroid tissue into the brachioradialis muscle of the non-dominant arm. The primary objective is to evaluate this technique with respect to both local complications arising from the transplantation procedure and the functional performance of the graft over time. Outcome measures include the PTH gradient between the transplanted and non-transplanted arms, parathyroid hormone levels measured in the antecubital fossa of both arms, and calcium levels. The study population comprises 100 patients, and the trial is designed as a prospective multicentre study. The risk-benefit assessment indicates that the risks associated with participation-particularly local complications and potential graft malfunction-are expected to be low. In patients with familial or renal hyperparathyroidism, autotransplantation of small parathyroid fragments (approximately 1 mm in diameter) has been standard practice for decades. Additionally, the injection of mashed parathyroid tissue into the sternocleidomastoid muscle during surgery has been performed in many centers for years. However, that approach has the limitation that PTH originating from the graft cannot be reliably measured due to anatomical constraints.

Parathyroid insufficiency is a frequent complication of thyroid surgery, occurring in approximately 6.6% to 24% of cases. Up to 4.4% of patients develop permanent hypoparathyroidism, requiring lifelong supplementation with calcium and vitamin D to maintain normal calcium homeostasis. To reduce the risk of permanent postoperative insufficiency, devascularized parathyroid glands are routinely re-implanted intramuscularly during thyroidectomy. Successful graft function depends on careful preparation and fragmentation of the tissue, allowing adequate nutrition by diffusion until revascularization occurs.

Despite long-standing clinical use, there is ongoing debate regarding the optimal technique for parathyroid autotransplantation and whether transplantation of normal parathyroid tissue achieves outcomes comparable to hyperplastic tissue, as seen in familial or renal hyperparathyroidism. In patients with renal hyperparathyroidism, favorable outcomes have been reported following intramuscular injection or forearm implantation of parathyroid autografts. Techniques for preparing tissue for injection have also been described. Evidence from prior studies indicates that, even when normal parathyroid tissue is transplanted during thyroidectomy, measurable gradients in parathyroid hormone (PTH) between grafted and non-grafted arms can be detected, suggesting preserved graft viability and function. The study is based on the premise that intramuscular injection of parathyroid tissue is a safe and effective method capable of achieving functional graft outcomes, even in patients without parathyroid hyperplasia. The risks associated with participation, including local complications such as bleeding or infection and potential graft dysfunction, are considered low. This assessment is supported by prior clinical experience in patients with renal hyperparathyroidism, where similar techniques have produced favorable results. As a precaution, in cases where all four parathyroid glands are inadvertently removed, at least one gland will be implanted into the sternocleidomastoid muscle, in accordance with current standard practice. Patients may benefit from a minimally invasive procedure that avoids muscle dissection. The broader aim is to establish a less invasive technique as a new standard of care. Overall, the risk-benefit profile is considered acceptable. The primary endpoint of the study is the PTH gradient between the transplanted and non-transplanted arms. Secondary endpoints include PTH levels measured in both arms, calcium levels, the number of autotransplanted glands, intra- and postoperative complications, and the need for postoperative calcium and vitamin D supplementation. This study is designed as a prospective, multicentre trial involving 100 patients. It will evaluate the technique of intramuscular injection of mashed normal parathyroid tissue, focusing on both local complications related to the transplantation procedure and the functional performance of the graft over time. A total of 100 patients will be enrolled. The primary analysis will assess the log-transformed ratio of PTH levels between the transplanted and non-transplanted arms six months after transplantation. Patients will be analyzed in two subgroups: those with low baseline PTH (approximately 10-15%) and those with normal baseline PTH (approximately 85-90%). In the low baseline PTH group, a sample of 10 patients provides over 90% statistical power to detect a difference between a null hypothesis mean corresponding to a PTH ratio of 1 and an alternative mean corresponding to a ratio of 1.5, assuming a standard deviation of 0.32. In the group with normal baseline PTH, a larger standard deviation is expected; with 85 patients, the same effect size can be detected with 90% power assuming a standard deviation of 1.15. Sample size calculations were performed using nQuery Advisor (version 2.0.1.0), with assumptions based on published patient-level data. Participating centres perform approximately 470 thyroid surgeries annually, with around 30% requiring autotransplantation. Across multiple centres, approximately 140 patients are expected to be enrolled per year, allowing completion of recruitment within one year. Participants will be recruited at participating centres when thyroidectomy (total or hemithyroidectomy) is planned for benign or malignant disease. Eligibility will be determined based on medical history and predefined inclusion and exclusion criteria. All eligible patients who provide informed consent will be enrolled.

Before study participation, all subjects will undergo a physical examination, medical history assessment, measurement of height and weight, and laboratory evaluation of relevant biochemical parameters, including preoperative serum calcium. Inclusion criteria comprise adult patients (18 years or older) undergoing thyroid surgery for benign or malignant disease in whom parathyroid autotransplantation is performed, and who provide signed informed consent. Exclusion criteria include patients without parathyroid autotransplantation, those with primary or secondary hyperparathyroidism, individuals under 18 years of age, and those who do not provide informed consent.

Inclusion Criteria:

• signed informed consent
• parathyroid autotransplantation in forearm performed during thyroid surgery
• 18 years of age and above

Exclusion Criteria:

• under 18 years of age
• informed consent not signed
• hyperparathyroidism
• no parathyroid autotransplantation performed