Impact of Dexmedetomidine On Secondary Hyperparathyroidism Recurrence In Uremic Patients Who Received Parathyroidectomy With Auto-Transplantation: A Retrospective Propensity-Matched Study

Background: Recurrence of secondary hyperparathyroidism (SHPT) remains a big challenge in uremic patients who underwent total parathyroidectomy with auto-transplantation (tPTX-AT). However, the relationship between perioperative intervention and recurrence of SHPT remains unclear. Dexmedetomidine has been used safely and effectively in uremic patients’ anesthesia. The aim of the study was to explore the effect of dexmedetomidine on the recurrence of SHPT and speculate the possible mechanism of action. Methods: Records of patients who underwent tPTX-AT between 2017 and 2018 were retrospectively analyzed. The study consisted of patients who received dexmedetomidine intra-operatively and the controls were patients who did not receive dexmedetomidine. The primary endpoint was the difference in the recurrence of SHPT one year after surgery between the two groups. The secondary endpoint was health-related quality of life scores. Analysis included propensity score matching and multivariable logistic regression. Results: Of 354 patients, 133 patients received dexmedetomidine intraoperatively, and the total recurrence rate of SHPT was 10.2%. After propensity score matching, patients who received dexmedetomidine had a 3.80-fold decreased risk of SHPT recurrence (odds ratio, 0.263; 95% condence interval, 0.081 to 0.854; P=0.026) and exhibited a better quality of life in terms of physical functioning and general health, and less emotional role limitations compared with those in control group. Conclusion: In uremic patients who received tPTX-AT, there was an association between dexmedetomidine use and decreased risk of SHPT recurrence. Further studies are needed to accurately assess the effects and mechanism of action of dexmedetomidine on the prognosis of this population. as the mean ± SD or median [IQR] for continuous variables, and number (%) for categorical variables. Data are presented as the mean ± SD or median [IQR] for continuous variables, and number (%) for categorical variables.


Introduction
Secondary hyperparathyroidism (SHPT) is a common complication in uremic patients. It is characterized by markedly elevated intact parathyroid hormone (iPTH) concentrations due to persistent stimulation of the parathyroid tissue and resultant parathyroid hyperplasia in response to hypocalcemia [1]. Chronically elevated iPTH causes bone pain, fractures, cardiovascular disease, hematopoiesis, immune dysfunction, all of which may in uence the length and quality of life (QOL) of uremic patients [2].
Surgical total parathyroidectomy with auto-transplantation (tPTX-AT) signi cantly improves calcium and phosphorus metabolism, resulting in reduced mortality and morbidity rates. However, due to the pathological changes in the remaining tissue, including in ammation and perioperative stress, the incidence of SHPT recurrence may reach as high as 20% [3,4]. Many cohort studies have demonstrated that perioperative anesthetic and analgesic intervention play a critical role on the long-term prognosis of multiple disease [5,6]. Therefore, the anesthetic impact on the recurrenc of SHPT as well as quality of life in uremic patients after surgery need to be identi ed.
Dexmedetomidine (DEX), a highly selective alpha-2 adrenoceptor agonist, is increasingly used with the bene cial effects of analgesia, sympathetic tone inhibition, anti-in ammation and surgical stress [7][8][9]. DEX also exhibited potential renal protection in patients with renal disease [10]. However, there are no current studies focussing on the impact of DEX on the outcome in uremic patients after surgery. Therefore, we performed a single-centre retrospective study to evaluate the relationship between DEX use and SHPT recurrence in uremic patients undergoing tPTX-AT. Speci cally, the primary aim was to test the hypothesis that infusion of DEX is associated with a lower incidence of SHPT recurrence. Second, we aimed to test the hypothesis that DEX infusion elevated both the postoperative short-term outcome and long-term QOL in uremic patients.

Study Design And Methods
The study protocol (PJ-YX2019-049F2) was reviewed and approved by Ethics Committee for Clinical Trials of the Second A liated Hospital of Anhui Medical University, Anhui, China (Chairperson Prof. Chao Lu) on 8th April 2020, which waived the requirement for written informed consent because all data were de-identi ed and handled anonymously. The study was registered at the Chinese Clinical Trial Registry (ChiCTR-2000033811). All the work was done in accordance with the Ethical Principles for Medical Research Involving Human Subjects outlined in the Declaration of Helsinki.
Data were collected from the electronic medical records of all uremic patients who underwent tPTX-AT for SHPT by the same surgical team at the Second A liated Hospital of Anhui Medical University from January 2017 to August 2018. Patients were excluded if they met any of the following criteria: an American Society of Anesthesiologists (ASA) physical status of V, primary or tertiary hyperparathyroidism, a history of a previous thyroid operation, operation performed by any other surgeons, and incomplete records for anesthesia or surgery.
All patients received propofol-sufentanil-based general anesthesia and were transferred to the post-anesthesia care unit (PACU) after tracheal extubation in the operating room. DEX use was de ned as a bolus infusion of 0.5 to 1 µg kg −1 for 10 min before induction followed by infusion of 0.3 to 0.5µg kg −1 h −1 intra-operatively and ceased about 30 min before the end of the surgery. Patients were divided into two groups: those who received DEX (DEX group) and those who did not (control, CON group).
The patients' characteristics included age, sex, body mass index, comorbidities, physical ASA status, serum concentrations of calcium, phosphorus, iPTH, and alkaline phosphatase at baseline, dialysis modality, and the length of dialysis. Surgical information included the year of surgery, duration of anesthesia, consumption of sufentanil, extubation time, length of PACU stay, comorbidities in the PACU, length of hospitalisation after surgery, and the concentrations of postoperative calcium, phosphorus, and iPTH at discharge. Patients were followed up for one year after the surgery. Follow-up assessments included the concentrations of iPTH concentrations, C-reactive protein (CRP) and a self-administered questionnaire on the health-related QOL, which was measured by a validated Chinese version of the 36-item Short Form Health Survey (SF-36) [11,12] as a generic core. The SF-36 was developed to assess 8 different aspects of the physical and mental health status: physical functioning (10 items), physical role limitation (4 items), emotional role limitation (3 items), social functioning (2 items), mental health (5 items), bodily pain (2 items), vitality (4 items), and general health perception (5 items). Each component was analyzed individually as the average of a prede ned sum of questions, ranging from 0 to 3 or from 0 to 5, depending on the number of possible answers. Each response was linearly transformed to 0 to 100, with higher scores indicating a better QOL.

Statistical Analysis
In order to correct for selection bias and confounding factors, we used the propensity score matching method without replacement, which could balance the covariates between the two groups. The following covariates were matched at a 1:2 ratio with a 0.03 calliper by the nearest neighbour method: patient characteristics at baseline, preoperative comorbidities, ASA physical status, modality of dialysis, length of dialysis, year of surgery, duration of anesthesia. To determine the balance between the two groups before and after propensity score matching, absolute standardized mean difference (ASD) was used; an ASD < 0.1 for the covariates indicated that the two groups were su ciently balanced.
Continuous variables were reported as mean ± SD or median [IQR], and categorical variables were reported as number (%). Data with normal distribution were compared using independent-samples t test. For data that did not have normal distribution, the rank sum test was used. For categorical data, Pearson's χ 2 test was used. Potential confounders associated with recurrence after tPTX-AT, which were chosen on the basis of their clinical signi cance as reported in the literature, were analysed using univariate and multivariable logistic regression. First, we performed a univariate analysis to identify potential risk factors for postoperative recurrence. Variables with P-values <0.5 were subjected to multivariable analysis, after which, the odds ratios (OR) and associated 95% con dence intervals (CI) were calculated.
The multivariable logistic regression processes were additively adjusted for several potential confounding. Multivariable associations between DEX administration and postoperative recurrence were also assessed by logistic regression analyses.
The study was powered to evaluate one primary outcome, the recurrence of SHPT one year after in uremic patients.
According to the previous study [3] and the historical medical data in our hospital, we hypothesized that uremic patients would have a 10% rate of recurrent SHPT. To detect a 4% (SD = 3%) difference in the incidence of SHPT recurrence between patients received or did not receive DEX with a 0.05 chance of type error and 80% power, 304 patients were required.
The package of the R program (version 2.15.X) was used as a propensity score matching tool; the analysis was performed with SPSS software version 22.0 (SPSS Inc., Chicago, IL). A P-value <0.05 was considered statistically signi cant.

Patients
Among the 399 uremic patients who underwent tPTX-AT between January 2017 and August 2018, we excluded 18 with an ASA status of V, two with tertiary hyperparathyroidism, nine with a history of previous thyroid operation, thirteen with tPTX-AT by other surgeons, and 3 with incomplete or missing records for surgery. Finally, 354 patients were included in the analyses (Fig. 1). One year after the surgery, recurrence occurred in 36 patients (10.2%) ( Table 1). Table 1 Characteristics of patients who received dexmedetomidine (DEX group) and those who did not receive dexmedetomidine (CON group).

Parameters
Before propensity score matching (n=354) After 1:2 propensity score matching (n=268) Comparison of characteristics between patients who did and did not receive DEX Table 1 shows the pre-propensity score matching (DEX group: n=133; CON group: n=221) and post-propensity score matching (DEX group: n=111; CON group: n=157) covariate comparisons. After propensity score matching, all covariates were well-balanced with an ASD < 0.1. The postoperative recurrence rate was 4.5% in the DEX group, which was signi cantly lower than that in the CON group (13.6%, P=0.006), and the recurrence rate remained signi cantly lower in the DEX group after propensity score matching (4.5% vs 12.1%, P=0.032).

Association between DEX and postoperative recurrence of SHPT
The factors associated with recurrence one year after tPTX-AT are presented in Table 2. After the univariate analysis, the covariates of patient characteristics at baseline and other relative parameters were adjusted in the multivariable analysis with propensity score matching, which showed that patients' age, DEX infusion, comorbidity of diabetes, and preoperative serum phosphorus were independent factors for SHPT recurrence, and that patients who received DEX had an estimated 3.80-fold decrease in the risk of SHPT recurrence (OR, 0.263; 95% CI, 0.081 to 0.854; P=0.026). Comparison of outcomes between patients did and did not receive DEX Patients who received DEX consumed less analgesics during the surgery. Speci cally, sufentanil consumption in the DEX group was signi cantly decreased compared with that in the CON group (25.6 ± 7.1 µg vs 28.1 ± 4.9 µg, P=0.001). Meanwhile, DEX provided better pain control postoperatively. The number of patients with a pain numerical rating scale (0 to 10) ≥ 4 in the PACU in the DEX group was signi cantly lower than that in the CON group. However, DEX resulted in a lower heart rate postoperatively, which was treated with atropine accordingly, and no severe hemodynamic instability occurred. There were no signi cant differences between the two groups in terms of the risk of postoperative nausea and vomiting, hypertension, and hypotension after the surgery, nor in the length of hospital stay after surgery and hospitalisation costs (Table 3). One year later, patients who received DEX exhibited a better QOL in terms of physical functioning, general health perception, and less emotional role limitation. However, there was no signi cant difference in the other items of the SF-36 assessment (Fig. 2).

Discussion
In this analysis of consecutive patients with end-stage renal disease (ESRD) undergoing tPTX-AT at our institution, we found that intraoperative DEX use was associated with a lower risk of SHPT recurrence. Meanwhile, patients who received DEX exhibited a higher health-related QOL one year after the surgery.
Parathyroidectomy with Auto-Transplantation involves the removal of all four parathyroid glands and the implantation of a section of one of the glands into a muscle, which leaves enough residual parathyroid tissue to support mineral homoeostasis. It has been reported that tPTX-AT has a high success rate and a slightly lower risk of hyperparathyroidism recurrence [13,14]. During the data collection, we chose the patients who were operated by the same surgical team to exclude the in uence of operative procedures on the results. The iPTH concentrations tested at discharge were all decreased to the normal level, which indicated a successful operation. However, because the pathogenic factors may persist and the residual parathyroid tissue may still show increased proliferation of parathyroid cells, SHPT recurrence remains a signi cant problem in the treatment of nephrogenic hyperparathyroidism.
Increased in ammation has been proposed to play an important role in the pathogenesis of multiple diseases contributing to a low QOL in dialysis patients [15]. Compared with uremic patients without SHPT, patients with SHPT may have a higher prevalence of serum in ammatory cytokines, such as CRP, which is an acute phase protein, and is most often used as an in ammatory biomarker in nephrology [16]. Additionally, surgical trauma induces a variety of stress responses and further aggravate perioperative in ammation [8]. Therefore, controlling the in ammatory response perioperatively could help inhibit hyperfunction of parathyroid cells. Clinical studies have shown that DEX can attenuate perioperative stress and in ammation induced by surgical trauma and exhibit multifaceted protective effects when administered as an adjuvant [17]. It was reported that patients receiving DEX perioperatively had a signi cant decrease in CRP concentration 24 to 48 h after surgery compared with those who did not [18,19]. In the current study, CRP concentrations were also collected from some patients, although some patients had missing data. Patients in the DEX group exhibited lower CRP concentrations compared with the CON group postoperatively. This partly indicated an association of DEX with reduced in ammation, which may have resulted in a lower risk of SHPT recurrence. However, this anti-in ammatory mechanism should be explored further with a larger and integral sample size or prospective studies in the future.
We also found that infusion of DEX decreased opioid consumption intraoperatively and enhanced postoperative pain control for patients in the PACU. Previous studies have demonstrated that the opioid receptor antagonist, naloxone, had a suppressive effect on iPTH in patients with renal failure [20]. Therefore, we speculated that reduced opioid consumption may similarly lead to the inhibition of hyperfunction in parathyroid cells and decrease the risk of SHPT recurrence. Meanwhile, with the development of opioid-sparing anesthesia, patients exhibit a better prognosis for multiple surgeries [21,22]. As we know, patients with ESRD usually experience substantial physical, emotional, mental, and psychological impairments that are re ected in the decreased QOL [13,23]. In the current study, DEX demonstrated a bene cial effect on the QOL in dialysis patients after tPTX-AT, and signi cant improvements were observed in physical functioning, general health, and role limitations due to emotional problems, which may be an indirect result of the opioid-sparing effects of DEX.
In addition to DEX infusion, we found three independent risk factors associated with SHPT recurrence: higher age, comorbidity of diabetes mellitus, and high preoperative phosphorus concentrations. Elderly patients are more likely to represent an extreme model for arteriosclerosis, vascular calci cation, and bone disorders with the progression of ESRD. Additionally, these pathological features are also relevant in other common chronic health abnormalities, such as diabetes mellitus and chronic in ammatory and electrolyte disturbances [24]. Thus, patients with higher age, comorbidity of diabetes mellitus, and high preoperative phosphorus concentrations may be vulnerable to SHPT recurrence.
There were some important limitations to this study. First, our study was limited by its relatively small sample size.
Nevertheless, this is the largest study to assess the effect of DEX on SHPT recurrence after tPTX-AT. Second, as for any retrospective study, unknown confounding factors were a major limitation. Although our ASD analysis was based on preoperative baseline data, some other variables might have still differed between the patients who did and did not receive DEX. For instance, CRP data was incomplete, and we did not consider the consumption of anesthetics, hemodynamics, and the depth of anesthesia intraoperatively. However, we adjusted for the anesthetic time in the multivariable analysis of unmatched and matched patients. Third, this was a single-centre study, which may have compromised the generalisability of the ndings, and the retrospective observational study design may have resulted in selection bias. Nevertheless, a large number of patients with SHPT visit our hospital; therefore, collecting data on the current cases of tPTX-AT for SHPT in a prospective registry would aid in future outcome analyses and high-quality research.

Conclusion
In conclusion, our clinical data suggest that intraoperative use of DEX is associated with a lower risk of SHPT recurrence in uremic patients undergoing tPTX-AT, and that DEX use can improve the QOL in this population. We believe that the use of DEX as an adjuvant in general anesthesia contributes positively to the prognosis of uremic patients. Prospective randomized controlled trials are needed to accurately assess the effects of DEX on the prognosis of patients with ESRD undergoing tPTX-AT, and basic research should further elucidate the potential mediating mechanisms in this population. Figure 1 Flow chart of patient selection. tPTX-AT, parathyroidectomy with auto-transplantation; ASA, American Society of Anesthesioligists; DEX, dexmedetomidine group; CON, control group Scores of Short Form (SF)-36 items of patients one year after surgery. a. Patients received dexmedetomidine exhibited a signi cantly higher score in terms of physical functioning (PF) and general health (GH) before propensity score matching