Subcutaneous injection is a simple and reproducible option to restore parathyroid function after total parathyroidectomy in patients with secondary hyperparathyroidism Jeremy C. F. Ng, MD,a Weining Wang, BSc,b Min-Jia Chua,a Mui-Suan Tan,a Ngian Chye Tan, MD,a,b Khee-Chee Soo, MD,a,b Hiang Khoon Tan, MD, PhD,a,b and N. Gopalakrishna Iyer, MD, PhD,a,b Singapore
Background. Secondary hyperparathyroidism is a common clinical problem seen in patients with endstage renal disease (ESRD) undergoing hemodialysis. In patients with severe persistent hyperparathyroidism, parathyroidectomies are often required. Objectives. We sought to evaluate the feasibility and efficacy of total parathyroidectomy followed by subcutaneous injection of parathyroid autograft compared with surgical implantation. Methods. We conducted a retrospective study of 132 patients with confirmed diagnoses of ESRD treated with hemodialysis or peritoneal dialysis, with secondary hyperparathyroidism who had undergone total parathyroidectomies. Clinical and biochemical characteristics, including preoperative and postoperative intact parathyroid hormone levels were recorded and compared between patients who had undergone subcutaneous injection or surgical implantation of autograft. Results. From February 2005 to February 2012, 132 patients who had undergone total parathyroidectomies were included in our study. To compare the techniques of subcutaneous injection and surgical implantation, pre- and postoperative biochemistry was recorded and analyzed. Preoperative biochemistry was comparable in both groups. However, autograft recovery was significantly faster in the group with subcutaneous injection compared with surgical implantation (P = .03). Median time to parathyroid recovery was 2 months for injection compared with 9 months for implantation. There was no remarkable difference in the recurrence rates between the 2 groups. Conclusion. Subcutaneous injection of parathyroid tissue is a feasible and simple alternative to the more commonly used method of surgical implantation. (Surgery 2014;155:682-8.) From the Head and Neck Service, Department of Surgery,a Singapore General Hospital, and the Head and Neck Service, Department of Surgical Oncology,b National Cancer Centre, Singapore
SECONDARY OR RENAL HYPERPARATHYROIDISM is a frequent clinical problem arising in patients with chronic renal failure undergoing long-term dialysis. It develops as a compensatory mechanism to phosphate retention and reduced vitamin D activation resulting in calcium deficiency, and worsens with disease progression. Consequently, the parathyroid glands are continuously overstimulated, and W.W., M.-J.C., and M.-S.T. contributed equally to the manuscript. Accepted for publication December 18, 2013. Reprint requests: N. Gopalakrishna Iyer, MD, PhD, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.12.019
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become hyperplastic. In some situations, parathyroid function becomes autonomous of the homeostatic mechanism that was the cause of this hyperplasia. Previous reports show that 10–30% of patients undergoing hemodialysis for >10 years develop secondary hyperparathyroidism.1 The rising incidence of end-stage renal disease (ESRD) over the past decade and a shortage of donor kidneys resulted in an increasing number of patients on long-term dialysis.2,3 In our local context, the preferred renal replacement therapy in patients with ESRD is hemodialysis (80–85%); the minority undergoes peritoneal dialysis.2,4 The primary treatment for secondary hyperparathyroidism is medical therapy.5,6 In the past decade, advancements in medical treatments have caused a marked decline in the number of
Surgery Volume 155, Number 4 parathyroidectomies being performed.7 Nevertheless, medical management is not always successful and operative intervention becomes necessary, and 5–15% of patients with secondary hyperparathyroidism would eventually require parathyroidectomy.8,9 There are several techniques described to manage hyperplastic parathyroid glands in secondary hyperparathyroidism.10 The commonest techniques involve an open midline approach, 4-gland exploration, and confident identification of all glands, followed by either subtotal or total parathyroidectomy. The former involves the removal of 3 complete parathyroid glands, and a significant part of the fourth, leaving behind a portion of parathyroid tissue in situ, with its own blood supply intact. The amount of tissue left behind is variable, accounting for the variability in outcome. Furthermore, several studies have shown that this approach results in higher recurrence rates, necessitating reexploration in a previously operated neck, which is always fraught with technical difficulties.10-12 Hence, many surgeons currently favor total parathyroidectomies, where all 4 glands are removed, and a small amount of parathyroid tissue is ectopically implanted in a surgically accessible site. The commonly used operative technique for parathyroid implantation is the Wells’ method, wherein the parathyroid tissue is transplanted surgically into the forearm muscle after total parathyroidectomy.1,8,13-15 However, there are drawbacks to this technique, including a longer surgery time, scarring of the forearm, the risk of local wound infections, notwithstanding surgery to a region that may require access in the future for construction of arteriovenous fistulas or grafts for hemodialysis.15 Alternatively, some authors have proposed subcutaneous or intramuscular injections of parathyroid tissue as feasible and simpler alternatives.15,16 However, the data on these techniques are limited to case series, and many surgeons are not confident that these ‘‘simpler’’ techniques are sufficient to restore adequate parathyroid function. The objective of this retrospective study was thus to evaluate the feasibility and efficacy of the subcutaneous injection technique compared with surgical implantation. PATIENTS AND METHODS Patients. This is a retrospective study of ESRD patients treated at the Singapore General Hospital between February 2005 and February 2012. Inclusion criteria for this study were all patients who had confirmed diagnoses of ESRD treated with hemodialysis or peritoneal dialysis, with secondary
Ng et al 683
hyperparathyroidism who underwent total parathyroidectomies. Patients with a diagnosis of primary hyperparathyroidism, or previous parathyroid or thyroid surgery, were excluded from this study. Demographic details of patients, clinical, treatment, and biochemical characteristics were recorded by review of patient charts and electronic records. This study was approved by the Singhealth Centralized Institutional Review Board. Operative approach. The decision to perform an operation was undertaken jointly by a multidisciplinary team composed of head and neck surgeons, nephrologists, dialysis coordinators, and renal nurse clinicians. Preoperative imaging of parathyroid glands was not routinely performed. In the study cohort, 2 main types of operative procedures were performed: total parathyroidectomy with surgical implantation of parathyroid tissue in the deltoid muscle and total parathyroidectomy with subcutaneous injection of parathyroid tissue into the deltoid region. The decision as to the technique for parathyroid autotransplantation was made by the primary surgeon; however, it is important to state that over the course of the study period, there was gradual adoption by all surgeons involved in the study, such that by the end of this study, all the surgeons had unanimously adopted the subcutaneous injection method. Operative techniques were as follows. Bilateral neck exploration was performed through a transverse skin crease incision under general anesthesia as previously described.12,17 Intraoperative parathyroid hormone (PTH) monitoring was not performed; however, all parathyroid glands were identified based on anatomic location, and confirmed routinely with frozen section analyses in all cases. Cervical thymectomies were not performed routinely. In patients with total parathyroidectomies and deltoid implantation, a portion of a parathyroid gland measuring 5 3 5 mm was diced using a fresh scalpel to 100 pmol/L, which is approximately the threshold at which most patients were referred for surgery in the initial setting.
Total parathyroidectomies
Preoperative iPTH (pmol/L) Median 172 Range 24.6–3710 Postoperative iPTH (pmol/L) Median 2.9 Range 0.2–50.6 iPTH on POD3 (pmol/L) Median 0.5 Range 0.1–5.4 Preoperative corrected calcium (mmol/L) Median 2.76 Range 2.24–3.77 Postoperative corrected calcium (mmol/L) Median 2.46 Range 1.93–3.46 Dose of calcium carbonate on discharge (g) Median 7.50 Range 0.8–20 Preoperative PO4 (pmol/L) Median 1.59 Range 0.62–3.45 Postoperative PO4 (pmol/L) Median 1.68 Range 0.73–3.29 iPTH, Intact parathyroid hormone; POD, postoperative day.
Statistical analysis. Statistical analyses were performed using SPSS software (SPSS, Inc, Chicago, IL). The Student t test and Mann–Whitney U test were used to compare group means and the Chi-square test was used to analyze other factors. The time taken to normalization of iPTH after parathyroidectomy was calculated using the Kaplan–Meier method. The log-rank test was used to compare the Kaplan–Meier plots. RESULTS Between February 2005 and February 2012, a total of 132 patients diagnosed with secondary hyperparathyroidism underwent total parathyroidectomies, and were included in this study. The majority of patients in this cohort were being treated with hemodialysis (n = 116; 87.9%) as renal replacement therapy, with only 24 (18.2%) having undergone a renal transplant. Clinical characteristics of these patients are summarized in Table I. Preoperative parathyroid status was evaluated through preoperative serum biochemistry (Table II). Postoperatively, serum iPTH level was measured and the lowest reading in the immediate postoperative period was used to determine
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Surgery Volume 155, Number 4
Table III. Clinical characteristics of patients who had undergone surgical implantation or subcutaneous injection of parathyroid tissue after total parathyroidectomy Characteristics
Surgical implantation
Subcutaneous injection
Total number of patients Age (y) Median Range Sex Male Female Dialysis Hemodialysis Peritoneal dialysis Neither Both Not available Renal transplant No Yes Operating time (min) Median Range
41
67
57 35–77
56 25–70
21 (51.2%) 20 (48.8%)
28 (41.8%) 39 (58.2%)
37 1 1 1 1
(90.2%) (2.4%) (2.4%) (2.4%) (2.4%)
60 (89.6%) 4 (6.0%) 3 (4.5%) NIL NIL
35 (85.4%) 6 (14.6%)
52 (77.6%) 15 (22.4%)
110 60–245
105 60–2490
P value .295
.340
.456
.323
.348
success rates for the procedures. The definition used for a successful total parathyroidectomy was postoperative iPTH levels 100 pmol/L (P = .277) (Fig 2). The number of patients requiring reoperative parathyroidectomies were 3 of 41 (7.3%) for patients in the surgical implantation group and 3 of 67 (4.5%) in the subcutaneous
injection group. The median corrected calcium level for patients requiring reoperations who previously underwent injection of parathyroid tissue was 2.54 mmol/L (range, 2.47–2.85), and in the implantation group it was 2.32 mmol/L (range, 1.66–2.83; reference range used for corrected calcium is 2.02–2.60). The mean operating time for reoperations was 30 minutes for the implantation group and 18 minutes for the injections group (P = .02; Fisher’s exact test). The procedures for all 3 patients in the implantation group were done under general anesthesia, whereas for the injection group, one was done under general anesthesia and the remaining 2 were done under local anesthesia. DISCUSSION The population of patients with ESRD and requiring long-term dialysis is rising and, with that, the incidence of secondary hyperparathyroidism. In 1960, Stanbury et al18 described 2 cases in which subtotal parathyroidectomy was used to treat secondary hyperparathyroidism. Since then, there have been numerous variations in the technique resulting in a range of practices across differing institutions and physicians in operative treatment of renal hyperparathyroidism. Owing to a lack of consensus, there is no standardized recommendation for the type of operative procedure performed and a large part of the decision is surgeon preference.5 Currently, the technique favored by many surgeons is total parathyroidectomy followed by
686 Ng et al
Surgery April 2014
Table IV. Biochemical characteristics of patients who had undergone surgical implantation or subcutaneous injection of parathyroid tissue after total parathyroidectomy Characteristics
Surgical implantation
Subcutaneous injection
154 29.2–3710
161 24.6–364
2.8 0.7–22.9
2.7 0.2–10.9
0.5 0.1–2.2
0.4 0.1–2.6
2.76 2.43–3.33
2.74 2.24–3.77
2.44 1.93–2.96
2.48 2.07–3.46
7.50 0.8–20
7.50 1–20
1.51 0.65–2.43
1.48 0.62–2.75
1.72 0.73–3.29
1.51 0.86–2.85
Preoperative iPTH (pmol/L) Median Range Postoperative iPTH (pmol/L) Median Range iPTH on POD3 (pmol/L) Median Range Preoperative corrected Ca (mmol/L) Median Range Postoperative corrected Ca (mmol/L) Median Range Dose of calcium carbonate on discharge (g) Median Range Preoperative PO4 (pmol/L) Median Range Postoperative PO4 (pmol/L) Median Range
P value .233
.203
.648
.601
.121
.382
.614
.439
iPTH, Intact parathyroid hormone; POD, postoperative day.
Fig 1. Kaplan–Meier curves showing time to normalization of intact parathyroid hormone (iPTH) levels in patients with successful total parathyroidectomy, comparing subcutaneous injection and surgical implantation (P = .03).
autotransplantation of parathyroid tissue. Most surgeons prefer to place the parathyroid tissue ectopically rather than in the neck, because reoperation
in the neck is fraught with complications. Nevertheless, the technique of parathyroid autotransplantation has also been evolving. Injection of parathyroid tissue is a technique that is gaining popularity in several different scenarios, especially in total thyroidectomy, where it is done routinely when the parathyroid gland has inadvertently been removed.19 Few previous publications have examined the use of ectopic parathyroid injection into the forearm or deltoid muscles, and these were performed on relatively limited patient cohorts.15,16 In this study, we examined the operative management of a series of consecutive patients managed for secondary hyperparathyroidism. Specifically, we examine the efficacy of autotransplantation of parathyroid tissue by subcutaneous injection compared with the conventional technique of implantation. Given the difficulties in managing postoperative calcium and phosphate levels in patients who have undergone total parathyroidectomies, there is a necessity for the surgeon to consider some method to replace or autotransplant parathyroid tissue in a convenient location, which can potentially be removed with minimal complications. Traditionally, this comprised surgical implantation of small
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Fig 2. Kaplan–Meier plots comparing recurrence of secondary hyperparathyroidism in patients with successful total parathyroidectomy, comparing subcutaneous injection and surgical implantation. (A) Recurrence defined as patients requiring reoperative parathyroidectomy (P = .629). (B) Recurrence defined by intact parathyroid hormone (iPTH) levels of >100 pmol/L (P = .277).
pieces of parathyroid tissue in the brachioradialis or deltoid muscles during the primary procedure. We have always preferred the latter, because the deltoid muscle can easily be accessed during neck surgery and, more important, does not compromise subsequent placement of arteriovenous fistula/grafts in the forearm, which is critical in our context. As an extension of this procedure, we postulated that subcutaneous injection of parathyroid tissue in the same region would achieve similar results. There are several advantages to this approach. First, the technique is simple, reproducible, and quick, with no scarring. Second, it ensures fine mincing of the parathyroid tissue, allowing for good imbibition in the first phase of graft placement. Third, access to the subcutaneous plane when planning reoperative surgery for recurrence can be done easily under local anesthesia, even in the office setting. The main opposition to this technique is the theoretical failure to regain function and persistent hypoparathyroidism. Our experience is that subcutaneous injection is indeed a simple technique that avoids any scarring, with 4 small tattoo spots indicating the site of injection. Interestingly, compared with the current ‘‘gold standard,’’ or parathyroid implantation, parathyroid function normalized faster after subcutaneous injections. Median time to recovery was 2 months in the subcutaneous injection group compared with 9 months in the group with surgical implantation. Moreover, there was no difference in recurrence rates between the 2 techniques. Other components of postoperative biochemistry were also similar between both groups. One reason that could account for the advantageous result in the
injection technique is the additional step of passing the parathyroid tissue through a syringe during the subcutaneous injection, resulting in further ‘‘mincing’’ of tissue. The greater surface area allows for better imbibition of the graft and possibly a better uptake as a result. Hence, the addition of this step may increase the recovery rates in the implantation group as well. Nonetheless, these data suggest that subcutaneous injection is a feasible alternative with a comparable, if not greater, efficacy than surgical implantation. In situations where operation was required to treat recurrences after subcutaneous injections, reoperations were easier, faster, and could easily performed under local anesthesia, as opposed to the muscular dissection required to remove implanted parathyroid tissue placed in muscle pockets, which take longer, tends to be bloodier, and is associated with higher risk. There are several issues to be considered in this study. First, this is a retrospective study involving 4 different surgeons with their own personal preferences with regard to the 2 techniques. Interestingly, however, all 4 surgeons switched to the injection technique at some point during the study period and subsequently do not perform parathyroid implantations by the open technique any more. Second, the medical environment in Singapore is rather unusual in that hemodialysis is the most commonly used renal replacement therapy (in >85% of patients), and it has been documented that secondary hyperparathyroidism tends to be more severe in these patients compared with patients on peritoneal dialysis.20 This accounts for our high patient volume undergoing total parathyroidectomy, and also affects
688 Ng et al
recurrence rates reported here. Finally, we defined our endpoints (surgical success and autograft recovery) biochemically, based on iPTH levels, not by intention of surgery. Although this gives more consistent results, caution should be made when comparing these data with other studies. In conclusion, our findings indicate that subcutaneous injection of parathyroid tissue is a simpler and more effective approach with an improvement in time to restoration of parathyroid autotransplant function. Hence, we propose this as a valid alternative to implantation in patients with persistent and medically refractory secondary hyperparathyroidism who require total parathyroidectomies. REFERENCES 1. Tominaga Y, Numano M, Tanaka Y, Uchida K, Takagi H. Surgical treatment of renal hyperparathyroidism. Semin Surg Oncol 1997;13:87-96. 2. Vathsala A. Twenty-five facts about kidney disease in Singapore: In remembrance of world kidney day. Ann Acad Med Singapore 2007;36:157-60. 3. Trends of end stage renal disease in Singapore. Singapore, Singapore: National Registry of Diseases Office; 2013. 4. Lin CH, editor. Eighth report of the Singapore Renal Registry 2009. Singapore, Singapore: National Registry of Diseases Office; 2012. 5. Riss P, Asari R, Scheuba C, Niederle B. Current trends in surgery for renal hyperparathyroidism (RHPT)---an international survey. Langenbeck Arch Surg 2013;398:121-30. 6. Felsenfield AJ. Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrol 1997;8:993-1004. 7. Cohen EP, Moulder JE. Parathyroidectomy in chronic renal failure: has medical care reduced the need for surgery? Nephron 2001;89:271-3. 8. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation
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9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. 20.
in secondary hyperparathyroidism: A randomized trial. World J Surg 1991;15:745-50. Koonsman M, Hughes K, Dickerman R, Brinker K, Dunn E, Feliciano DV, et al. Parathyroidectomy in chronic renal failure. Am J Surg 1994;168:631-5. Madorin C, Owen RP, Fraser WD, Pellitteri PK, Radbill B, Rinaldo A, et al. The surgical management of renal hyperparathyroidism. Eur Arch Oto-Rhino-Laryngol 2012;269: 1565-76. Cheung PS, Borgstrom A, Thompson NW. Strategy in reoperative surgery for hyperparathyroidism. Arch Surg 1989;124:676-80. Phitayakorn R, McHenry CR. Parathyroidectomy: overview of the anatomic basis and surgical strategies for parathyroid operations. Clin Rev Bone Miner Metab 2007;5:89-102. Rothmund M, Wagner PK. Total parathyroidectomy and autotransplantation of parathyroid tissue for renal hyperparathyroidism. A one- to six-year follow-up. Ann Surg 1982;197:7-16. Chou FF, Lee CH, Chen HY, Chen JB, Hsu KT, Sheen-Chen SM. Persistent and recurrent hyperparathyroidism after total parathyroidectomy with autotransplantation. Ann Surg 2002;235:99-104. Yoon JH, Nam KH, Chang HS, Chung WY, Park CS. Total parathyroidectomy and autotransplantation by the subcutaneous injection technique in secondary hyperparathyroidism. Surg Today 2006;36:304-7. Tan CC, Cheah WK, Tan CT, Rauff A. Intramuscular injection of parathyroid autografts is a viable option after total parathyroidectomy. World J Surg 2010;34:1332-6. Bergenfelz A, Lindbolm P, Tibblin S, Westerdahl J. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: five-year follow-up of a randomized controlled trial. Ann Surg 2002;246:976-80. Stanbury SW, Lumb GA, Nicholson WF. Elective subtotal parathyroidectomy for renal hyperthyroidism. Lancet 1960;275:793-8. Iyer NG, Shaha AR. Complications of thyroid surgery: prevention and management. Minerva Chir 2010;65:71-82. Messa P, Castelnovo C, Scalamogna A. Calcimimetics in peritoneal dialysis patients. Contrib Nephrol 2012;178: 143-9.
Background. Secondary hyperparathyroidism is a common clinical problem seen in patients with endstage renal disease (ESRD) undergoing hemodialysis. In patients with severe persistent hyperparathyroidism, parathyroidectomies are often required. Objectives. We sought to evaluate the feasibility and efficacy of total parathyroidectomy followed by subcutaneous injection of parathyroid autograft compared with surgical implantation. Methods. We conducted a retrospective study of 132 patients with confirmed diagnoses of ESRD treated with hemodialysis or peritoneal dialysis, with secondary hyperparathyroidism who had undergone total parathyroidectomies. Clinical and biochemical characteristics, including preoperative and postoperative intact parathyroid hormone levels were recorded and compared between patients who had undergone subcutaneous injection or surgical implantation of autograft. Results. From February 2005 to February 2012, 132 patients who had undergone total parathyroidectomies were included in our study. To compare the techniques of subcutaneous injection and surgical implantation, pre- and postoperative biochemistry was recorded and analyzed. Preoperative biochemistry was comparable in both groups. However, autograft recovery was significantly faster in the group with subcutaneous injection compared with surgical implantation (P = .03). Median time to parathyroid recovery was 2 months for injection compared with 9 months for implantation. There was no remarkable difference in the recurrence rates between the 2 groups. Conclusion. Subcutaneous injection of parathyroid tissue is a feasible and simple alternative to the more commonly used method of surgical implantation. (Surgery 2014;155:682-8.) From the Head and Neck Service, Department of Surgery,a Singapore General Hospital, and the Head and Neck Service, Department of Surgical Oncology,b National Cancer Centre, Singapore
SECONDARY OR RENAL HYPERPARATHYROIDISM is a frequent clinical problem arising in patients with chronic renal failure undergoing long-term dialysis. It develops as a compensatory mechanism to phosphate retention and reduced vitamin D activation resulting in calcium deficiency, and worsens with disease progression. Consequently, the parathyroid glands are continuously overstimulated, and W.W., M.-J.C., and M.-S.T. contributed equally to the manuscript. Accepted for publication December 18, 2013. Reprint requests: N. Gopalakrishna Iyer, MD, PhD, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610. E-mail: [email protected]. 0039-6060/$ - see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2013.12.019
682 SURGERY
become hyperplastic. In some situations, parathyroid function becomes autonomous of the homeostatic mechanism that was the cause of this hyperplasia. Previous reports show that 10–30% of patients undergoing hemodialysis for >10 years develop secondary hyperparathyroidism.1 The rising incidence of end-stage renal disease (ESRD) over the past decade and a shortage of donor kidneys resulted in an increasing number of patients on long-term dialysis.2,3 In our local context, the preferred renal replacement therapy in patients with ESRD is hemodialysis (80–85%); the minority undergoes peritoneal dialysis.2,4 The primary treatment for secondary hyperparathyroidism is medical therapy.5,6 In the past decade, advancements in medical treatments have caused a marked decline in the number of
Surgery Volume 155, Number 4 parathyroidectomies being performed.7 Nevertheless, medical management is not always successful and operative intervention becomes necessary, and 5–15% of patients with secondary hyperparathyroidism would eventually require parathyroidectomy.8,9 There are several techniques described to manage hyperplastic parathyroid glands in secondary hyperparathyroidism.10 The commonest techniques involve an open midline approach, 4-gland exploration, and confident identification of all glands, followed by either subtotal or total parathyroidectomy. The former involves the removal of 3 complete parathyroid glands, and a significant part of the fourth, leaving behind a portion of parathyroid tissue in situ, with its own blood supply intact. The amount of tissue left behind is variable, accounting for the variability in outcome. Furthermore, several studies have shown that this approach results in higher recurrence rates, necessitating reexploration in a previously operated neck, which is always fraught with technical difficulties.10-12 Hence, many surgeons currently favor total parathyroidectomies, where all 4 glands are removed, and a small amount of parathyroid tissue is ectopically implanted in a surgically accessible site. The commonly used operative technique for parathyroid implantation is the Wells’ method, wherein the parathyroid tissue is transplanted surgically into the forearm muscle after total parathyroidectomy.1,8,13-15 However, there are drawbacks to this technique, including a longer surgery time, scarring of the forearm, the risk of local wound infections, notwithstanding surgery to a region that may require access in the future for construction of arteriovenous fistulas or grafts for hemodialysis.15 Alternatively, some authors have proposed subcutaneous or intramuscular injections of parathyroid tissue as feasible and simpler alternatives.15,16 However, the data on these techniques are limited to case series, and many surgeons are not confident that these ‘‘simpler’’ techniques are sufficient to restore adequate parathyroid function. The objective of this retrospective study was thus to evaluate the feasibility and efficacy of the subcutaneous injection technique compared with surgical implantation. PATIENTS AND METHODS Patients. This is a retrospective study of ESRD patients treated at the Singapore General Hospital between February 2005 and February 2012. Inclusion criteria for this study were all patients who had confirmed diagnoses of ESRD treated with hemodialysis or peritoneal dialysis, with secondary
Ng et al 683
hyperparathyroidism who underwent total parathyroidectomies. Patients with a diagnosis of primary hyperparathyroidism, or previous parathyroid or thyroid surgery, were excluded from this study. Demographic details of patients, clinical, treatment, and biochemical characteristics were recorded by review of patient charts and electronic records. This study was approved by the Singhealth Centralized Institutional Review Board. Operative approach. The decision to perform an operation was undertaken jointly by a multidisciplinary team composed of head and neck surgeons, nephrologists, dialysis coordinators, and renal nurse clinicians. Preoperative imaging of parathyroid glands was not routinely performed. In the study cohort, 2 main types of operative procedures were performed: total parathyroidectomy with surgical implantation of parathyroid tissue in the deltoid muscle and total parathyroidectomy with subcutaneous injection of parathyroid tissue into the deltoid region. The decision as to the technique for parathyroid autotransplantation was made by the primary surgeon; however, it is important to state that over the course of the study period, there was gradual adoption by all surgeons involved in the study, such that by the end of this study, all the surgeons had unanimously adopted the subcutaneous injection method. Operative techniques were as follows. Bilateral neck exploration was performed through a transverse skin crease incision under general anesthesia as previously described.12,17 Intraoperative parathyroid hormone (PTH) monitoring was not performed; however, all parathyroid glands were identified based on anatomic location, and confirmed routinely with frozen section analyses in all cases. Cervical thymectomies were not performed routinely. In patients with total parathyroidectomies and deltoid implantation, a portion of a parathyroid gland measuring 5 3 5 mm was diced using a fresh scalpel to 100 pmol/L, which is approximately the threshold at which most patients were referred for surgery in the initial setting.
Total parathyroidectomies
Preoperative iPTH (pmol/L) Median 172 Range 24.6–3710 Postoperative iPTH (pmol/L) Median 2.9 Range 0.2–50.6 iPTH on POD3 (pmol/L) Median 0.5 Range 0.1–5.4 Preoperative corrected calcium (mmol/L) Median 2.76 Range 2.24–3.77 Postoperative corrected calcium (mmol/L) Median 2.46 Range 1.93–3.46 Dose of calcium carbonate on discharge (g) Median 7.50 Range 0.8–20 Preoperative PO4 (pmol/L) Median 1.59 Range 0.62–3.45 Postoperative PO4 (pmol/L) Median 1.68 Range 0.73–3.29 iPTH, Intact parathyroid hormone; POD, postoperative day.
Statistical analysis. Statistical analyses were performed using SPSS software (SPSS, Inc, Chicago, IL). The Student t test and Mann–Whitney U test were used to compare group means and the Chi-square test was used to analyze other factors. The time taken to normalization of iPTH after parathyroidectomy was calculated using the Kaplan–Meier method. The log-rank test was used to compare the Kaplan–Meier plots. RESULTS Between February 2005 and February 2012, a total of 132 patients diagnosed with secondary hyperparathyroidism underwent total parathyroidectomies, and were included in this study. The majority of patients in this cohort were being treated with hemodialysis (n = 116; 87.9%) as renal replacement therapy, with only 24 (18.2%) having undergone a renal transplant. Clinical characteristics of these patients are summarized in Table I. Preoperative parathyroid status was evaluated through preoperative serum biochemistry (Table II). Postoperatively, serum iPTH level was measured and the lowest reading in the immediate postoperative period was used to determine
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Surgery Volume 155, Number 4
Table III. Clinical characteristics of patients who had undergone surgical implantation or subcutaneous injection of parathyroid tissue after total parathyroidectomy Characteristics
Surgical implantation
Subcutaneous injection
Total number of patients Age (y) Median Range Sex Male Female Dialysis Hemodialysis Peritoneal dialysis Neither Both Not available Renal transplant No Yes Operating time (min) Median Range
41
67
57 35–77
56 25–70
21 (51.2%) 20 (48.8%)
28 (41.8%) 39 (58.2%)
37 1 1 1 1
(90.2%) (2.4%) (2.4%) (2.4%) (2.4%)
60 (89.6%) 4 (6.0%) 3 (4.5%) NIL NIL
35 (85.4%) 6 (14.6%)
52 (77.6%) 15 (22.4%)
110 60–245
105 60–2490
P value .295
.340
.456
.323
.348
success rates for the procedures. The definition used for a successful total parathyroidectomy was postoperative iPTH levels 100 pmol/L (P = .277) (Fig 2). The number of patients requiring reoperative parathyroidectomies were 3 of 41 (7.3%) for patients in the surgical implantation group and 3 of 67 (4.5%) in the subcutaneous
injection group. The median corrected calcium level for patients requiring reoperations who previously underwent injection of parathyroid tissue was 2.54 mmol/L (range, 2.47–2.85), and in the implantation group it was 2.32 mmol/L (range, 1.66–2.83; reference range used for corrected calcium is 2.02–2.60). The mean operating time for reoperations was 30 minutes for the implantation group and 18 minutes for the injections group (P = .02; Fisher’s exact test). The procedures for all 3 patients in the implantation group were done under general anesthesia, whereas for the injection group, one was done under general anesthesia and the remaining 2 were done under local anesthesia. DISCUSSION The population of patients with ESRD and requiring long-term dialysis is rising and, with that, the incidence of secondary hyperparathyroidism. In 1960, Stanbury et al18 described 2 cases in which subtotal parathyroidectomy was used to treat secondary hyperparathyroidism. Since then, there have been numerous variations in the technique resulting in a range of practices across differing institutions and physicians in operative treatment of renal hyperparathyroidism. Owing to a lack of consensus, there is no standardized recommendation for the type of operative procedure performed and a large part of the decision is surgeon preference.5 Currently, the technique favored by many surgeons is total parathyroidectomy followed by
686 Ng et al
Surgery April 2014
Table IV. Biochemical characteristics of patients who had undergone surgical implantation or subcutaneous injection of parathyroid tissue after total parathyroidectomy Characteristics
Surgical implantation
Subcutaneous injection
154 29.2–3710
161 24.6–364
2.8 0.7–22.9
2.7 0.2–10.9
0.5 0.1–2.2
0.4 0.1–2.6
2.76 2.43–3.33
2.74 2.24–3.77
2.44 1.93–2.96
2.48 2.07–3.46
7.50 0.8–20
7.50 1–20
1.51 0.65–2.43
1.48 0.62–2.75
1.72 0.73–3.29
1.51 0.86–2.85
Preoperative iPTH (pmol/L) Median Range Postoperative iPTH (pmol/L) Median Range iPTH on POD3 (pmol/L) Median Range Preoperative corrected Ca (mmol/L) Median Range Postoperative corrected Ca (mmol/L) Median Range Dose of calcium carbonate on discharge (g) Median Range Preoperative PO4 (pmol/L) Median Range Postoperative PO4 (pmol/L) Median Range
P value .233
.203
.648
.601
.121
.382
.614
.439
iPTH, Intact parathyroid hormone; POD, postoperative day.
Fig 1. Kaplan–Meier curves showing time to normalization of intact parathyroid hormone (iPTH) levels in patients with successful total parathyroidectomy, comparing subcutaneous injection and surgical implantation (P = .03).
autotransplantation of parathyroid tissue. Most surgeons prefer to place the parathyroid tissue ectopically rather than in the neck, because reoperation
in the neck is fraught with complications. Nevertheless, the technique of parathyroid autotransplantation has also been evolving. Injection of parathyroid tissue is a technique that is gaining popularity in several different scenarios, especially in total thyroidectomy, where it is done routinely when the parathyroid gland has inadvertently been removed.19 Few previous publications have examined the use of ectopic parathyroid injection into the forearm or deltoid muscles, and these were performed on relatively limited patient cohorts.15,16 In this study, we examined the operative management of a series of consecutive patients managed for secondary hyperparathyroidism. Specifically, we examine the efficacy of autotransplantation of parathyroid tissue by subcutaneous injection compared with the conventional technique of implantation. Given the difficulties in managing postoperative calcium and phosphate levels in patients who have undergone total parathyroidectomies, there is a necessity for the surgeon to consider some method to replace or autotransplant parathyroid tissue in a convenient location, which can potentially be removed with minimal complications. Traditionally, this comprised surgical implantation of small
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Fig 2. Kaplan–Meier plots comparing recurrence of secondary hyperparathyroidism in patients with successful total parathyroidectomy, comparing subcutaneous injection and surgical implantation. (A) Recurrence defined as patients requiring reoperative parathyroidectomy (P = .629). (B) Recurrence defined by intact parathyroid hormone (iPTH) levels of >100 pmol/L (P = .277).
pieces of parathyroid tissue in the brachioradialis or deltoid muscles during the primary procedure. We have always preferred the latter, because the deltoid muscle can easily be accessed during neck surgery and, more important, does not compromise subsequent placement of arteriovenous fistula/grafts in the forearm, which is critical in our context. As an extension of this procedure, we postulated that subcutaneous injection of parathyroid tissue in the same region would achieve similar results. There are several advantages to this approach. First, the technique is simple, reproducible, and quick, with no scarring. Second, it ensures fine mincing of the parathyroid tissue, allowing for good imbibition in the first phase of graft placement. Third, access to the subcutaneous plane when planning reoperative surgery for recurrence can be done easily under local anesthesia, even in the office setting. The main opposition to this technique is the theoretical failure to regain function and persistent hypoparathyroidism. Our experience is that subcutaneous injection is indeed a simple technique that avoids any scarring, with 4 small tattoo spots indicating the site of injection. Interestingly, compared with the current ‘‘gold standard,’’ or parathyroid implantation, parathyroid function normalized faster after subcutaneous injections. Median time to recovery was 2 months in the subcutaneous injection group compared with 9 months in the group with surgical implantation. Moreover, there was no difference in recurrence rates between the 2 techniques. Other components of postoperative biochemistry were also similar between both groups. One reason that could account for the advantageous result in the
injection technique is the additional step of passing the parathyroid tissue through a syringe during the subcutaneous injection, resulting in further ‘‘mincing’’ of tissue. The greater surface area allows for better imbibition of the graft and possibly a better uptake as a result. Hence, the addition of this step may increase the recovery rates in the implantation group as well. Nonetheless, these data suggest that subcutaneous injection is a feasible alternative with a comparable, if not greater, efficacy than surgical implantation. In situations where operation was required to treat recurrences after subcutaneous injections, reoperations were easier, faster, and could easily performed under local anesthesia, as opposed to the muscular dissection required to remove implanted parathyroid tissue placed in muscle pockets, which take longer, tends to be bloodier, and is associated with higher risk. There are several issues to be considered in this study. First, this is a retrospective study involving 4 different surgeons with their own personal preferences with regard to the 2 techniques. Interestingly, however, all 4 surgeons switched to the injection technique at some point during the study period and subsequently do not perform parathyroid implantations by the open technique any more. Second, the medical environment in Singapore is rather unusual in that hemodialysis is the most commonly used renal replacement therapy (in >85% of patients), and it has been documented that secondary hyperparathyroidism tends to be more severe in these patients compared with patients on peritoneal dialysis.20 This accounts for our high patient volume undergoing total parathyroidectomy, and also affects
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recurrence rates reported here. Finally, we defined our endpoints (surgical success and autograft recovery) biochemically, based on iPTH levels, not by intention of surgery. Although this gives more consistent results, caution should be made when comparing these data with other studies. In conclusion, our findings indicate that subcutaneous injection of parathyroid tissue is a simpler and more effective approach with an improvement in time to restoration of parathyroid autotransplant function. Hence, we propose this as a valid alternative to implantation in patients with persistent and medically refractory secondary hyperparathyroidism who require total parathyroidectomies. REFERENCES 1. Tominaga Y, Numano M, Tanaka Y, Uchida K, Takagi H. Surgical treatment of renal hyperparathyroidism. Semin Surg Oncol 1997;13:87-96. 2. Vathsala A. Twenty-five facts about kidney disease in Singapore: In remembrance of world kidney day. Ann Acad Med Singapore 2007;36:157-60. 3. Trends of end stage renal disease in Singapore. Singapore, Singapore: National Registry of Diseases Office; 2013. 4. Lin CH, editor. Eighth report of the Singapore Renal Registry 2009. Singapore, Singapore: National Registry of Diseases Office; 2012. 5. Riss P, Asari R, Scheuba C, Niederle B. Current trends in surgery for renal hyperparathyroidism (RHPT)---an international survey. Langenbeck Arch Surg 2013;398:121-30. 6. Felsenfield AJ. Considerations for the treatment of secondary hyperparathyroidism in renal failure. J Am Soc Nephrol 1997;8:993-1004. 7. Cohen EP, Moulder JE. Parathyroidectomy in chronic renal failure: has medical care reduced the need for surgery? Nephron 2001;89:271-3. 8. Rothmund M, Wagner PK, Schark C. Subtotal parathyroidectomy versus total parathyroidectomy and autotransplantation
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