Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism

Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism Bryan M. Clary, MD, Sanford C. Garner, PhD, and George S. Leight, Jr., MD, Durham,, N.C.

Background. The surgical management of secondary hyperparathyroidism by experiencedsurgeons is associatedwith excellent results. The presenceof supernumerary glands and inadequate initial parathyroidectomy can &ad to reoperationsfm recurrence. Intraoperative parathyroid hormone monitoring (qPTH), which has been describeddwing parathyroidectomy for primary hyperparathyroidism, may be helpful in preventing or predicting the needfor reoperution. This ,reportdescribesthe use of qPTH assays during parathyroidectomy in patients with secondary hyperparathyroidism. Methods. Intraoperative parathyroid hormone (PTH) levels were de&mined in 13 patients with secondary hyperparathyroidism undergoing total parathyroidectomy with autotransplantation (n = 3) or subtotal parathyroidectomy {n = IO). Levels were determined using a, modified immunochemiluminometric assay (qPTH). Results. The average PTH levels beforeand afterparathyroidectomy were 1599pg/ml(620 to 2486 pg/ml) and 230.3 pg/ml(129 to 345 pg/ml), respectively All patients had sigraijicant decreasesin PTH levels af& paratlayroidectomy (meala, 84.6 %). Sjmptonas were improved in all patients after operation. PTH levels at early follow-up were consistently below intraoperative levels. ConcEusions. Intraoperative PTH monitoring reproducibly demonstratesthe clinically relevant decrease in PTH levels after parathyroidectomy for secondary,hyperparathyroidism similar to thosepreviously documented in patients with primary hyp¶thyroidasm. Long-term follow-up and increasing numbers of patients are crucial in defining the role of qPTH monitoring duringparathyroidectomy for secondary hyperparathyroidism. (Surgery 1997;122:1034-9.) From the Departmentof Surgery, Dde Univmity Medical Cente
VIRTUALLYALL PATIENTS with chronic kidney failure requiring dialysis have some degree of secondary hyperparathyroidism. Despite effective medical management, approximately 5% to 10% require surgical treatment for symptoms or metabolic complications. Several studies have documented recurrence of secondary hyperparathyroidism after both subtotal parathyroidectomy (#TX) and total parathyroidectomy (tPTX) with or without autotransplantation. I,* These studies suggest that most reoperations for secondary hyperparathyroidism are performed because of hyperfunction of residual tissue in the neck or in the mediastinum.le3 The reasons for this include hyperplasia of remnant parathyroid tissue, inadequate Presented at the Eighteenth Annual Meeting of the American Association of Endocrine Surgeons, Baltimore, Md., April 6-8, x997. Reprint requests: Bryan M. Ciary, MD, Box 3324, Duke University Medical Center, Durham, NC 27710. Copyright

0 1997 Mosby-Year

0039-6060/97/$5.00

1034 SURGERY

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11/S/84656

parathyroidectomy at initial operation, and the presence of supernumerary glands, the latter of which occurs in approximately 5% to 6% of patients4 Intraoperative measurements of intact parathyroid hormone (PTH) using a rapid assay technique in conjunction with preoperative sestamibi scintigram localization has recently been advocated as a means of limiting the extent of exploration necessary to remove hyperfunctioning glands during parathyroidectomy for primary hyperparathyroidism.5V10 This approach leads to reduced operative times and an enhanced ability to perform parathyroidectomy for primary hyperparathyroidism on an outpatient basis in selected patients. An appropriate decrease (50%) in the intraoperative PTH level after removal of the affected gland(s) predicts a return to normal calcium level. The presence of multiple hyperfunctioning glands is suggested when removal of a clearly abnormal gland fails to result in a decrease of greater than 50% in the intraoperative PTH level. The value of intraoperative PTH monitoring

Clary, Garner; and Leight

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Volume 122, Number 6 during parathyroidectomy for secondary hyperparathyroidism has not been addressed. Potential benefits include the detection of supernumerary glands and confirmation of an adequate degree of parathyroidectomy, both of which would help avoid unnecessary reoperations. This report presents our experience with intraoperative PTH monitoring during parathyroidectomy in patients with secondary hyperparathyroidism. PATIENTS

AND

;

7 minute incubation at 45°C with constant shaking

METHODS

Patients. Intraoperative plasma PTH levels were determined in 13 consecutive patients with secondary hyperparathyroidism undergoing tPTX with autotransplantation (n = 3) or sPTX (more than 3.5 glands, n = 10) from March 1994 to March 1997. Patient records were reviewed retrospectively, and follow-up data were confirmed through the patients’ nephrologists. PTH assay. Blood samples were collected at four times during the operation for secondary hyperparathyroidism into standard ethylenediaminetetraacetic acid-containing vacutainers. The first baseline (B-l) for circulating PTH concentration is determined immediately after anesthesia is induced and an intravenous line placed. A second baseline sample (B-2) is collected after all parathyroid glands have been identified, but before any tissue has been excised. Once parathyroid tissue, either 31/2 or 4 glands, has been removed, additional samples are collected at 5 and 10 minutes after excision. In performing the assay, plasma is obtained from anticoagulated whole blood samples by centrifugation at 13,000 rpm for 45 seconds. Plasma (200 ~1) is then mixed with 100 yl anti-PTH (N-terminal epitope) antibody labeled with acridinium ester. An anti-PTH (C-terminal epitope) antibody-coated polystyrene bead is then added, followed by incubation at 45” C for 7 minutes on a shaker at 400 rpm. The bead is then washed three times in 3 ml of saline solution. The bead is then placed in the luminometer and a 2-second count performed. Correlation of immunochemiluminometric assay-derived intact PTH levels with standard immunoradiometric assay was demonstrated in preliminary studies. Standard immunoradiometric assay. Comparisons of the quick PTH assay with standard immunoradiametric assay (IRMA) measurement were performed to validate the rapid monitoring system. In performing the standard IRMA, 200 ~1 of serum was mixed with 100 ~1 of 12jI-PTH antibody (Nichols Intact PTH Immunoassay System; San Juan Capistrano, Calif.). Beads coated with antibody directed against PTH were then added to

Calculate

PTH

concentrations

Fig. 1. Intraoperative PTH assay.

Table I. Patient characteristics

41.8 (range, 23-69) Race (black/white) 8/5 Years dialysis dependent 6.2 (range, 3-14) Cause of kidney failure (n = 13) 6 Hypertension 2 Interstitial nephritis 1 Diabetes mellitus 1 Systemic lupus erythematosus 1 Polycystic kidney disease 1 Immunoglobulin A nephropathy 1 Glomerulonephritis Symptoms 11 Bone pain 6 Pruritis 1 Paresthesias Operative procedures Subtotal PTX 10 3 Total PTX

Age bean) (~1

Table II. Preoperative

laboratory indexes in patients with secondary hyperparathyroidism undergoing parathyroidectomy Intact PTH Calcium Phosphorus Alkaline nhosphatase

2027 pg/ml 10.2 mg/dl 6.8 mg/dl 642 units/l

each test tube and incubated at room temperature for 22 hours. Beads were then washed with deionized water and counted in the gamma counter. RESULTS

Tables I and II list the patient characteristics and preoperative laboratory indexes in the 13 patients who underwent parathyroidectomy for secondary hyperparathyroidism. The mean age of the patients

1036

Clary, Garnq and Leight

surgery December1997

-

7 min&

Ir&batio”n

Fig. 2. Correlation between standard overnight IRMA and rapid intraoperative immunochemiluminometric assays. Values are given in picograms per milliliter.

3000 3 E sl2500 4 zi 2 2000 J i+ g 1500 8 = 1000 .E i? g 500 !I p” 0 Pre-Excslon

Pre-Exploration

Fig. 3. Effect of surgical manipulation during neck exple ration before gland excision on PTH levels.

was 41.8 years, and the average length of dialysis dependence was 6.2 years. The most common cause of kidney failure was hypertension, which occurred

in 6 of 13 patients.

Other

causes included

interstitial nephritis, diabetes, polycystic kidney disA nephropathy, and ease, immunoglobulin glomerulonephritis. Bone pain was the most common symptomatic presentation (85%)) followed by pruritis (46%). The average preoperative PTH level was 2027 pg/ml. Ten patients underwent sPTX and three tPTXs with forearm autotransplantation. There were no operative deaths or complications. Seven patients required intravenous calcisupplementation immediate um in the perioperative period for symptomatic hypocalcemia. An additional two patients were readmitted

for intravenous calcium therapy at 10 and 13 days after operation, respectively. Mean follow-up for these patients was 14.3 months (range, 1 to 33 months). Two patients died at 5 and 25 months after parathyroidectomy of unrelated causes. Follow-up parathyroid levels were obtained in 7 of the 13 patients. All patients experienced symptomatic improvement after operation. Intraoperative PTH monitoring was performed as outlined in Fig. 1. Turnaround time for the assay is less than 15 minutes when performed by experienced personnel. In preliminary studies in patients with primary hyperparathyroidism, we have demonstrated excellent correlation between intraoperative quick PTH levels and those obtained via standard IRMA (Fig. 2). In the present study, PTH levels were drawn before incision, after exploration, and 5 minutes after excision of the last parathyroid (or segment). The effect of surgical manipulation (exploration) on the baseline intraoperative PTH level is shown in Fig. 3. PTH levels were variably affected by surgical manipulation. In some patients decrements were seen in preexcision values, whereas in others, minimal changes or even an increase was seen. All patients experienced a decrease of more than 65% in their PTH level after parathyroidectomy in comparison to the highest recorded baseline (Fig. 4, A). Eleven of thirteen patients had decreases of more than 75% (Fig. 4, B). There was no correlation between the magnitude of the fall in PTH and the need for intravenous calcium in the perioperative period. As expected with universal glandular involvement characteristic of secondary hyperparathyroidism, parathyroid levels obtained 5 minutes after the removal of each gland demonstrate a sequential decrease (Fig. 5). PTH levels in early follow-up (within 1 year of operation) were available in seven patients (Fig. 6). The mean PTH level in these patients was 118 pg/ml, ranging from 27 to 223 pg/ml (normal, 10 to 65 pg/ml). In six of seven patients, postoperative PTH levels obtained within this time window were lower than the final intraoperative level. Most patients have had moderately increased levels above normal, and one patient who has been monitored for 3 years maintained a level of 57 to 112 pg/ml for 34 months at which time the PTH level rose to 387 pg/ml. The percentage

decrement

in intraoperative

absolute postparathyroidectomy dictive

of the follow-up

PTH

or the

level was not pre-

PTH levels.

DISCUSSION The surgical treatment of medically refractory secondary hyperparathyroidism by experienced

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Volume 122, Number 6

Baseline

Post-Excision

Percentage

Decrease in iPTH Levels

Fig. 4. A, Baseline and postparathyroidectomy PTH levels as measured by intraoperative Histogram representation of the percentage decrement in PTH levels.

monitoring.

B,

2000 zi E 3 1600f 4 a 1200s Ii g 800.E E p 400;;I 0.z 0

I 100

I 120

Baseline

I 140

I 160

Partial 4th I 180

Minutes

Fig. 5. PTH levels obtained 5 minutes after total removal of the first, second, and third glands and partial excision of the fourth gland in a patient with secondary hyperparathyroidism.

surgeons is associated with excellent results. Despite this and continued medical treatment, however, reoperation is necessary for recurrent secondary hyperparathyroidism in up to 15% of cases. The presence of supernumerary glands (not seen in our small series), inadequate initial parathyroidectomy, and continued hyperplasia of remnant tissue are all potential contributors to this failure. In our study all patients experienced a dramatic decrease in PTH levels after parathyroidectomy. In six of seven patients with available PTH levels, these levels continued to decline during the first year. Three patients reported in this study receive their care at different, distant dialysis centers, and thus different laboratory schedules are used that preclude collection of levels at the same points in time after parathyroidectomy. It is likely that part of the decline in PTH levels seen in follow-up is related to the fact that the half-life of PTH is 3 to 5 minutes, and thus a steady-state level is not represented in the 5-minute postparathyroidectomy level. The amount of decline or the absolute postparathyroidectomy PTH level was not predictive of return-

400 23350g3004 E 250E $ 200I .I 150e &oo2 2 soI

O( lntraoperative

Follow-Up

Fig. 6. PTH levels obtained 5 minutes after parathyroidectomy and at follow-up within the first year after parathyroidectomy.

ing to normal PTH levels in the small number of patients examined (Fig. 6). This suggests that other factors relating to the patient’s medical management have an effect on the postoperative levels. It is not clear from this small series what the

1038

Clary, Garnq and Leight

surgery December1997

appropriate decrease in PTH level should be after parathyroidectomy for secondary hyperparathyroidism. Because sPTX at the least is required for successful treatment, one would expect that the value of 50% used in estimating an appropriate therapeutic response in primary hyperparathyroidism6ss may be inadequate. The average decline in this study was 84.670 and was associated with symptomatic improvements and low PTH levels in follow-up. The observation that intraoperative PTH

levels

were

manipulation

variably

is consistent

affected

by surgical

with previously

pub-

lished results.ll Both increases and decreases of 50% to 60% were seen. In secondary hyper-

parathyroidism,

neck exploration

can lead to

devascularization and thus result in an artificially low baseline. In determining the magnitude of the decrease with operative treatment, convention has

been to use the highest baseline. The role of intraoperative PTH monitoring during parathyroidectomy for secondary hyperparathyroidism is not as well defined as it is in primary hyperparathyroidism. Its ability to detect unexpected hyperfunctioning glands in primary hyperparathyroidism is well establishedlO but as yet unproven in secondary hyperparathyroidism. The ability to detect inadequate degrees of parathyroid resection during sPTX remains to be proven as well. Long-term follow-up is necessary to assess whether there exists an absolute PTH level or per-

centage decrement for reoperation.

that is predictive

of the need

CONCLUSIONS Intraoperative PTH monitoring reproducibly demonstrates the clinically relevant decrease in PTH levels after parathyroidectomy for secondary hyperparathyroidism similar to those previously documented in patients with primary hyper-

parathyroidism. Long-term follow-up and increasing numbers of patients will be crucial in defining the role of qPTH monitoring during parathyroidectomy for secondary hyperparathyroidism. REFERENCES 1. Rothmund M, Wagner P. Reoperations for persistent and recurrent secondary hyperparathyroidism. Ann Surg 1988;207:3104. 2. Henry J, Denizot A, Audiffret J, France G. Results of reoperations for persistent or recurrent secondary hyperparathyroidism in hemodialysis patients. World J Surg 1990;14:303-7. 3. Kim H, Cheigh J, David D, Stubenbord W, Sullivan J, Rubin A, et al. Long-term results of subtotal parathyroidectomy in patients with end-stage renal disease. Am Surg 1994;60:641-9.

4. Wang C. The anatomic basis of parathyroid surgery. Ann Surg 1976;183:271-5. 5. Boggs J, Irvin GI, Molinari A, Deriso G. Intraoperative parathyroid hormone monitoring as an adjunct to parathyroidectomy. Surgery 1996;120:9548. 6. Irvin GI, Dembrow V, Prudhomme D. Clinical usefulness of an intraoperative “quick” parathyroid hormone assay. Surgery 1993;114:1019-23. ‘7. Irvin GI, Deriso G. A new, practical intraoperative parathyroid hormone assay. Am J Surg 1994;168:466-8. 8. Irvin GI, Prudhomme D, Deriso G, Sfakianakis G, Chandarlapaty S. A new approach to parathyroidectomy. Ann Surg 1994;219:57481. 9. Kao P, van Heerden J, Taylor R. Intraoperative monitoring of parathyroid surgery by a 15-minute PTH immunochemiluminometric assay. Mayo Clin Proc 199+69:532-T. 10. Molinari A, Irvin GI, Deriso G, Bott L. Incidence of multiglandular disease in primary hyperparathyroidism determined by parathyroid hormone secretion. Surgery 1996;120:9347. 11. Irvin GI, Dembrow V, Prudhomme D. Operative monitoring of parathyroid gland hyperfunction. Am J Surg 1991;162:299-302. DISCUSSION Dr. Christopher

R. McHenry (Cleveland, Ohio). In what percentage of patients who underwent sPTX did the PTH levels normalize after operation? In terms of your follow-up of these patients, what percentage experienced recurrence after sPTX? Dr. Clary. Follow-up PTH levels were available in 7 of 13 patients at variable time points. This is due to the referral pattern of these patients. Most are cared for at distant dialysis centers with variable laboratory schedules. Two of seven patients had normalization of levels below 65 pg/ml. All seven patients had levels below 225 pg/ml. The average length of follow-up in these patients is 14 months (range, 1 to 33 months). None of these patients have required any further operative procedures. One

patient

maintained

PTH

levels

below

115 pg/ml

until 33 months when it increased to 300 pg/ml. Dr. Lawrence A. Danto (Davis, Calif.). I certainly think it is being demonstrated over and over that intraoperative PTH monitoring is going to be of great benefit. A

quick question.

Have you developed

any cost-benefit

analysis of intraoperative PTH monitoring in this particular group of patients? Dr. Clary. This is a very small number of patients. Therefore it is inappropriate at this time to advocate routine PTH monitoring. Cost-benefit analyses have not been performed. Dr. Jeffrey A. Norton (St. Louis, MO.). I wonder

whether I might give you a clinical situation to help me understand

removed

the

meaning

three abnormal

of

this

data.

parathyroid

If you

have

glands and the

PTH levels haven’t dropped or you have removed four glands and the PTH levels haven’t dropped, how would

you alter the surgical procedure? Dr. Clary. If the PTH levels after parathyroidectomy (subtotal or total) do not fall significantly, a careful exploration should again be carried out. If the remaining glands are still not identified, closure with postoperative localization studies should be carried out. What

Clary, Garner; and Leight

SUrg@y Volume 122, Number 6 constitutes a significant drop is arbitrary at this point. Our data demonstrate dramatic declines in the PTH levels in patients who achieved symptomatic benefit and who had persistently lower postoperative levels of PTH. Dr. John L. Doppman (Bethesda, Md.). Parathyroid venous sampling doesn’t work in patients with secondary hyperparathyroidism because they have decreased renal clearance of PTH. Do these patients undergo dialysis before operation? Do you do anything to lower their high PTH levels? Dr. Clary. Cleavage of intact PTH occurs within the liver by the Kupffer cells and is responsible for the short half-life of intact PTH of 3 to 4 minutes. Thus dramatic declines in PTH levels can be seen 5 minutes after parathyroidectomy. Dr. Orlo H. Clark (San Francisco, Calif.). Is your study ongoing? What does it cost you and the patient to do these studies? How much are you charging the patient? Do you really think it influences how you manage your patients? I have visited a few places that have reported the use of intraoperative PTH assays, but they are not using intraoperative PTH assays after the studies have been completed. Dr. Leight. This study was conducted as a preliminary project to determine whether intraoperative PTH levels would fall rapidly enough in patients with end-stage renal disease to be of potential value in determining the adequacy of parathyroid resection. We have shown that the PTH levels do decrease significantly. In this small experience we have not yet encountered a situation

1039

where PTH levels did not fall, so this information has not yet been used to alter the surgical procedure in these patients. At this time one can conclude that this technique has the potential to influence how patients are managed operatively. We use the procedure in all our patients. Patients have not been charged, and the actual cost per patient is approximately $200.00. Dr. Hans D. Roeher (Dusseldorf, Germany). You lost two patients from unrelated reasons. What were they? Dr. Clary. Correct. One died of cardiopulmonary arrest and the second of pneumonia. Dr. Roeher. Cardiovascular disease is related to secondary hyperparathyroidism, and according to our experience at least 30% of patients with secondary hyperparathyroidism experience serious episodes of heart failure or even death within 3 years after operation. This is a possible sign, among others, that the procedure was performed too late. Dr. Clary. I don’t think you can make the statement that cardiovascular arrest is solely due to hyperparathyroidism. The patient who died had normal PTH levels in postoperative follow-up. Dr. Edwin L. Kaplan (Chicago, Ill.). Have you ever made the remnant smaller because of the number that you get after the Sminute sample in a sPTX? Can you ever determine the presence of hyperparathyroidism or the absence of parathyroids using this technique? Dr. Clary. On the basis of the small patient population, it would be premature to draw conclusions regarding the degree of resection during sPTX.

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