Concise parathyroidectomy: The impact of preoperative SPECT ggmTc sestamibi scanning and intraoperative quick parathormone assay Sally E. Carty, MD, FACS, M. Jonathan Worsey, MBBS, FRCS(Engl), Mohamed A. Viii, MD, PhD, Manuel L. Brown, MD, and Charles G. Watson, MD, FACS, Pittsburgh, Pa. Background. Results of initial operation for sporadic primary hyperparathyroidism are generally excel- lent, yet today there is pressure to improve outcome and resource utilization. Methods. We designed a prospective longitudinal cohort study comparing two approaches to concise parathyroidectomy. Strategy A was defined as the palpation method for selective unilateral exploration. Strategy B was defined as the routine use of both preoperative y9mTc sestamibi single photon emission computed tomography (SPECT) imaging and intraoperative quick parathormone assay. With either strategy the study period was 19 months and patients explored unilaterally were candidates for same-day discharge. We compared surgical outcome for 128 consecutive consenting patients each with 6 months or more offollow-up (mean 12 f 7.6 months). Results. Demographic, biochemical, and pathologic findings did not dffer between groups. SPECT imaging precisely localized hyperf unctioningparathyroid tissue. Compared with Strategy A (n = 61), the 67 patients treated by use of Strategy B experienced a higher rate of unilateral exploration (41.0 % ver- sus 62.7%, p c 0.00001) and a shorter length of stay (1.07 versus 1.90 days, p c 0.00001) and tend- ed to have shorter operative times, fewer operative failures, and less morbidity. Total perioperative costs did not d$fm between groups. Conclusions. Routine use of intraoperative quick parathormone measurement and preoperative 99mTc sestamibi SPECT is as safe, effective, and cost-effective as conventional approaches to parathyroidectomy. Use of this strategy is associated with significant reductions in extent of surgery and length of hospital stay. (Surgery 1997;122:1107-16.) From the Departments of Surgery, Pathology, and Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pa. SURGERY FOR SPORADIC PRIMARY hyperparathy- roidism (PHPTH) has a high success rate (95% to 98%) and a low likelihood of complications (1% to 5%) .lm4 Of patients with sporadic PHPTH some 6% to 20% have multiglandular disease rather than a single adenoma, a situation that the surgeon must recognize intraoperatively on the basis of skill and care. Because most failures arise when the surgeon fails to remove all hyperfunctioning parathyroid tissue, the standard operative approach is routine- ly to explore both sides of the neck and to identify Presented at the Eighteenth Annual Meeting of the American Association of Endocrine Surgeons, Baltimore, Md., April 6-8, 1997. Reprint requests: Sally E. Carty, MD, FACS, 497 Scaife Hall, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261. Copyright 0 1997 by Mosby-Year Book, Inc. 0039-6060/97/$5.00 t 0 11/6/85139 all four parathyroid glands.2 Techniques to allow a more directed operation have long been sought, but none have proved to be both effective and cost-effective. In fact the often quoted truism, attributed to Dr. John A. Doppman, is that the best localization procedure is an experienced parathy- roid surgeon. Intraoperative strategies to deter- mine whether all hyperfunctioning parathyroid tis- sue has been removed have included methylene blue staining of parathyroid tissue, intraoperative fat staining, and monitoring of levels of total serum calcium, ionized calcium, urinary cyclic adenosine monophosphate, and immunoreactive intact parathyroid hormone, but for a variety of reasons these have been of limited success. The currently recommended approach relies on both the surgeon’s estimate of parathyroid size and on frozen section confirmation of parathyroid tissue presence and weight.* SURGERY 1107
Transcript
Concise parathyroidectomy: The impact of preoperative SPECT ggmTc sestamibi scanning and intraoperative quick parathormone assay Sally E. Carty, MD, FACS, M. Jonathan Worsey, MBBS, FRCS(Engl), Mohamed A. Viii, MD, PhD, Manuel L. Brown, MD, and Charles G. Watson, MD, FACS, Pittsburgh, Pa.
Background. Results of initial operation for sporadic primary hyperparathyroidism are generally excel- lent, yet today there is pressure to improve outcome and resource utilization. Methods. We designed a prospective longitudinal cohort study comparing two approaches to concise parathyroidectomy. Strategy A was defined as the palpation method for selective unilateral exploration. Strategy B was defined as the routine use of both preoperative y9mTc sestamibi single photon emission computed tomography (SPECT) imaging and intraoperative quick parathormone assay. With either strategy the study period was 19 months and patients explored unilaterally were candidates for same-day discharge. We compared surgical outcome for 128 consecutive consenting patients each with 6 months or more offollow-up (mean 12 f 7.6 months). Results. Demographic, biochemical, and pathologic findings did not dffer between groups. SPECT imaging precisely localized hyperf unctioningparathyroid tissue. Compared with Strategy A (n = 61), the 67 patients treated by use of Strategy B experienced a higher rate of unilateral exploration (41.0 % ver- sus 62.7%, p c 0.00001) and a shorter length of stay (1.07 versus 1.90 days, p c 0.00001) and tend- ed to have shorter operative times, fewer operative failures, and less morbidity. Total perioperative costs did not d$fm between groups. Conclusions. Routine use of intraoperative quick parathormone measurement and preoperative 99mTc sestamibi SPECT is as safe, effective, and cost-effective as conventional approaches to parathyroidectomy. Use of this strategy is associated with significant reductions in extent of surgery and length of hospital stay. (Surgery 1997;122:1107-16.)
From the Departments of Surgery, Pathology, and Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pa.
SURGERY FOR SPORADIC PRIMARY hyperparathy- roidism (PHPTH) has a high success rate (95% to 98%) and a low likelihood of complications (1% to 5%) .lm4 Of patients with sporadic PHPTH some 6% to 20% have multiglandular disease rather than a single adenoma, a situation that the surgeon must recognize intraoperatively on the basis of skill and care. Because most failures arise when the surgeon fails to remove all hyperfunctioning parathyroid tissue, the standard operative approach is routine- ly to explore both sides of the neck and to identify
Presented at the Eighteenth Annual Meeting of the American Association of Endocrine Surgeons, Baltimore, Md., April 6-8, 1997. Reprint requests: Sally E. Carty, MD, FACS, 497 Scaife Hall, Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15261. Copyright 0 1997 by Mosby-Year Book, Inc. 0039-6060/97/$5.00 t 0 11/6/85139
all four parathyroid glands.2 Techniques to allow a more directed operation have long been sought, but none have proved to be both effective and cost-effective. In fact the often quoted truism, attributed to Dr. John A. Doppman, is that the best localization procedure is an experienced parathy- roid surgeon. Intraoperative strategies to deter- mine whether all hyperfunctioning parathyroid tis- sue has been removed have included methylene blue staining of parathyroid tissue, intraoperative fat staining, and monitoring of levels of total serum calcium, ionized calcium, urinary cyclic adenosine monophosphate, and immunoreactive intact parathyroid hormone, but for a variety of reasons these have been of limited success. The currently recommended approach relies on both the surgeon’s estimate of parathyroid size and on frozen section confirmation of parathyroid tissue presence and weight.*
SURGERY 1107
1108 Carty et al. surgery December 1997
1800 1800 1400
E 1200
2 1000
;;I 800 k 600
400
200
0
PRE EXC. 15’ POST 30' POST Fig. 1. Intraoperative ICMA quick parathormone levels for 67 patients managed by using Strategy B. Results are depicted for 66 preexcision (PRE EXCJ levels and 70 postexcision (POST) levels drawn as described in Methods. The preexcision quick parathormone level for one patient (6358 pg/ m 1) . is not depicted to adjust scale.
Table I. Patient demographics and biochemical profiles
Strategy A Strategy B
No. of patients 61 67 Age (yr) (mean + SD) 53.4 + 18.2 59.9 + 12.0 Male gender (%) 26.2 26.9 Presenting manifestations (%) *
Serum level of calcium (mg/dl, mean ? SD) 11.5 f 0.8 11.3 * 1.0 Serum parathormone level(%)t 243 ziz 223 239 + 217 24Hour urine calcium level (ma, mean f SD) 335 f 156 326 f 131
*Percentage of patients presenting with a historical or physical finding indicative of each listed manifestation of PHPTH.
tExpressed as percentage of upper limit of the normal range for each value obtained clinically.
On the one hand our human instinct to make every parathyroid operation a success, coupled with recent technological developments and pres- sure to decrease costs of care, must be addressed. On the other hand no sacrifice of safety or efficacy is acceptable. Potential advantages of a unilateral exploration include decreased risk of postoperative hypocalcemia, nerve injury, and obliterative scar- ring, and shorter operating time and hospital stay. One recent innovation is ggmTc-sestamibi scintigra- phy, which is quite accurate in localizing parathy- roid adenomas but less accurate in identifying parathyroid hyperplasia.5-11 Using this modality, scan-directed excision of an adenoma could be curative if the surgeon could be sure that no other hyperfunctioning parathyroid tissue was present.
By using a complementary innovation, which is intraoperative “quick” intact parathyroid hormone measurement that provides biochemical confirma- tion of the adequacy of operation, several groups have suggested that the two techniques together prompt an evolutionary change in the surgical conduct of parathyroidectomy.12M17 We designed a prospective longitudinal cohort study to test this hypothesis.
METHODS
Two strategies for perioperative management of hyperparathyroidism. We systematically compared the surgical outcome of two different approaches to selective unibateral exploration for sporadic PHPTH. Strategy A, defined as the intraoperative
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Table II. Accuracy of preoperative sestamibi imaging in Strategy B
palpation method, has been previously character- Table III. Intraoperative quick parathormone lev-
ized in detai1.l els during thyroidectomy
In Strategy A, preoperative imaging is obtained only in high risk patients (severe cardiac disease, prior thyroid surgery, bleeding diathesis, morbid obesity). Patients are then examined for neck nodularity intraoperatively after division of the median raphe. Unless a palpable abnormality directs attention to the left, the right side of the neck is arbitrarily explored first. When an adeno- ma and an ipsilateral normal gland are identified, operation is terminated without exploring the other side. During the past 20 years we have rou- tinely used Strategy A at initial operation for spo- radic PHPTH and have found it to be both safe and effective, with a 0.8% rate of missed hyperplasia and a 34% rate of unilateral exploration.’
Since 1993 all patients explored unilaterally by use of Strategy A have been considered as candi- dates for same-day discharge. A formal clinical pathway was initiated: (1) Unilaterally explored patients are observed after operation for 8 hours and are then examined by the surgical team. In the absence of factors necessitating longer stay (pro- longed side effects of general anesthetic, signs or symptoms of hypocalcemia, patient reluctance or social isolation) patients are discharged the after- noon of operation without a determination of post- operative serum calcium level. (2) Bilaterally explored patients are not considered candidates for same-day discharge because of the chance that additional dissection may have compromised parathyroid function and are required to meet the additional criterion of a postoperative morning serum calcium level of 7.8 mg/dl or less before discharge. (3) All patients are discharged on 5 days of oral calcium supplementation (Oscal, 1.0 gm three times a day).
In January 1995 we instituted a different strate- gy for selective unilateral exploration with same- day discharge. Strategy B is defined as the routine
use of both preoperative single photon emission computed tomography (SPECT) ggmTc-sestamibi imaging and intraoperative quick parathormone measurement. Patients are managed using identi- cal postoperative discharge criteria, but at opera- tion the results of preoperative sestamibi scanning are used to direct neck exploration. Default right- sided exploration is performed if imaging and pal- pation are negative. After division of the median raphe a baseline intraoperative rapid parathor- mone level is drawn by the surgeon from the ipsi- lateral internal jugular vein with the thyroid lobe retracted medially. As the adenoma is excised or subtotal parathyroidectomy is completed, the exact time is noted and 15 minutes later, after search for and biopsy of a normal parathyroid gland, a second quick parathormone level is drawn from the same internal jugular vein. If the second quick parathor- mone level is both (1) 50% or less of the baseline intraoperative level and (2) below the upper limit of normal (less than 65 pg/ml), the operation is concluded. If the quick parathormone level does not drop by these criteria, the incision is reopened and the other side explored, with a subsequent quick parathormone level drawn 15 minutes after excision of additional parathyroid tissue.
Surgical technique. Using Strategy A or B the conduct of parathyroid exploration in this investi-
Bilateral exploration Search for adenoma 16 14 Concern of hyperplasia 18 10 Thvroid disease 2 1
*Level of significance by Pearson chisquared test.
gation was performed in the following way. Using meticulous avascular dissection the thyroid was retracted medially as much as possible and the nor- mal and ectopic locations for normal and enlarged parathyroid glands were explored. We routinely used frozen section to confirm parathyroid tissue presence and weight. For parathyroid adenoma the enlarged gland was excised and a normal gland was biopsied and marked with a clip. If hyperplasia was identified, a 3 l/2 gland subtotal parathyroidecto- my was performed with cryopreservation of excised parathyroid tissue. The number of normal parathy- roid glands biopsied in patients with suspected adenoma was kept to a minimum of one. Postoperative analysis of oil red 0 staining was obtained in every case.
Sestamibi imaging. On the basis of the method of Taillefer et al.l* we have described our tech- nique and initial experience with the single radionuclide imaging technique of ggmTc-sestamibi and SPECT imaging. I1 Briefly, the technique involves the administration of approximately 25 mCi (925 MBq) of ggmT~ sestamibi. SPECT imaging is begun at 15 to 30 minutes for the early phase scan and 2 to 4 hours for the delayed phase scan. Patients are positioned supine with the neck hyper- extended, and the field of view includes the base of the skull to the base of the heart. The data are reconstructed, and the transaxial data are repro- jetted and reviewed in a tine format. Images are read as positive if there was a definite focus of increased or separate uptake relative to the thyroid tissue on either early or delayed SPECT images, or if an area of delayed washout is identified on the delayed scan. With this method the sensitivity for localization of adenomas is significantly greater with the early SPECT images (92%) compared to delayed images (74%). For patients with hyperpla- sia the sensitivity was uniformly low (25% for early and 40% for late SPECT images) .I1
In each patient managed with Strategy B, ggmTc- sestamibi SPECT was ordered before operation.
However, if a patient was referred with a sestamibi scan already performed outside our institution, we did not insist on a repeat scan unless the outside study results were negative. A small number of patients in the Strategy B group were not willing or able to comply with preoperative ggmTc- sestamibi testing, but on the basis of study design they were nevertheless included in cohort analysis of Strategy B (see Results).
Measurement of intraoperative rapid parathor- mone levels. We modified a commercially available chemoluminometric parathormone assay (Nichols Institute, San Juan Capistrano, Calif.). The modifi- cation in incubation temperature from 37” C to 45” C reduced the performance time from 2 hours to 7 minutes. Blood samples were drawn into ethylene- diaminetetraacetic acid for rapid process of plasma for analysis (3 minutes). Linearity (up to 1300 pg/ml) and precision (coefficent of variation < 10%) of the modified assay were comparable with the manufacturer’s specifications. The lower end sensitivity for the assay, however, was 40 pg/ml. The reference range for parathormone is 10 to 65 pg/ml in healthy volunteers. Because in patients with hyperparathyroidism parathormone concen- trations are usually well above the upper limit of normal, a sensitivity of 40 pg/ml was considered to be applicable for intraoperative use.
Rapid parathormone testing was performed on- site in the operating room. Total turnaround time ranged from 10 to 14 minutes but was always less than 15 minutes. The laboratory staff was generally notified a day in advance but was available for emergency cases with short notice. The technician arrived to set up the instruments as the surgical procedure was initiated. The patient charge for quick parathormone, based on cost accounting analysis, was the same whether performed during operation or in the laboratory.
Patient population. All patients presenting for initial surgical therapy of PHPTH were evaluated with a standard biochemical panel consisting of fasting intact parathormone and concurrent calci- um levels and a 24hour urine collection for calci- um and creatinine. Patients with prior paratbyroid operation or preoperative evidence for multiple endocrine neoplasia type 1 or type 2A, familial hyperparathyroidism, or familial hypocalciuric hypercalcemia were excluded from this study.
The study group consisted of 128 consecutive consenting patients each with 6 months or more of follow-up. Sixty-one patients were treated by using Strategy A, and 67 patients were managed by using Strategy B. For each group the study period was 19 months. Mean follow-up interval (*SD) was 12.0 +
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Table V. Operative outcomes
Mean operating time (min + SD) Mean length of stay (days * SD) Perioperative costs* ($)
Strategy A
108 i- 52.5 1.9 + 0.94
3636.03
Strategy B
96.2 + 36.4 1.07 + 0.82
3325.29
p Value
NS <0.00001
NS
AJS, Not significant. :“Determined as detailed in Methods section.
7.6 months. This investigation was part of a larger protocol approved by the Institutional Review Board of the University of Pittsburgh. Minimum follow-up consisted of a serum calcium level and examination and in many cases included an intact parathormone level.
Statistical and cost analyses. Data were entered prospectively from standardized forms into a com- prehensive computer database comprising 908 parathyroidectomies performed by two academic endocrine surgeons. Statistical analyses were per- formed, as appropriate, with Pearson chi-squared analysis and the Mann-Whitney rank sum test. Level of significance was set at fi I 0.05.
There is no fixed relationship between costs and hospital charges, so we examined costs, with the exception of operating room charges and hospital daily charge for which there are no readily avail- able estimates. For both study groups perioperative costs were calculated on the basis of (Mean length of stay x Hospital charge) plus (Mean operative time x Operating room charge) plus (Costs of peri- operative testing) (includes the following where applicable, depending on study group A or B: costs of outpatient ggmTc-sestamibi SPECT, intraopera- tive quick parathormone measurement, and/or postoperative serum calcium level). Cost data are expressed in 1997 dollars regardless of the date of operation.
RESULTS
The distribution of demographic, clinical, and biochemical findings among the two study groups (Strategy A and Strategy B) is given in Table I. No preoperative differences were noted between groups. No patient in this series has been subse- quently identified to have familial hypocalciuric hypercalcemia or a familial form of PHPTH.
For the Strategy B cohort, analysis of the use of preoperative ggmTc-sestamibi SPECT is detailed in Table II. Not every patient (32.8%) in the Strategy B group was able to comply with SPECT sestamibi scanning because the use of the procedure was not recognized by all insurers during the study period. Compared with the surgical and pathologic find- ings, sestamibi results in the 45 scanned Strategy B
patients were assessed as true positive if they cor- rectly identified the laterality of an adenoma (right versus left) or the presence of multiglandular dis- ease. As may be seen, SPECT sestamibi scanning was quite sensitive (93.1%) and accurate (97.4%) in identifying adenoma, with an overall positive predictive value of 96.4%. Only one SPECT ses- tamibi scan was negative, and the rate of false-posi- tive SPECT imaging was 2.9% (1 of 34). Of real benefit to the surgeon was the rotating three- dimensional data provided by SPECT imaging, which frequently aided preoperative detection by allowing dynamic visualization of an adenoma in an inferior, superior, or ectopic gland location. Outside ggmTc-sestamibi scans were considerably less accurate especially in patients with hyperplasia (Table I) and in fact accounted for 75% of the false-positive ggmTc-sestamibi results. In addition, we found the static two-dimensional images provid- ed by outside scans to be subjectively less useful.
Results of intraoperative quick parathormone measurement for the 67 patients in the Strategy B group are given in Fig. 1. In 63 of 67 patients the first postexcision quick parathormone level dropped to within the normal range or less than 50% of baseline. Long-term follow-up in these 63 patients has confirmed adequate parathyroidecto- my with no observed cases of persistent or recur- rent hyperparathyroidism. In three patients an ele- vated postexcision quick parathormone level prompted bilateral exploration for what proved to be multiglandular disease, and a second postexci- sion quick parathormone level after subtotal parathyroidectomy or excision of a second adeno- ma met criteria for termination of the operation; hypercalcemia has not recurred in these patients. In a single patient (diamond, Fig. 1.) an elevated postexcision level confirmed an unsuccessful exploration for missing adenoma. Examples of the use of intraoperative quick parathormone mea- surement are provided by (1) the facilitation of intraoperative identification of patients with nodu- lar hyperplasia; (2) the cases of eight Strategy B patients successfully managed with unilateral exploration and adenomectomy; and (3) an elder- ly woman in whom, after 3 gland parathyroidecto-
1112 Carty et al. surgery December 1997
my for sporadic nodular hyperplasia, an elevated postexcision quick parathormone level correctly prompted reexploration for fifth and sixth supranumerary glands.
To address the potential question of whether dis- section around the parathyroid glands can iatro- genitally raise the intraoperative parathormone level, we measured parathormone levels in seven patients undergoing thyroidectomy. Specimens were drawn from the internal jugular vein just before and 15 minutes after thyroid lobectomy with preservation of the ipsilateral parathyroid glands in situ (Table III.) There was no difference in mean quick parathormone level attributable to perturba- tion of normal parathyroid glands, although small variations were noted in individual patients.
At operation, unilateral exploration was possible more frequently in Strategy B patients than in Strategy A patients (Table IV). In Strategy A group, unilateral exploration was guided by palpation in 11 of 61 patients and by default right-sided explo- ration in 4 of 61. The fact that only 30% of Strategy A patients referred with various types of preopera- tive localization procedures were able to undergo successful unilateral exploration provides further support for the efficacy of SPECT ggmTc-sestamibi in facilitating unilateral exploration by using Strategy B. In both groups suspicion of hyperplasia prompted bilateral exploration with comparable frequency. In the entire series single adenomas, double adenomas, and hyperplasia were encoun- tered at incidences of 87.50/o, 3.9%, and 8.6%, respectively, with no significant differences detect- ed between groups. Single adenomas were equally distributed with respect to laterality and embry- ologic origin, were intrathyroidal in five patients, and were not observed in the mediastinum. The overall incidence of multiglandular disease was 12.5%. No cases of parathyroid carcinoma were encountered.
Initial operation’was successful in 58 (95%) of 61 patients managed by using Strategy A, 66 (98.5%) of 67 patients managed by using Strategy B, and 124 (96.9%) of 128 patients overall. Of the three failures with Strategy A, one patient had per- sistent hyperparathyroidism caused by a missed adenoma that was later excised after positive SPECT imaging, and two patients had pathologi- cally proven double adenomas presenting as recur- rent hyperparathyroidism at 2.5 and 3 months after operation; each was successfully treated by reoper- ation. With Strategy B there was a single operative failure caused by persistent disease from a cervical adenoma that could not be located at initial opera- tion; this patient had had a false-positive outside
sestamibi scan. There was no major morbidity in the Strategy B cohort, whereas in the Strategy A group one patient had permanent vocal cord injury. Minor morbidity was considerably more fre- quent with Strategy A (one transient cardiac arrhythmia, one case of retained drain, and 26 cases of temporary postoperative hypocalcemia) than with Strategy B (two cases of postoperative pseudogout, p < 0.00001). There were no instances of hematoma, permanent hypocalcemia, or death in either group.
Length of hospital stay was shorter in the group treated with Strategy B (Table V). The median length of stay with Strategy B was 1 day, and 18% of patients in this group were discharged the after- noon of operation. The mean length of stay for the 45 of 67 patients who were able to comply with ggmTc-sestamibi imaging was even shorter at 0.93 days. There were no readmissions for postoperative hypocalcemia in either group. Operative time was somewhat less in the Strategy B group managed with ggmTc-sestamibi and intraoperative quick parathormone measurement, but the difference did not reach statistical significance in this series. Total perioperative costs did not differ between Strategy A and Strategy B (Table V) .
DISCUSSION
Prior experience has shown that a selective uni- lateral approach in sporadic HPTH can be safe and effective with the potential benefits of a more lim- ited operation, less morbidity, and a shorter stay. Further refinement of this technique would be an attractive option if adenomas could be accurately localized before operation and if removal of the source of the excess parathormone could be con- firmed intraoperatively. Routine preoperative ggmTc-sestamibi SPECT and intraoperative quick parathormone measurement were used in a prospective longitudinal cohort study to evaluate this approach. Using the new strategy we found that safety, efficacy, and perioperative costs are at least comparable with conventional approaches to parathyroidectomy.
We have found SPECT ggmTc-sestamibi to be superior to static two-dimensional sestamibi imag- ing. We believe that the lower sensitivity and accu- racy of outside scanning, especially in the crucial arena of hyperplasia, demand use of SPECT methodology. We now request that our referring physicians forego outside imaging in the evaluation of PHPTH patients to avoid duplication. Invaluable information is also provided by routine preopera- tive review of the three-dimensional SPECT ses- tamibi study by the operating surgeon. It is, howev-
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er, important to emphasize that in any strategy for selective unilateral parathyroidectomy, the results of currently available imaging studies can only tell the surgeon where to start the dissection, not when to stop.
Operations to treat hyperparathyroidism tend to proceed either gratifyingly well or with great frus- tration.’ In addition to its demonstrated utility, use of intraoperative quick parathormone measure- ment also brings fresh satisfaction to the perfor- mance of parathyroidectomy by confirming the findings of surgery in such a way as to allow expe- ditious closure. It is not difficult to initiate quick parathormone methodology now that the intact immunofluorescent assay is available, avoiding the need for use of radioactive reagents. Many clinical laboratories already have a luminometer. By using the assay modifications reported herein that mini- mize the turnaround time to 10 to 14 minutes, the concerns of many who have attempted to use intra- operative parathormone measurement may be sat- isfied. Reoperation for failed initial parathyroidec- tomy is costly. rg It may be that further experience with intraoperative quick parathormone measure- ment at major centers of endocrine surgery may not only further enhance the success of initial operation but may also tend to geographically favor the performance of parathyroid surgery by high- volume providers.
Rather than efficiency, the outcome measures of paramount importance must always be safety and efficacy. Because the success rate of initial parathy- roidectomy is already high, it takes a potent tech- nique to show further improvement in results. The current study has shown Strategy B for concise parathyroidectomy to be safe and effective with zero missed hyperplasia and a 62.7% rate of unilat- eral exploration, but the sample size is small. Further experience with the technique will be required before a strong recommendation can be made. Patients with familial disease need to be rig- orously identified before, operation because they are emphatically not candidates for unilateral exploration. Quick parathormone methodology lends itself handily, however, to the treatment of patients with secondary or tertiary hyperparathy- roidism. There may be other logical extensions to the concise strategy. 2o For example, we did not see a significant decrease in operating room time, which we believe is largely due to time spent locat- ing a normal parathyroid gland to biopsy. Irvin et a1.,21 having dispensed with that step almost entire- ly, do note a decrease in operative time by using quick parathormone methodology. However, we continue to recommend both the biopsy of a nor-
mal parathyroid gland and the maintenance of a low threshold for bilateral exploration if any find- ings prompt suspicion of multiglandular disease.
Unilateral exploration is probably associated with less morbidity, an attractive idea because theo- retically two fewer parathyroid glands and one fewer recurrent laryngeal nerve are placed at risk, and tissue plane obliteration on a side of the neck not harboring disease is avoided. Although we observed much less transient hypocalcemia in the Strategy B group, the majority of which constituted symptomatic hypocalcemia, because we did not measure early postoperative calcium levels in those patients explored unilaterally, the results are not strictly comparable. Based on the results presented here in which no unilaterally explored patient had symptoms of hypocalcemia when discharged on a 5-day course of low-dose calcium supplementation, however, we believe the measurement of postoper- ative serum calcium level can be confidently omit- ted in such patients.
In planning this study in 1993 we considered using a randomized design (necessarily nonblind- ed.) We determined that cohort design was best suited to test the hypothesis of this study for rea- sons that include (1) the near impossibility of blinding both patient and surgeon to the results of ggmTc-sestamibi scan, which inevitably influence the subjective results of palpation; (2) the finding that the utility of SPECT sestamibi readily prompts the use of more and more scans in “high-risk” patients; (3) the fact that quick parathormone early on was so useful that it seemed a disservice to limit use of the technique. With a cohort design it is of course possible that whether the patient had a unilateral or bilateral exploration was not the only variable influencing length of hospital stay, espe- cially in this rapidly changing medical era. It has been pointed out, however, that surgeons must pre- pare to better understand relevant models evaluat- ing surgical outcome,** and that in the ideal situa- tion randomized controlled trials can be performed to evaluate only 40% of treatment ques- tions involving surgical procedures.‘3
In conclusion, the findings of this study support the hypothesis that in initial operation for sporadic PHPTH, routine SPECT ggmTc- sestamibi imaging and intraoperative quick parathormone measure- ment can be as safe, effective, and cost-effective as conventional approaches to parathyroidectomy. Patients managed with this approach to selective unilateral exploration benefit by significant reduc- tions in extent of operation and length of hospital stay.
1114 Carty et al. surgx??“y December 1997
We acknowledge with thanks Dr. George I. Irvin for his assistance in establishing our quick intraoperative assay for intact parathormone, and John Wilson and Roger Day for their statistical expertise.
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intraoperative intact PTH measurement in parathyroid surgery. Ann R Co11 Surg Engl 1995;77:28-30.
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DISCUSSION Dr. Lawrence A. Danto (Davis, Calif.). You have
opened up Pandora’s box. More and more of us are beginning to realize that there is a place for routine pre- operative imaging. Sestamibi is the most commonly used. There probably is a place for quick intraoperative parathormone assay. But, looking at your statistics, I wonder whether you have really demonstrated a distinct value for intraoperative parathormone measurements separate from preoperative imaging. You lump it in with preoperative imaging, and you really don’t separate them out. I think that needs to be done.
Dr. Carty. We did do that, in detail, and both studies are required. Because the use of sestamibi imaging was not recognized by all insurers during the study period, only 67% of the Strategy B patients actually got a ses- tamibi scan. We agonized with our statisticians about whether to do subgroup analysis or to include these patients in the Strategy B cohort, and the honest thing to do was to include them in the cohort. If only patients who got both a SPECT sestamibi scan and quick parathormone testing are evaluated, the resulting length of stay, operative time, and rate of unilateral exploration are even more favorable than the results reported here for Strategy B. Our conclusion was that you have to do both SPECT sestamibi imaging and quick parathormone together to get the best effect.
Dr. Danto. In follow-up to that, at University of California-Davis we have an 8% to 10% incidence of sec- ond adenomas that do not show on sestamibi scan. We have been doing a directed exploration, a quick explo- ration of the contralateral side that does not increase operative time significantly or length of stay significantly. But we have picked up these second adenomas. From your statistics you had one or maybe two, which seems like a relatively small number compared with ours. That
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leads me to a final question. Are there parathyroid ade- nomas that are visualized on scan but do not function?
Dr. Carty. I don’t know. Our rate of double adenoma was 5%.
Dr. Norman W. Thompson (Ann Arbor, Mich.). I think you have presented a very convincing argument. It is clear that in your hands the results are excellent. You can’t beat 98.5%. Nevertheless, let’s analyze a few of the points that I think are important. First of all, you lose 15 minutes of operating room time because you wait that long after you have taken out a tumor to clear the parathormone. Is that necessary? Isn’t the half-life of parathormone only 2 minutes? Could you save 13 min- utes right there if you are worried about time?
Dr. George L. Irvin (Miami, Fla.) . The half-life is 3 to 4 minutes usually.
Dr. Thompson. So why not wait just 5 minutes and proceed?
Dr. Carty. What we actually do is begin our closure while we are waiting. So we lose 0 to 4 minutes while we are waiting for the quick parathormone to come back, usually 0. When the parathormone comes back, we are ready to put the dressing on.
Dr. Thompson. You made it very clear in your paper that sestamibi scanning missed multiple gland disease. I think everybody recognizes that you can’t reliably identi- fy multiple gland disease with sestamibi scanning. In your paper you make it clear that you missed identifying double adenomas, of which you had a 5% incidence. What then is the value of the preoperative sestamibi scan- ning? The real question is, in all the preoperative ses- tamibi scans, was there any scan that would have changed your operation or allowed a good surgeon to have found a tumor that would not have been discovered with a decent exploration? In other words, were there any truly ectopic parathyroids seen in the mediastinum, the vagus nerve, under the angle of the jaw, or other exotic sites? Could you have found all of your abnormal parathyroids with a reasonable exploration?
Dr. Carty. The goal of this study was to do selective unilateral exploration. There were no mediastinal or carotid bifurcation adenomas, and if you did a thorough bilateral exploration you would have found all abnormal parathyroid glands. However, in a patient not in this study because her follow-up is too short (every patient had at least 6 months of follow-up) I found fifth and sixth supranumerary parathyroid glands after subtotal parathyroidectomy, solely on the basis of quick parathor- mone results intraoperatively.
Dr. James G. Norman (Tampa, Fla.). I want to con- gratulate you again on your minimal approach to the parathyroid. Why do you only have a 58% unilateral exploration in your Strategy B group, when you have a 97.6% accuracy with the sestamibi scan? You mentioned earlier that not everybody in Strategy B group had a ses- tamibi scan, so to some degree this is confusing.
Dr. Carty. The rate of unilateral exploration was 63% using Strategy B, because we use a low threshold for bilat- eral exploration if there is any suspicion of hyperplasia. We also have a low threshold for bilateral exploration if
we can’t identify and biopsy an ipsilateral normal parathyroid gland. About half of the bilateral explo- rations using Strategy B were for suspicion of hyperplasia or because we couldn’t find a normal gland. One could make the point that these results prompt the perfor- mance of adenomectomy, instead of adenoma excision with biopsy of a normal gland. We are not ready to do that, again because of concern about unrecognized hyperplasia.
Dr. Norman. Was any operation performed with the patient under local anesthesia?
Dr. Carty. We have started to do that in the last couple of months and are thrilled with it so far, but you have to carefully select your patients.
Dr. Paul LoGerfo (New York, N.Y.). I guess I am not sure what a longitudinal study is. My interpretation was that your study in group A had been done first and then group B had been done second.
Dr. Carty. Yes. We considered a randomized prospec- tive design but abandoned it for several reasons, one of which is that I had to be dragged kicking and screaming into doing this study at all. It was Dr. Watson who initiat- ed our dialogue about it, so we decided to do it in a very systematic manner.
Dr. LoGerfo. During the 34-month period of time that this study covers, the length of postoperative stays at almost all institutions decreased markedly. At our own institution the length of the postoperative stay has gone from 0.9 days down to 0.4 days. A longitudinal study would have reflected this bias. This has nothing to do with sestamibi scans or intraoperative parathormone. It only reflects the changing of surgeons’ attitudes to dis- charges. I am sure most of what you are seeing reflects this change in attitudes and that the decrease in length of hospital stays is not due to the addition of new tests.
Dr. Carty. Yes, that is an important potential flaw. However, at the University of Pittsburgh we experienced pressure to decrease length of stay quite early, beginning in our department in 1992. That is one reason we includ- ed potential same-day discharge in both arms of the study.
Dr. Jeffrys A. Ma&e (Greenville, S.C.). I routinely do not do sestamibi scans. I have been doing Dr. Irvin’s intraoperative parathormone assay for more than a year now and presented a paper on 61 patients during a year’s period of time, and I am adding to that. The beauty of this particular assay is that it works so good in hyperplas- tic disease and double adenomas, or whatever you want to call patients with multiglandular disease. In my group of patients we had a 13% incidence of multiglandular disease. Initially, I was getting frozen sections in addition to my intraoperative assay. I have stopped doing frozen sections on single gland disease, which saves a consider- able amount of cost to our hospital. A frozen section costs about $200, and you probably get two of those if you don’t do the intraoperative parathormone assay. An additional saving of $1300 will be for the sestamibi scan that I don’t do except for reoperations.
Dr. Carty. We continue to rely on frozen section con- firmation of parathyroid tissue. To sum up, what we
1116 Cutiy et al. surgery December 1997
teach our residents is that this strategy is not something they should advocate on their oral boards or intend to perform when they are first starting out or until they are specializing in endocrine surgery. What we tell our resi- dents is that the results are comparable, and that we use sestamibi scanning and quick parathormone together because the results of sestamibi scanning tell you where to start operating and quick parathormone tells you when you can stop.
Dr. George S. Leight (Durham, N.C.). Just a quick comment about one of the technical aspects. You men- tioned that you used samples from the internal jugular vein. Our practice has been to use a peripheral sample. The few times when we have not had good access and have had to use jugular vein samples, the baseline mea- surement seemed to be wildly variable. Have you had any problem with that? We have been happier using a periph- eral sample.
Dr. Carty. We have not had any variability even when switching to the contralateral internal jugular vein. We always get the baseline level after dividing the median raphe and before beginning any thyroid mobilization or parathyroid dissection. Using the internal jugular vein is convenient because you are right there; it is so much eas- ier to just draw it yourself than to wait for the anesthesi- ologist or to have to prep out the arm.
Dr. Robert Udelsman (Baltimore, Md.). This is an interesting study. I am concerned that you have estab- lished length of stay as one of your end points, but the
experimental design is biased. One group by definition has an overnight length of stay, whereas the other group is able to be discharged on the same day. Therefore I think it is not a fair comparison in your end-point analysis.
Dr. Carty. How would you do it differently? Both groups were candidates for same-day discharge if unilat- eral exploration had been done, and this occurred much less frequently using Strategy A.
Dr. Udelsman. My point is if you are using length of stay as an end point and by definition one group will always stay longer, of course that group is going to have a longer length of stay. If that translates into increased costs, then the design is biased. It is a predictable out- come not based on your findings at operation but predi- cated by the fact that once you do a bilateral exploration those patients have to stay overnight.
Dr. Carty. We did not define our study groups in terms of length of stay but in strict terms of differing pre- operative and intraoperative strategy. To me, our assumption that unilaterally explored patients could be safely discharged the same day was a leap of faith, even a potential flaw. However, the decision was borne out by our results, which showed that patients who did experi- ence symptomatic postoperative hypocalcemia were in group A with a high rate of bilateral exploration. On the basis of safety concerns, it was an assumption at the beginning of the study that bilaterally explored patients required an overnight stay; this notion may be chal- lenged by subsequent investigations.
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