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Using rapid PTH assay in the OR: it’s about time

October 2004
Karen Lusky

The evidence is on the table for intraoperative rapid immunoassay of parathyroid hormone: The test saves money and improves patient outcomes in surgery for primary hyperparathyroidism, according to new draft laboratory practice management guidelines.

The draft guidelines of the National Academy of Clinical Biochemistry recommend that surgeons routinely use intraoperative parathyroid hormone testing for initial surgery and reoperation for primary hyperparathyroidism and strongly recommend its use in minimally invasive and directed procedures.

Primary hyperparathyroidism is most commonly due to a benign adenoma (or adenomas) or hyperplastic glandular tissue that over-secretes PTH, which leeches calcium from the bones into the bloodstream. People with the condition thus develop chronic hypercalcemia and can suffer from renal calculi, gastrointestinal discomfort, bone and joint pain, osteoporosis, and fractures.

Surgery cures primary hyperparathyroidism in 90 to 95 percent of cases, even without intraoperative parathyroid hormone monitoring. Yet use of intraoperative PTH testing allows the surgeon to perform laparoscopic-type surgery with small incisions or radioisotope-directed surgeries, says James Nichols, PhD, DABCC, FACB, who chaired the NACB coordinating committee for developing evidence-based guidelines for point-of-care testing, including rapid PTH. "Without the testing," he notes, "surgeons have to do exploratory, usually bilateral, surgery where they open the neck on both sides."

The rapid PTH test lets surgeons know in almost real time when they have removed all of the abnormally secreting parathyroid tissue, thereby saving the patient from additional time in surgery. The approach works because "PTH has a half-life of less than five minutes, so you see a rapid decrease of the hormone once the surgeon has excised the abnormal tissue," says Lori Sokoll, PhD, chair of the NACB focus committee that developed the guidelines, in a presentation on evidence-based practice for POC testing at the annual American Association for Clinical Chemistry meeting in July.

A drop in PTH of 50 percent or more 10 minutes post-resection signals success in removing the abnormally secreting parathyroid tissue.

The NACB draft guidelines don’t say yeah or nay to the use of intraoperative PTH testing for surgery to treat secondary or tertiary hyperparathyroidism.

Although numerous case series suggest a role for intraoperative PTH monitoring during surgery for secondary or tertiary hyperparathyroidism, the studies lacked control groups of patients that did not receive intraoperative PTH testing. "In addition," the draft guidelines state, "criteria for expected changes in PTH concentrations following total or subtotal parathyroidectomy require further study."

The draft guidelines are also neutral on using intraoperative PTH testing in surgery for parathyroid carcinoma, which occurs in five in 100,000 cases of hypersecretion of PTH.

The NACB committee developed the guidelines for intraoperative PTH testing by following strict criteria for grading evidence and choosing articles to use as the basis for recommendations, says Dr. Sokoll, who is associate director of the Division of Clinical Chemistry at Johns Hopkins Medical Institutions. Grade I evidence comes from properly randomized controlled studies—and the highest recommendation is an ’A’ or language where the NACB strongly recommends a practice, which the draft guidelines do for use of intraoperative PTH testing in minimally invasive and directed surgeries for primary hyperparathyroidism.

The committee is seeking comments on the guidelines for rapid PTH testing and guidelines for other point-of-care tests posted on its Web site (www.nacb.org). "While the guidelines are based on the evidence available in the literature, someone may point out articles or interpretation of evidence that the committee overlooked," Dr. Sokoll told CAP TODAY in an interview.

The point of POC parathyroid testing isn’t so much to improve the surgical cure rate for primary hyperparathyroidism. The biggest benefits come from the lower costs and risks associated with less invasive surgery.

To achieve a 90 to 95 percent cure rate without using intraoperative PTH testing, surgeons have to do a bilateral neck dissection to inspect all four parathyroid glands and obtain biopsies, says Alan Remaley, MD, PhD, of the National Institutes of Health Department of Laboratory Medicine, and a member of the NACB committee that developed the intraoperative PTH guidelines.

The exploratory surgery can leave patients with noticeable scars, especially those who undergo reoperation. And it increases the odds of a rare but dreaded complication: damage to the recurrent laryngeal nerve, which can cause permanent difficulty speaking.

The majority of the articles the NACB committee reviewed showed that intraoperative PTH testing, typically incorporated with other techniques, such as preoperative imaging, saves institutions money, primarily by decreasing the length of hospital stay, Dr. Sokoll says. Performing minimally invasive parathyroid surgery on an outpatient basis introduces major savings, she adds.

Without intraoperative PTH testing, surgeons have to rely on preoperative studies to localize hypersecreting parathyroid tissue, frozen sections (to see if they have removed parathyroid tissue), and sometimes gut instinct and luck to completely remove abnormal parathyroid tissue. That surgical feat becomes even more difficult in cases involving multiple adenomas, four-gland hyperplasia, or parathyroid tissue in ectopic locations.

At the University of Tennessee Medical Center, Knoxville, use of intraoperative PTH testing has lowered the rate of repeat parathyroid surgeries. Before it implemented the testing, the hospital had an 85 percent success rate in completely excising parathyroid tumors in a case mix of 90 percent adenomas and 10 percent parathyroid hyperplasia, says Pennell Painter, PhD, director of laboratory operations for the LabCorp/Dynacare Tennessee Laboratory at the medical center. After it implemented the testing, the success rate jumped to 100 percent, even though 33 percent of the hospital’s parathyroid surgical cases now represent the more difficult hyperplasia variety (the remaining 67 percent are adenomas).

Clear evidence also shows the rapid PTH assay has utility in reoperation to remove abnormal tissue left behind in a previous surgery, according to the draft guidelines. "Five to 10 percent of patients may fail the first surgery," Dr. Remaley says, noting that the NIH, which has been using intraoperative PTH testing since 1998, receives many referrals for patients who remain hypercalcemic after one or more surgeries for primary hyperparathyroidism.

In cases requiring reoperation, "the parathyroid tissue has sometimes over- or undermigrated from its embryonic position to a position in the adult that’s high [behind the neck or behind the ear] or low [in the chest cavity] compared to its normal location," Dr. Remaley says. The patient requiring reoperation may have ectopic or supernumerary glands. "Most people have four glands, but some have five, or they have some abnormal anatomy—or a patient may have double adenomas," he adds.

Optimal surgical outcomes in initial or subsequent surgeries for primary hyperparathyroidism can’t be achieved by rapid intraoperative PTH testing alone. Radiologists help map abnormal parathyroid glands preoperatively using an assisted radiological test or by drawing blood from various parts of the neck for testing with a rapid PTH assay.

For example, the University of Tennessee Medical Center uses technetium99-sestamibi radioisotopic imaging preoperatively to identify the approximate location of the abnormal parathyroid tissue. "Then during surgery, a Neoprobe detects the highest concentration of radioactivity to localize the overactive parathyroid gland, which the surgeon then removes with minimal radio-guided surgery," Dr. Painter says. The surgeons use intraoperative PTH testing to see if they have removed all of the abnormal tissue.

Patients whose noninvasive imaging studies prove inconclusive may be referred for selective venous sampling with rapid PTH analysis and arteriography to locate the abnormal parathyroid tissue. Using this approach, the laboratory runs repeat rapid PTH tests on specimens collected from catheterized veins in the neck and mediastinum. "[The rapid testing] lets the radiologist know in almost real time if he or she is getting warm, cold, or hot in locating the abnormally secreting tissues," Dr. Remaley says.

Before rapid PTH testing was used at NIH, he adds, radiologists there would collect 40 samples, and the results would not be available until the next day.

The draft NACB guidelines recommend using rapid PTH measurements for venous localization of hyperfunctioning parathyroid glands in the angiography suite but not during surgery, notes Dr. Sokoll. "Further research could determine," she says, "whether an intraoperative approach to venous localization of abnormal parathyroid tissue is superior to preoperative imaging or adds to it—and, if so, identify the patient population most appropriate for its use."

The studies the NACB committee reviewed were performed using intraoperative intact PTH assays that can cross-react with fragments of biologically inactive parathyroid hormone (amino-terminally truncated PTH fragments) in addition to the full-length PTH molecule. (An automated biointact PTH assay for intraoperative use that measures only biologically active parathyroid hormone is now available.)

The NACB found no evidence that any of the several intraoperative intact PTH assays in use are superior, including the Nichols Quick-Intraoperative Intact PTH assay, which was the first one approved by the Food and Drug Administration in the mid-1990s. According to the draft guidelines, "Two small studies in parathyroidectomy patients, one comparing the Nichols assay and the Immulite Turbo assay (n=10) and another comparing Nichols to the Elecsys 1010 intact PTH assay (n=13), showed complete diagnostic agreement."

The NACB committee did recommend additional studies on the usefulness of the biointact or whole PTH assay, which doesn’t cross-react with inactive PTH fragments. The latter compose 20 to 25 percent of total PTH and accumulate in renal failure. Only Nichols Institute Diagnostics currently offers the biointact rapid PTH assay.

The cost of rapid PTH assays has decreased significantly since the Nichols Quick-Intraoperative Intact PTH assay was introduced, says Kent Lewandrowski, MD, director of the core lab at Massachusetts General Hospital, which began offering intraoperative PTH monitoring last April. "The intraoperative PTH matches clinically the values one can achieve with routine PTH testing," he adds.

Outcomes of studies using intraoperative PTH testing in surgery for primary hyperparathyroidism can vary based on when samples are drawn for testing and the criteria for expected change in PTH value. Based on current evidence, the NACB committee recommends obtaining baseline specimens before the operation/exploration and before the suspected hyperfunctioning glands are excised.

The surgical team should then draw specimens for PTH testing five and 10 minutes after resection. A 50 percent reduction in PTH concentrations from the highest baseline indicates the abnormal tissue has been removed. Additional samples may be necessary, according to the guidelines.

But Dr. Remaley notes that it can sometimes be difficult logistically to draw a specimen at five and 10 minutes after the tissue is removed. "And there hasn’t been a good study to look at the effect of drawing the specimen at different times," he says.

Dr. Remaley and Steven Libutti, MD, of the National Cancer Institute, have proposed a kinetic analysis model to predict the success of parathyroid surgery based on the rate that PTH decays. While rigid timing of samples isn’t required using this approach, Dr. Remaley believes the model is "probably too complicated for people to use in a practical sense, so the committee’s recommendation is to stick with the guidelines."

In Dr. Painter’s view, health care systems that intend to do intraoperative PTH testing need to think through what the plasma PTH values will look like when the tumor is removed. "The PTH values drop rapidly if surgery is successful, but if the surgeon doesn’t get all of the abnormal tissue out, the PTH may go up because the surgeon is cutting through the parathyroid gland or stimulating it by cutting around it," he says.

Mass General medical technologists who perform intraoperative PTH testing were shocked when they encountered a patient with a pre-excision PTH of 100 one month before the operation and then found the first sample to be 4,600. "It turns out the pre-excision sample was drawn close to the adenoma, which the lab hadn’t experienced yet," Dr. Lewandrowski says.

The University of Tennessee Medical Center has plotted the PTH values in various surgical cases and found that "the percentage by which the PTH level drops after complete removal of hyperactive parathyroid tissue depends on how long the surgeon waits after removing the tissue to draw the sample," Dr. Painter says. "If the surgeon waits 15 to 20 minutes, you might see a 70 percent drop," he adds. "That’s one of the things that people will be modeling out and eventually will settle on in terms of when most surgeons can expect the best outcome in terms of how long they wait to draw the specimen during surgery to look for the drop in PTH."

As for where on the patient to draw samples for intraoperative PTH testing, "the majority of published studies used samples drawn from peripheral veins as opposed to internal jugular veins," Dr. Sokoll says. "But that represents more of a practice than a defined guideline, as the committee didn’t find studies specifically looking at sampling sites."

In Dr. Remaley’s view, a peripheral vein is the best site for drawing specimens. At the NIH, "usually the OR staff will put in a venous line and draw the specimen from that," he says. "If you draw in the arm, you get the average blood concentration of PTH, but if you draw blood near the parathyroid, it may be higher, especially if the gland was manipulated in some way during the surgery."

The University of Tennessee Medical Center has found that drawing specimens from the same site on the patient produces the most accurate comparison of the baseline and subsequent values. Dr. Painter cautions that "intraoperative PTH isn’t like a common lab test where you use set values—the subsequent PTH results must be compared to your first baseline result."

Does intraoperative PTH measurement performed in or adjacent to the operating room improve turnaround and operative times compared with testing in the central lab?

Although one might assume closer would be faster, no studies have been conducted to confirm that. And regardless of the evidence, turnaround times would be "institution specific" depending on the assay used, the distance from the OR to the lab, and the mode of transportation to the central lab, according to the draft guidelines.

Thus, "the decision of whether to do the testing in the OR, a satellite location, or in the central laboratory is one that the laboratory should make in consultation with the surgical staff," Dr. Sokoll says.

When Mass General implemented rapid intraoperative PTH testing earlier this year, the laboratory weighed the pros and cons of doing the test in the OR suite versus its blood gas lab near the operating room. Says Dr. Lewandrowski: "Operationally, we thought it would be more difficult to train the doctors and nurses to use the device, which is a complex test, than for trained medical technologists to perform it in the laboratory. So MGH opted to set up the testing in the blood gas lab." Nurses send specimens to the blood gas lab via a pneumatic tube system.

James Flood, PhD, who heads up the clinical chemistry laboratory at Mass General, says surgeons are pleased with the test but would like a little faster turnaround from the lab. "Right now, we are producing the results within 19 to 20 minutes from the draw, but once the specimen hits the lab, the fastest you can do it in is 13 minutes," he says. "And we are hitting that 80 percent of the time. So there’s an extra six minutes getting lost as the specimen makes its way to the lab, and we are looking at improving that."

The University of Tennessee Medical Center also does intraoperative PTH testing in the central lab and transports specimens from the OR using a direct pneumatic tube system. "The surgeon is very frequently in the lab when the test results come off the analyzer and is very knowledgeable about how the test is done," Dr. Painter says.

In the opinion of Frank Wians Jr., PhD, of the University of Texas Southwestern Medical Center, Dallas, who is a member of the committee that wrote the guidelines, intraoperative PTH testing is likely to move into the OR in the future as part of what he sees as an emerging trend toward use of more rapid hormone assays to direct surgery. A number of homebrew rapid hormone assays are now available, including tests for adenocorticotropic hormone, cortisol, gastrin, growth hormone, insulin, and testosterone, with applications for intraoperative monitoring during resection and diagnostic localization.

In the meantime, health care systems and laboratories that routinely use intraoperative PTH monitoring will have to grapple with the resulting shift in care and revenue streams.

For example, intraoperative PTH monitoring may phase out the use of frozen sections during parathyroid surgery, which surgeons order to confirm that they have removed parathyroid tissue and to differentiate parathyroid adenomas from hyperplasia. "Frozen sections are a static measure . . . they don’t tell you anything about the function of the parathyroid gland," unlike intraoperative PTH testing, Dr. Sokoll said in her AACC presentation.

Dr. Remaley says studies show the frequency of frozen sections declining with use of intraoperative PTH testing. "The pathologist still looks at the tissue postoperatively on permanent sections, but the question is: Do you need a pathologist in the OR to do a frozen section and try to make a diagnosis within one hour? That’s probably not necessary," he says. Parathyroid carcinoma is rare and often difficult to diagnose definitively based on frozen sections.

(Upcoming NACB guidelines, which may be released by year-end, will recommend diagnostic tests to help identify the cause of hyperparathyroidism preoperatively, including gene mutations strongly linked to parathyroid gland carcinoma, says Dr. Wians, who is helping to develop the guidelines. By doing the testing preoperatively, clinicians can identify patients who are candidates for a biopsy and resection of a parathyroid tumor.)

Since intraoperative PTH testing became available at Mass General, surgeons have been requesting "fewer and fewer frozen specimens of the parathyroid tissue, which are expensive and time-consuming," Dr. Lewandrowski says.

Deciding what’s medically necessary, cost-effective, and desirable is difficult, he admits, but the rapid PTH test passes what Dr. Lewandrowski calls the "ultimate benchmark"—that is, the "mother" or "self-test." That’s where you consider whether you’d want the surgeon to use intraoperative PTH monitoring if the patient were your mother or if you were the patient.

"And the answer will usually be yes," he says.

Karen Lusky is a writer in Brentwood, Tenn. Readers may wish to consult a recent article by Drs. Sokoll, Wians, and Remaley titled "Rapid Intraoperative Immunoassay of Parathyroid Hormone and Other Hormones: A New Paradigm for Point-of-Care Testing." ClinChem. 2004;50:1126-1135.