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Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy.



Surgical treatment of patients suffering from biochemically confirmed primary hyperparathyroidism primary hyperparathyroidism Parathyroid related hypercalcemia Endocrinology Parathyroid gland hyperactivity with excess PTH secretion because of hyperplasia or adenoma of 1 or more glands Clinical Calcium deposits may occur in bone, the GI tract, kidney, muscle,  (pHPT) [3] is undergoing an evolution. The traditional surgical approach visualizing all four parathyroids and resecting the apparently enlarged gland(s) has been increasingly replaced by minimally invasive (unilateral) surgical procedures Surgical procedures have long and possibly daunting names. The meaning of many surgical procedure names can often be understood if the name is broken into parts. For example in splenectomy, "ectomy" is a suffix meaning the removal of a part of the body. "Splene-" means spleen.  aided by preoperative pre·op·er·a·tive
adj.
Preceding a surgical operation.



preoperative

preceding an operation.


preoperative care
the preparation of a patient before operation.
 imaging and intraoperative rapid parathyroid hormone parathyroid hormone or parathormone, a hormone secreted by the parathyroid glands that regulates the metabolism of calcium and phosphate in the body.  (PTH PTH
abbr.
parathyroid hormone


Parathyroid hormone (PTH)
A chemical substance produced by the parathyroid glands. This hormone is a major element in regulating calcium in the body.
) measurements (1-8). In most cases, the improved imaging techniques enable exact preoperative localization Customizing software and documentation for a particular country. It includes the translation of menus and messages into the native spoken language as well as changes in the user interface to accommodate different alphabets and culture. See internationalization and l10n.  of the parathyroid adenoma parathyroid adenoma A benign tumor of the parathyroid, which may be functionally active.  (9). PTH monitoring during the surgical procedure can confirm the removal of all hyperfunctioning parathyroid parathyroid /par·a·thy·roid/ (-thi´roid)
1. situated beside the thyroid gland.

2. see under gland.


par·a·thy·roid
adj.
1.
 tissue as the half-life of intact (1-84) PTH is short. An insufficient decrease in PTH indicates persisting pHPT, leading to more extended (bilateral) exploration within the same session. Although PTH monitoring ignores possible changes in the physiologic state of the patient during surgery (e.g., changes of clearing rate) and is deemed invalid if the volume is expanded by intraoperative infusions, it helps to reduce the frequency of repeat surgery.

Measurement of PTH has also undergone evolution. The early generation of PTH RIAs was restricted to N-terminal, midregion, or C-terminal fragments, all of which circulate in high concentrations as they are cleared slowly (10, 11). By use of two monoclonal antibodies specific for the N- and C-terminal regions of the hormone (12), rapid measurement of intact (1-84) PTH became feasible. The sensitivity of tests was further improved by replacement of radiolabels with chemiluminescent chem·i·lu·mi·nes·cence  
n.
Emission of light as a result of a chemical reaction at environmental temperatures.



chem
 groups. Special assay formats allow rapid detection within 15 min, a time-span suitable for intraoperative PTH monitoring (2). To test whether automated analysis by a new generation of assays provides reliable results, we compared two recently developed methods running on immunoassay Immunoassay

An assay that quantifies antigen or antibody by immunochemical means. The antigen can be a relatively simple substance such as a drug, or a complex one such as a protein or a virus.
 analyzers with an established manual assay for quick PTH.

Commonly, a 50% decrease versus baseline PTH 5-10 min after resection of the suspected parathyroid adenoma indicates "cure" (1). However, the definition of this "baseline" seems vague, especially as plasma PTH is markedly influenced by surgical manipulations during preparation of the affected gland(s). In addition, the recommendation does not account for interindividual variability of PTH half-life and residual concentration (13). We evaluated these crucial factors by two kinetic models and addressed several questions: (a) Which model fits better to the PTH results and which starting concentration is relevant for kinetic calculations (the preoperative baseline or the PTH concentration just at adenectomy)? (b) Do the assays produce comparable kinetic results and is there an advantage in using automated PTH analyses? (c) Can intraoperative kinetic calculations support the assessment of PTH patterns?

Patients and Methods

PATIENTS

To date, minimally invasive parathyroidectomy Parathyroidectomy Definition

Parathyroidectomy is the removal of one or more of the parathyroid glands. The parathyroid glands are usually four in number, although the exact number may vary from three to seven.
 has been performed at our institution (9) in >170 patients suffering from pHPT. Patients gave informed consent for surgery and blood collection via an extra catheter. All operations were performed by the same surgeon (B.N.). We report here on 20 consecutive patients (18 females and 2 males; mean age, 57.8 [+ or -] 12.1 years) with single-gland disease. Renal failure renal failure
n.
Acute or chronic malfunction of the kidneys resulting from any of a number of causes, including infection, trauma, toxins, hemodynamic abnormalities, and autoimmune disease, and often resulting in systemic symptoms, especially edema,
 was excluded in all these patients. Adenomas were localized preoperatively by high-resolution ultrasound and by [sup.99m.Tc]-sestamibi scans with single photon emission computed tomography single photon emission computed tomography
n. Abbr. SPECT
Tomographic imaging of local metabolic and physiological functions in tissues.
. Blood was collected before skin incision (preoperative baseline concentration), at the time of adenoma adenoma: see neoplasm.  resection, and thereafter at intervals coming or happening with intervals between; now and then.

See also: Interval
 of 5 min (0, 5, 10, and 15 min). The surgeon asked for additional blood samples from some patients (e.g., in case of prolonged adenoma preparation or a slow decrease in PTH); the exact time points of these samples were documented. Blood specimens were centrifuged for 1 min in Eppendorf cups and subsequently analyzed.

Success of surgical intervention was judged by an intraoperative PTH decrease (at least 50% within 10 min after adenectomy) related to the preoperative baseline PTH. In case of atypical PTH increase until adenectomy, a later sample was collected for confirmation. Parathyroid tissue was examined histologically. At 1 year after operation, calcium was normal in all patients.

ANALYTICAL METHODS AND ORGANIZATION

Two chemiluminescence chemiluminescence /chemi·lu·mi·nes·cence/ (kem?i-loo?mi-nes´ens) luminescence produced by direct transformation of chemical energy into light energy.  immunoassays [Quick-IntraOperative[TM] intact PTH (Nichols Laboratories) and TurboPTH-intact (Diagnostic Products Corporation; DPC DPC Department of Premier and Cabinet (Victoria, Australia)
DPC Dutch Power Cows
DPC Deferred Procedure Calls (Microsoft Windows NT 4.
)] and one electrochemiluminescence method (intact-PTH; Roche-Diagnostics were used for rapid PTH measurements. All assays had been evaluated previously (18,14-16) and are approved by the US Food and Drug Administration. The manual assay by Nichols was carried out with the "QuiCk-Pack" system from Nichols Laboratories. If the CV of duplicates exceeded 10%, the sample was reanalyzed. The DPC assay was performed on the Immuno-1 automated analyzer (DPC). The Roche intactPTH test was performed on an Ele[c.sub.s] ys-1010 immunoassay analyzer (Roche Diagnostics Roche Diagnostics Division is a subsidiary of Hoffmann-La Roche which manufactures equipment and reagents for research and medical diagnostic applications. Internally, it is organized into six major business areas: Roche Applied Science, Roche Centralized Diagnostics, Roche  with its "Stat-function". Single determinations were sufficient with automated methods, because CVs of duplicates were <4%. Instruments maintenance and test calibration were performed in the main laboratory.

The analytical instruments and other laboratory tools were transported on trolleys to the operating theater, where control samples were reanalyzed. Ten patients were monitored intraoperatively with the Nichols test and another 10 with the Roche test. Direct contact was always possible between surgical and analytical teams because samples were processed in a preparation room adjacent to the operating theater. However, there was too little space for two trolleys; thus, immediate comparative analyses with the other tests were performed in the main laboratory on sample aliquots transported in an ice bath. Although the DPC analyzer could have been transported on a large trolley, for organizational reasons the comparative data on the DPC assay were collected retrospectively from samples stored at -80 [degrees]C. Marked influence of one freezing/thawing had been excluded in a pre-experiment.

Assay precision was determined by use of control samples supplied by the respective companies. Day-today CVs (n = 12) were 17% (37 ng/L) and 9% (251 ng/L) for the Nichols, 11% (84 ng/L) for the DPC, and 7% (at 54 and 169 ng/L) for the Roche EL1010, respectively. Intraassay CVs (n = 6) were 9% and 7% (Nichols), 6% (DPC), and 4% and 3% (Roche) at the control sample concentrations indicated above.

METHOD COMPARISONS AND STATISTICS

Method comparisons (17) were calculated from 109 samples, and individual comparisons for each patient were calculated as well (5-10 samples per patient). Significance of differences (P <0.05) was evaluated by ANOVA anova

see analysis of variance.

ANOVA Analysis of variance, see there
 and the Tukey-Kramer post-test.

KINETIC ANALYSES

Intraoperative PTH half-life and the residual concentrations were calculated by two kinetic models by use of Microsoft Excel (tool) Microsoft Excel - A spreadsheet program from Microsoft, part of their Microsoft Office suite of productivity tools for Microsoft Windows and Macintosh. Excel is probably the most widely used spreadsheet in the world.

Latest version: Excel 97, as of 1997-01-14.
 on a personal computer. Model A was recently published by Libutti et al. (13) and describes relief of the total suppressed PTH secretion from healthy glands after adenectomy. In this model (Fig. 1, top), the exponential decay Noun 1. exponential decay - a decrease that follows an exponential function
exponential return

decay, decline - a gradual decrease; as of stored charge or current
 of PTH from the adenoma (concentration [c.sub.t] = [c.sub.0][e.sup.-kt], where t is time, [c.sub.0] is the concentration at t = 0, and k is the rate constant of decay) is superimposed by a time-dependent additive concentration ([c.sub.m] = [c.sub.t] + [Delta][c.sub.t], where [c.sub.m] is the measured concentration at time t and [Delta][c.sub.t] is the additive concentration at time t). This additive concentration stems from the healthy glands, which recover PTH secretion, and is a function of a constant residual PTH concentration R, which is calculated according to according to
prep.
1. As stated or indicated by; on the authority of: according to historians.

2. In keeping with: according to instructions.

3.
 Libutti et al. (13) (Eqs. 3 and 4) by:

R = [[Delta]c.sub.t] (2.sup.kt/ln2) / [2.sup.kt/ln2] - 1

thus:

[[Delta]c.sub.t] = R - [Re.sup.-kt]

Because [[Delta]c.sub.t] = [c.sub.m] - [c.sub.0][e.sup.-kt], the equation may be expressed as:

R = [C.sub.m][e.sup.kt] - [C.sup.0] / [e.sup.kt] - 1 (1)

and solved for k:

k = ln[([c.sub.0] - R)/([c.sub.m] - R)] / t (2)

For iterative calculations, Libutti et al. (13) used a preoperative baseline PTH concentration (instead of a true [c.sub.0]); [c.sub.1] and [c.sub.2] were the concentrations 5 and 10 min after adenectomy. Briefly, k (Eq. 2) was approximated in a first iterative step from [c.sub.0] and [c.sub.1] by assuming R = [c.sub.2] . This estimated k value and [c.sub.2] were used to calculate a new R (Eq. 1), which made calculation of a better fitting k value possible, and so forth. After reaching convergence, the half-life was [t.sub.l/2] = 1n2/k. We performed additional calculations by choosing [c.sub.0] at the time of adenectomy as well as for [c.sub.3] at 15 min.

[FIGURE 1 OMITTED]

We developed a second model, basing it on the assumption that the healthy glands were not totally suppressed and secreted constant concentrations of PTH ([rho]) during surgery, adding to the exponential decay of PTH from the removed adenoma (model B; Fig. 1, bottom). Because an exponential decay follows a constant percentage of decrease per identical time intervals (i; e.g., 5 min), the measured concentration [c.sub.m] has to be corrected for [rho]:

[C.sub.m] i + 1 - [rho]/[C.sub.m]i - [rho] = a = constant (3)

We set up a matrix (Eq. 4) for calculating the intercept (b) and the slope (a) of a linear regression Linear regression

A statistical technique for fitting a straight line to a set of data points.
 line: y = ax + b.

[MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII ASCII or American Standard Code for Information Interchange, a set of codes used to represent letters, numbers, a few symbols, and control characters. Originally designed for teletype operations, it has found wide application in computers. ] (4)

where [C.sub.m0] is the PTH concentration at adenectomy.

Combining Eqs. 3 and 4 yields p = (ax - y)/(a - 1). Because a = (y - b)/x, the residual concentration p was calculated (Eq. 5) from the slope and the intercept of the regression line Noun 1. regression line - a smooth curve fitted to the set of paired data in regression analysis; for linear regression the curve is a straight line
regression curve
 (Fig. 1, inset for model B)

[rho] = -b / (a - 1) (5)

All measured PTH concentrations were corrected for the residual PTH concentration, followed by an exponential regression analysis In statistics, a mathematical method of modeling the relationships among three or more variables. It is used to predict the value of one variable given the values of the others. For example, a model might estimate sales based on age and gender. : ln([[c.sub.m] - [rho]) = a't + b'. The decay constant decay constant
n.
Symbol The constant ratio for the number of atoms of a radionuclide that decay in a given period of time compared with the total number of atoms of the
 was k = -a', and the approximated PTH concentration at adenectomy was [C.sub.0app = e.sup.b'].

Results

The performance and costs of the Nichols, DPC, and Roche tests for rapid PTH differed. The turnaround time from starting the analysis until print-out of results was 16 min for the DPC, 14 min for the Nichols, and 10 min for the Roche assay. Approximately 4 min had to be added to all methods for sample collection, transport to the adjacent room, and centrifugation Centrifugation

A mechanical method of separating immiscible liquids or solids from liquids by the application of centrifugal force. This force can be very great, and separations which proceed slowly by gravity can be speeded up enormously in centrifugal
 when the assay was performed at the site of surgery. Although each assay may be performed by a single person, the Nichols manual method was carried out by two technicians because there was a need for exact time-shifted manipulations. All analytical systems were leased. The costs of reagents per test for the DPC and Roche were 12% and 4%, respectively, of the Nichols test costs. Depending on contracts with the companies, costs may be different for other hospitals. Recently, a detailed cost analysis was presented that included working time and auxiliary costs (18).

[FIGURE 2 OMITTED]

Correlation analyses for PTH from 109 samples yielded the following equations: DPC = 1.07(Nichols) - 12 ng/L (r = 0.95; [S.sub.y|x] = 26 ng/L) and Roche = 1.16(Nichols) - 2.8 ng/L (r = 0.98; [S.sub.y|x] = 16 ng/L). Deviations between the assays became more obvious when comparability was tested for each patient (Fig. 2). The slopes of the individual regression lines were between 0.56 and 1.67, and their intercepts were between -98 and 17 ng/L (Nichols vs DPC, r = 0.92-1.0; [S.sub.y|x] = 1.8-43 ng/L). Comparisons between Nichols and Roche analyses produced individual slopes from 0.60 to 1.32 and intercepts from -59 to 27 ng/L (r = 0.96-1.0; SyjX = 1.2-20 ng/L).

We next investigated how these discrepancies influenced the calculation of PTH elimination kineti[c.sub.s] . Table 1 summarizes the kinetic results obtained from models A and B for the three assays. Model A was applied to data from the preoperative baseline and 5 and 10 min, as suggested by Libutti et al. (13). Use of the PTH at adenectomy instead of the preoperative baseline led to lower residual concentrations (significant for DPC and Roche) and significantly longer half-lives with all assays (mean, 1.8 vs 3.7 min). However, model A calculations led to nonsensical results for 11 patients because of unreasonably high negative residual PTH concentrations and prolonged half-lives. Model B (PTH at adenectomy and 5, 10, and 15 min) produced meaningful results for all 20 patients and assays. Lower residual PTH values were produced by the DPC (mean, 15 ng/L; range, 1-46 ng/L) and Nichols (mean, 20 ng/L; range, 0-79 ng/L) assays than by the Roche assay (mean, 27 ng/L; range, 0-89 ng/L). The mean half-life was 3.7 [+ or -] 1.4 min (range, 1.8-6.0 min) with the DPC, 4.0 [+ or -] 1.6 min (range, 1.8-7.7 min) for the Nichols, and 4.3 [+ or -] 1.6 min (range, 2.4-8.1 min) for the Roche assay. Differences in residual PTH and half-lives were significant only between the DPC and Roche assays.

[FIGURE 3 OMITTED]

Considering whether these differences in kinetic results are clinically relevant, we first inspected the intraoperative PTH patterns. Shown in Fig. 3 are the results when we used the Nichols PTH assay as an example. The time intervals between starting anesthesia and adenectomy ranged from 20 to 77 min, and the average preparation time of the adenoma was 38 min. In 14 of 20 patients, PTH concentrations decreased until adenectomy (Fig. 3A), but 6 patients presented with an atypical PTH surge during adenoma preparation (Fig. 3B).

[FIGURE 4 OMITTED]

Interestingly, up to one-half of the patients with a decrease in PTH during adenoma preparation (n = 14) already exhibited a PTH <50% of the preoperative baseline value at the time of adenectomy (Table 2). Within 10 min, all 14 of these patients fulfilled the criteria for cure (PTH decrease >50% of preoperative baseline value), irrespective of irrespective of
prep.
Without consideration of; regardless of.

irrespective of
preposition despite 
 the assay. The results from the six patients with an atypical PTH surge during preparation differed. The DPC PTH assay was the only test that predicted cure at 10 min for all patients. It took 15 min until the Roche PTH was <50% of the preoperative baseline in patients with a transient PTH surge. The Nichols assay failed to predict a cure at 15 min in one case, and samples had to be obtained at later time points to confirm surgical success.

In contrast to the measured PTH values, the calculated residual PTH was always <50% of the preoperative baseline, apparently serving as a more precise criterion for cure (Fig. 4). Furthermore, residual PTH had dropped below the upper reference limit (65 ng/L PTH) for all but two patients with the Nichols assay (74 and 79 ng/L) and in one of them with the Roche test (89 ng/L). Results were available from these two patients at later time points. When these results were added for recalculations, all residual PTH concentrations were within the reference interval (not shown). Cure of all patients was confirmed by their 1-year outcome of normocalcemia.

Discussion

Rapid intraoperative PTH monitoring serves as a "biochemically frozen section" (2) and has become an important prerequisite for minimally invasive parathyroidectomy. Major experience has been gathered with the manual Nichols test that was compared with automated assays from DPC and Roche. In principle, the entire analytical system may be transported by trolley to the operating theater, but in this study the DPC analyzer was used only in the main laboratory. We recommend direct contact between surgical and analytical teams; this minimizes the time for transporting blood samples and improves communication.

Methodologic comparison among the three PTH assays produced good overall correlation; however, when we calculated regression lines for each patient, remarkable individual deviations appeared. To investigate the clinical relevance of these differences, we used two approaches: calculation of PTH elimination kineti[c.sub.s] and evaluation of criteria to predict cure by intraoperative PTH monitoring.

We retrospectively applied two kinetic models to the data obtained: Model A had already been published by Libutti et al. (13) but did not fit properly. Therefore, we established an alternative procedure (model B). Both models are based on an ideal exponential decay, superimposed by an additive value that is either a function of time ([Delta][c.sub.t]; model A) or a constant ([rho]; model B). Model A describes fast relief of healthy glands from total PTH suppression after adenectomy because of an unconfirmed assumption that the relief mathematically depends on the same rate constant (k) as the adenomatous adenomatous /ad·e·nom·a·tous/ (ad?e-nom´ah-tus)
1. pertaining to an adenoma.

2. pertaining to nodular hyperplasia of a gland.


ad·e·nom·a·tous
adj.
1.
 PTH decay. Such a "swing-off/swing-on" mechanism seems debatable during the short time frame of surgery. Similarly not verified, model B assumes a constant contribution of PTH from suppressed healthy glands, which may be a more likely condition during surgery. Despite the different suppositions, both models yield identical half-lives and residual concentrations in an ideal setting, but they differ in [c.sub.0] and the "true" PTH decay curve of the adenoma (Fig. 1).

In model A, the curve function was solved by iterations, assuming three error-free measurements (a minimum of data sets to calculate a curve); because of this rigidity, some calculations yielded nonsensical results. This model could not be used in cases without uniform decreases in PTH, e.g., in most patients with a PTH surge until adenectomy (see footnote a to Table 1). Incongruous results were observed more frequently with the Nichols PTH assay, which exhibited a greater analytical inaccuracy than the other tests. In model B, the disadvantage of requiring an additional (fourth) time point is counterbalanced by its usefulness in allowing interpolation interpolation

In mathematics, estimation of a value between two known data points. A simple example is calculating the mean (see mean, median, and mode) of two population counts made 10 years apart to estimate the population in the fifth year.
 to correct deviating curve data. In addition, the late PTH at 15 min was more reliable for calculating the residual concentration. A less skilled team has a major drawback in that the algorithm used for model B requires equally spaced (in time) blood collections, which can be overcome by calculations with Prism software (GraphPad Software Inc.). This commercial software requires entry of at least four, but arbitrarily spaced, data sets for interpolation. By appropriate program selection ("analyze/non linear regression fit/one phase exponential decay"), the half-life, the constant residual concentration (called the plateau), and [c.sub.0] (called the span) are calculated together with 95% confidence limits, a correlation coefficient Correlation Coefficient

A measure that determines the degree to which two variable's movements are associated.

The correlation coefficient is calculated as:
, and a graph. Results from calculations with model B and the software were nearly identical (not shown).

Our main complaint against the method of Libutti et al. (13) concerns the use of a preoperative baseline concentration as a surrogate for co. During minimally invasive parathyroidectomy, the manipulations by the surgeon influence the PTH concentrations until adenectomy (Fig. 3) obviously to a larger extent than with conventional techniques (19). The preparation of the affected gland within a small unilateral 1.5-[c.sub.m] skin incision may cause squeezing of the glands as a result of mobilization or untimely clamping of small vessels. Extirpation ex·tir·pa·tion
n.
The surgical removal of an organ, part of an organ, or diseased tissue.



extir·pate
 of the adenoma no doubt stopped its PTH efflux efflux Medtalk That which flows outward  into circulation, irrespective of a previous stepwise stepwise

incremental; additional information is added at each step.


stepwise multiple regression
used when a large number of possible explanatory variables are available and there is difficulty interpreting the partial regression
 clamping. The short half-life (1.7 min; range, 0.4-3.8 min) reported by Libutti et al. (13) agrees with the calculations from our data with the preoperative baseline PTH (Table 1, model A; baseline, 5, 10); apparently the decrease in PTH until adenectomy causes an underestimation of the half-life. With a two-compartment model, Maier et al. (19) calculated a PTH half-life of 3.4 min based on data from an immunoradiometric Nichols test, yielding results similar to those for model B. However, we do not abandon the procedure of Libutti et al. (13) because when it is applied to later time points, it frequently produces valid results. The calculations with the 0-, 5-, and 15-min data sets more closely matched most results obtained with model B, confirming the necessity to use [c.sub.0] at adenectomy in kinetic calculations and the benefit gained by use of a late time point. Neither model A nor B is suitable for describing complex elimination kineti[c.sub.s] (19) because of the single-compartment assumption when investigating within a short time frame.

Kinetic results from the three PTH assays differed, and the DPC assay produced a significantly shorter half-life and lower residual PTH concentrations than did the Roche assay; results from the Nichols assay were between the two. Presumably pre·sum·a·ble  
adj.
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster.
 the assays are influenced by cross-reactions in a different manner because commercially "intact" PTH assays may detect (1-84) PTH as well as non-(1-84) fragments (20, 21).

A major clinical question that presents itself is the problem as to which PTH concentration, either PTH at adenectomy or preoperative baseline, should be used for reference when calculating the 50% decrease within 10 min. No standard procedure is recommended in the literature. Although for kinetic calculations the PTH at adenectomy was shown to be superior to the concentration at t = 0, it is a different thing to estimate a sufficient PTH decrease. For several reasons, when judging the PTH decrease, the preoperative PTH value should serve as the baseline:

Case 1 (14 patients; Table 2). The decrease in PTH from the preoperative baseline to adenectomy indicates that the vessels of the affected gland have indeed been clamped before excision. Especially if PTH at adenectomy is <50% and within the reference interval, cure is indicated. PTH at 5 min should serve for confirmation, and additional monitoring may be omitted. If the PTH at excision is >50%, monitoring is required to exclude multiple gland disease. Kinetic calculations are helpful for estimating the residual PTH concentration and the patient's clearance rate. A slow decrease in PTH may also be caused by a prolonged half-life and not necessarily by additional hyperfunctioning glands. If the residual PTH is within the reference interval, monitoring may be stopped.

Case 2 (6 patients; Fig. 3B). Increasing PTH from the preoperative baseline to adenectomy originates from squeezing of the glands or the adenoma by surgical manipulations. This causes a rapid and sometimes very high efflux of PTH, which thereafter decreases (our own unpublished observation). Such a manipulation complicates the assessment of monitoring because there is an additional overlay by the PTH decay curve of the previously squeezed gland. Most likely, the rate constants (k) are identical with reference to the PTH decay from the manipulated gland as well as from the resected adenoma. Thus, assuming a constant PTH contribution from the residual bland glands ([rho]), the measured PTH is: [c.sub.m] = ([c.sub.0] + [c.sub.s)[e.sup.-kt] + [rho], where [c.sub.0] is the PTH from the adenoma at resection and [c.sub.s] is the contribution from the PTH decay of the manipulated gland at the time of adenectomy. The problem is that the ratio between [c.sub.0] and [c.sub.s] is unknown and [c.sub.0] + [c.sub.s] is the starting concentration observed when monitoring at adenectomy. In other words Adv. 1. in other words - otherwise stated; "in other words, we are broke"
put differently
, by referring only to the concentration at adenectomy, it is uncertain whether the PTH decrease reflects resection of the adenoma alone (assuming that the PTH of the manipulated gland has already come back to its presqueezed value), both PTH sources (unknown [c.sub.0]/[c.sub.s] ratio), or the manipulated gland alone (assuming that by mistake the adenoma was left in situ In place. When something is "in situ," it is in its original location.  and a bland gland was removed).

Thus, for clinical judgement, the preoperative baseline is necessary (a) to be able to distinguish between the effects of surgical preparations such as clamping of vessels or unintentional squeezing of parathyroids, (b) for estimating cure [conceivably PTH at the end of monitoring has to be much lower than before the start the operation, i.e., <50% of baseline (1)], and (c) for estimating the duration of monitoring. Prolonged monitoring may be necessary in cases with an atypical PTH surge until adenectomy (case 2) if the criterion (1) of PTH <50% within 10 min is missed, as shown in Table 2. Comparing results of intraoperative monitoring, kinetic calculation of residual PTH may help to reduce the need for expanded monitoring. Although in one case PTH at 15 min was still >50% (Table 2), all assays provided a residual PTH <50% (Fig. 4). Currently we are testing a large group of patients to determine whether calculating the residual PTH from bland glands, which we propose to be normal to below-normal values, may replace the recommended "50% criterion" (1). A more detailed discussion on the pitfalls in PTH monitoring is beyond the scope of this report and will be published elsewhere.

In conclusion, monitoring of the PTH decay appeared to be influenced by surgical manipulations during the more difficult adenoma preparation in minimally invasive parathyroidectomy. Data reduction by kinetic calculations may support assessments by providing additional information on individual half-lives and residual PTH. Kinetic estimations by interpolation of at least four data sets (model B; calculations done either by the algorithm described above or by a commercial software) are a promising alternative to exact calculations on three data sets (model A), which sometimes yield incongruous results because of deviating measurements. Preoperative baseline PTH is inadequate for kinetic calculations and must not be used as a surrogate for the concentration at adenectomy. On the other hand, estimation of cure calls for a relation to the PTH before the treatment starts (preoperative baseline). Understandably, the PTH at the end of monitoring has to be much lower than the preoperative baseline value. In our opinion, it was beneficial to monitor at the site of surgery to keep short distances between sampling as well as analyzing and transporting information. Although interindividual methods of comparing as well as calculating half-life and residual PTH concentrations revealed differences among the three assays, in clinical practice they may be neglected. Because multiple intraoperative measurements are necessary (routinely we do at least five), costs and efficiency may be the main criteria when choosing an automated assay, and it seems advantageous to use the same chemistry as for routine PTH analyses.

We greatly appreciate the skillful skill·ful  
adj.
1. Possessing or exercising skill; expert. See Synonyms at proficient.

2. Characterized by, exhibiting, or requiring skill.
 technical assistance of M. Fritz, S. Gaderer, S. Genner, A. Handler, H. Kieweg, B. Kohler, K. Rettner, C. Rbhrer, and I. Samonig. We also thank H. Reichelt, H. Ruis, and W. Rubisch for valuable discussions on interpreting the kinetic models. The study was supported by "Jubilaumsfonds der 0sterreichischen Nationalbank" Grant 9307.

Received May 6, 2002; accepted July 12, 2002.

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n.
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CHRISTIAN BIEGLMAYER, [1] * GERHARD GERHARD German Harvest Automated Retrieval and Directory  PRAGER, [1] AND BRUNO NIEDERLE [2]

[1] Clinical Institute for Medical and Chemical Laboratory Diagnosti[c.sub.s] and

[2] Department of Surgery (Division of General Surgery, Section of Endocrine Surgery), AKH Vienna, A1090 Vienna, Austria.

* Address correspondence to this author at: Clinical Institute for Medical and Chemical Laboratory Diagnostics , AKH Vienna (University Hospital), Waehringerguertel 18-20, A1090 Vienna, Austria. Fax 43-1-40400-6752; e-mail christian.bieglmayer@univie.ac.at.

[3] Nonstandard non·stan·dard  
adj.
1. Varying from or not adhering to the standard: nonstandard lengths of board.

2.
 abbreviations: pHPT, primary hyperparathyroidism; PTH, parathyroid hormone; and DPC, Diagnostic Product Corporation.
Table 1. Residual PTH and PTH half-lives calculated by different
kinetic models (n = 9 patients). (a)

                     Mean [+ or -] SD

                     Time points           Nichols

Residual PTH, ng/L

Model A              Baseline, (b) 5, 10   15  [+ or -] 22
                     0,5,10                4 [+ or -] 4
                     0,5,15                7 [+ or -] 12
                     0,10,15               9 [+ or -] 17
Model B              0,5,10,15             7 [+ or -] 12

PTH half-life, min

Model A              Baseline, (b) 5, 10   1.7  [+ or -] 0.6 (c)
                     0,5,10                3.6 [+ or -] 1.6
                     0,5,15                3.6 [+ or -] 1.2
                     0,10,15               3.7 [+ or -] 1.2
Model B              0,5,10,15             3.5 [+ or -] 1.1

                     DPC                   Roche

Residual PTH, ng/L

Model A              18  [+ or -] 12 (c)   28 + 21 (c)
                     12 [+ or -] 10        11 [+ or -] 18
                     12 [+ or -] 9         22 [+ or -] 16
                     12 [+ or -] 9         23 [+ or -] 16
Model B              12 [+ or -] 9         22 [+ or -] 16

PTH half-life, min

Model A              1.7  [+ or -] 0.7 (c) 1.9  [+ or -] 0.7 (c)
                     3.4 [+ or -] 1.3      3.8 [+ or -] 1.3
                     3.5 [+ or -] 1.2      3.6 [+ or -] 1.0
                     3.7 [+ or -] 1.3      3.5 [+ or -] 0.8
Model B              3.3 [+ or -] 1.4      3.7 [+ or -] 0.9

(a) Model A yielded overall valid kinetic results for only nine
patients. Incongruous results were observed as follows: for the
(baseline, 5, 10) data set, six each with the Nichols and Roche
assays and three with the DPC assay; for the (0, 5, 10) data set,
three with the Nichols and one each with the DPC and Roche assays;
for the (0, 5, 15) data set, one with the Nichols assay; for the
(0, 10, 15) data set, two with the DPC assay. Data sets from the
Nichols, DPC, and Roche assays produced invalid results 10, 6,
and 7 times, respectively.

(b) Preoperative baseline PTH (before skin incision).

(c) Significantly (P <0.05) different from other calculations.

Table 2. Number of patients with PTH <50% of preoperative
baseline values at indicated time points.a

Time after        Nichols   DPC      Roche
adenectomy, min

0                 7 (0)     6 (0)    6 (0)
5                 14 (0)    14 (2)   14 (0)
10                14 (2)    14 (6)   14 (3)
15                14 (5)    14 (6)   14 (6)

(a) Values in parentheses indicate patients with a PTH
surge until adenectomy (compare with Fig. 3; in 14 patients
PTH decreased and in 6 patients PTH increased until adenectomy).
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Title Annotation:Endocrinology and Metabolism
Author:Bieglmayer, Christian; Prager, Gerhard; Niederle, Bruno
Publication:Clinical Chemistry
Article Type:Report
Date:Oct 1, 2002
Words:5449
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