Evaluation of preoperative serum concentrations of ionized calcium and parathyroid hormone as predictors of hypocalcemia following parathyroidectomy in dogs with primary hyperparathyroidism: 17 cases (2001–2009)

Melissa Arbaugh Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Daniel Smeak Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Eric Monnet Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523.

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Abstract

Objective—To determine whether preoperative serum ionized calcium (iCa) or parathyroid hormone (PTH) concentrations help predict postoperative hypocalcemia following parathyroidectomy in dogs with primary hyperparathyroidism.

Design—Retrospective case series.

Animals—17 dogs with primary hyperparathyroidism treated with parathyroidectomy.

Procedures—Medical records were evaluated from years 2001 to 2009. Data evaluated included age, breed, sex, clinical signs, diagnostic tests performed, preoperative and postoperative iCa concentrations, preoperative PTH concentrations, and whether calcium supplementation was provided following surgery. Two groups were identified on the basis of whether dogs became hypocalcemic (iCa < 1.2 mmol/L) following parathyroidectomy.

Results—12 dogs developed hypocalcemia after surgery. Preoperative (within 24 hours before surgery) iCa concentrations for the hypocalcemic group (mean ± SD, 1.82 ± 0.22 mmol/L) and the nonhypocalcemic group (1.83 ± 0.29 mmol/L) were not significantly different. Calcium concentrations decreased in a linear fashion during the 24 hours following parathyroidectomy, and the slopes of the decrease over that time were not significantly different between the 2 groups. Preoperative PTH concentrations were not significantly different between the hypocalcemic and nonhypocalcemic groups.

Conclusions and Clinical Relevance—Preoperative iCa and PTH concentrations were not predictive of postoperative hypocalcemia in dogs undergoing parathyroidectomy for primary hyperparathyroidism. Future studies to evaluate whether calcium supplementation should be provided on an individual basis with perhaps more emphasis on clinical signs than iCa concentrations after surgery may be warranted.

Abstract

Objective—To determine whether preoperative serum ionized calcium (iCa) or parathyroid hormone (PTH) concentrations help predict postoperative hypocalcemia following parathyroidectomy in dogs with primary hyperparathyroidism.

Design—Retrospective case series.

Animals—17 dogs with primary hyperparathyroidism treated with parathyroidectomy.

Procedures—Medical records were evaluated from years 2001 to 2009. Data evaluated included age, breed, sex, clinical signs, diagnostic tests performed, preoperative and postoperative iCa concentrations, preoperative PTH concentrations, and whether calcium supplementation was provided following surgery. Two groups were identified on the basis of whether dogs became hypocalcemic (iCa < 1.2 mmol/L) following parathyroidectomy.

Results—12 dogs developed hypocalcemia after surgery. Preoperative (within 24 hours before surgery) iCa concentrations for the hypocalcemic group (mean ± SD, 1.82 ± 0.22 mmol/L) and the nonhypocalcemic group (1.83 ± 0.29 mmol/L) were not significantly different. Calcium concentrations decreased in a linear fashion during the 24 hours following parathyroidectomy, and the slopes of the decrease over that time were not significantly different between the 2 groups. Preoperative PTH concentrations were not significantly different between the hypocalcemic and nonhypocalcemic groups.

Conclusions and Clinical Relevance—Preoperative iCa and PTH concentrations were not predictive of postoperative hypocalcemia in dogs undergoing parathyroidectomy for primary hyperparathyroidism. Future studies to evaluate whether calcium supplementation should be provided on an individual basis with perhaps more emphasis on clinical signs than iCa concentrations after surgery may be warranted.

Primary hyperparathyroidism is a disorder of calcium homeostasis.1–6 The parathyroid gland is responsible for calcium homeostasis.1–5 In the event of hypocalcemia, the parathyroid gland produces PTH, which acts on the kidneys and intestines and bone tissue to increase serum total and iCa concentration in the blood.1–5 Patients with primary hyperparathyroidism have a normal or high PTH concentration in the face of a high serum calcium concentration. However, to make a diagnosis of primary hyperparathyroidism, all other causes of hypercalcemia must be ruled out. Approximately 90% of dogs with primary hyperparathyroidism have parathyroid adenomas, 5% have carcinomas, and the rest have parathyroid hyperplasia.1,4,7,8

Removal or ablation of the affected parathyroid glands is the recommended treatment in affected dogs.1,9–14 Following surgery, these patients may develop transient hypocalcemia while the suppressed parathyroid gland regains appropriate function.1 If hypocalcemia occurs, it generally does so within the first 7 days following surgery,1,14 and affected dogs often require extensive hospitalization and monitoring of iCa concentration. Previously, it was thought that patients with total serum calcium concentrations > 14 mg/dL prior to surgery should receive supplementation with calcium and calcitriol prior to surgery because they were thought to be at a greater risk of developing hypocalcemia after parathyroidectomy.1 These data are not evidence based and may result in unnecessary treatment that has the potential to delay stimulation of the suppressed parathyroid gland. Feldman1 commented that oral supplementation with calcium before serum calcium concentration has decreased does not prevent decreases in serum calcium concentration below the reference range. Therefore, calcium supplementation immediately after surgery does not preclude monitoring of serum calcium concentration. Currently, there are no predictors to indicate which patients will become hypocalcemic and require calcium supplementation following parathyroidectomy. It has been shown that PTH concentrations decrease in a linear fashion within the first 24 hours after surgery1,10,13,15 and then usually reach a plateau afterward. This suggests that evaluating preoperative iCa concentrations and iCa concentrations during the first 24 hours following surgery could be a useful estimator for prediction of postoperative hypocalcemia.

The purpose of the study reported here was to evaluate predictors of postoperative hypocalcemia in dogs following parathyroidectomy. We hypothesized that the preoperative calcium concentrations would aid in predicting postoperative hypocalcemia. We also hypothesized that the slope of the regression line for this variable over the first 24 hours would aid in prediction of hypocalcemia following surgery.

Materials and Methods

Animals—Medical records from Colorado State University Veterinary Teaching Hospital were reviewed for 2001 to 2009 to identify cases of primary hyperparathyroidism in dogs. Patients with primary hyperparathyroidism with recorded preoperative serum iCa and PTH concentrations that underwent cervical ultrasonography, thoracic radiography, and abdominal ultrasonography were entered in the study. All patients had been treated with parathyroidectomy and had histologic evaluation performed on the removed glands. Ionized calcium concentration must have been monitored every 4 to 5 hours while in the hospital, and a 5-day follow-up determination of iCa concentration must have been performed. Dogs that received calcium supplementation before identifying an iCa concentration below the reference range were excluded from the study. Dogs were distributed in a hypocalcemic group if their iCa concentration was < 1.2 mmol/L any time after surgery or allocated to a nonhypocalcemic group.1

Data collection—Variables examined included age, breed, sex, preoperative and postoperative clinical signs, preoperative and postoperative iCa concentrations, preoperative PTH concentrations, histologic analysis of the removed parathyroid tissue, and whether the patient received postoperative calcium and vitamin D supplementation.

Statistical analysis—A Shapiro-Wilk test was used to evaluate whether the data were normally distributed. Baseline iCa concentration was not normally distributed; therefore, a Kruskal-Wallis rank sum test was used to compare the baseline iCa concentration between the hypocalcemic and nonhypocalcemic groups. Baseline was defined as the iCa concentration immediately following surgery. Because PTH concentration was normally distributed, ANOVA was used to compare PTH concentrations between the hypocalcemic and nonhypocalcemic groups. Linear regression was performed evaluating the decrease of iCa concentrations over the first 24 hours following surgery. The slopes of the regression between the hypocalcemic and nonhypocalcemic groups were compared with ANOVA because the slopes were normally distributed. Data are reported as mean ± SD. Values of P < 0.05 were considered significant.

Results

Animals—Seventeen dogs met the inclusion criteria. Twelve dogs developed hypocalcemia (serum iCa concentration < 1.2 mmol/L) within 39 ± 20.2 hours (median, 34 hours; range, 19 to 96 hours) after surgery and were assigned to the hypocalcemic group. Five dogs did not develop hypocalcemia in the first 5 days following surgery and were assigned to the nonhypocalcemic group. There were 11 males and 6 females (10 castrated males, 1 sexually intact male, and 6 spayed females). The median age at the time of initial evaluation was 11.7 years (range, 7 to 18 years). The following breeds were represented: Labrador Retriever (n = 2), mixed (2), Shih Tzu (1), Australian Shepherd Dog (1), German Shorthair Pointer (1), Rhodesian Ridgeback (1), German Shepherd Dog (1), Golden Retriever (2), Dachshund (1), American Eskimo (1), Heeler (1), Beagle (1), and Miniature Poodle (1). Thirteen dogs did not receive calcium supplementation following surgery, and 4 dogs received calcium and vitamin D supplementation. Histologic analysis revealed parathyroid adenoma (n = 16) and parathyroid hyperplasia (1). According to the medical records, all adenomas were solitary.

Clinical signs—The most commonly reported clinical signs of hyperparathyroidism were polyuria and polydypsia (n = 4), followed by seizures and neurologic signs (3), hind end weakness (3), and weight loss and gastrointestinal upset (2). Six patients had no apparent clinical signs, with hypercalcemia being identified on routine blood analysis.

Diagnostic testing—Cervical ultrasonography revealed a hypoechoic nodule within the thyroid tissue in 15 of 17 dogs. One dog did not have evidence of an obvious nodule within the thyroid tissue, and 1 dog had evidence of thyroid enlargement, but a discrete nodule was not noted.

Parathyroid hormone concentrations were recorded in 12 of 17 dogs (mean, 13.6 ± 7.9 pg/mL; median, 14.8 pg/mL; range, 2.8 to 28.4 pg/mL). Comparison of preoperative PTH concentrations and postoperative calcium concentrations between the hypocalcemic (13.4 ± 9.9 pg/mL) and nonhypocalcemic (12.1 ± 6.7 pg/mL) groups was not significant (P = 0.516; power = 0.60). Ionized calcium concentration significantly (P = 0.04) decreased over time following a linear model regardless of group (R2 = 0.91; Figures 1 and 2). Coefficients of correlations were 0.91 for the hypocalcemic group and 0.90 for the nonhypocalcemic group for a linear regression model (P = 0.91; power = 0.91).

Figure 1—
Figure 1—

Linear regression of serum iCa concentration (mmol/L) of 12 hypocalcemic dogs 24 hours following parathyroidectomy. Linear regression analysis was used to develop a model for predicting the iCa concentration by use of the following equation: iCa = a + bT, where a is the y-intercept, b is the slope of the regression line, and T is time. The horizontal line represents the iCa concentration below which dogs were considered to have hypocalcemia. Mean ± SD slope of the regression line was −0.019 ± 0.006. Correlation was very good (R2 = 0.97; P = 0.003).

Citation: Journal of the American Veterinary Medical Association 241, 2; 10.2460/javma.241.2.233

Figure 2—
Figure 2—

Linear regression of iCa concentration (mmol/L) of 5 nonhypocalcemic dogs 24 hours following parathyroidectomy. Mean ± SD slope of the regression line was −0.016 ± 0.0076. Correlation was very good (R2 = 0.91; P = 0.041). See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 241, 2; 10.2460/javma.241.2.233

Concentrations of iCa before surgery were 1.82 ± 0.22 mmol/L (median, 1.8 mmol/L; range, 1.66 to 2.40 mmol/L) for the hypocalcemic group and 1.83 ± 0.29 mmol/L (median, 1.6 mmol/L; range, 1.56 to 2.30 mmol/L) for the nonhypocalcemic group (P = 0.66; power = 0.66). Slopes of the linear regression of iCa concentrations against time were −0.019 ± 0.006 mmol/L/h for the hypocalcemic group and −0.016 ± 0.0076 mmol/L/h for the nonhypocalcemic group (P = 0.423; power = 0.56).

The iCa concentration was 1.3 ± 0.21 mmol/L (median, 1.3 mmol/L; range, 1.1 to 1.74 mmol/L) for the nonhypocalcemic group at 19.6 ± 2.0 hours after surgery and 1.3 ± 0.16 mmol/L (median, 1.3 mmol/L; range, 1.1 to 1.6 mmol/L) for the hypocalcemic group at 21.2 ± 2.0 hours after surgery (P = 0.59; power = 0.64). Four dogs in the hypocalcemic groups received calcium and vitamin D supplementation on the basis of clinician decision after the iCa concentration decreased to < 1.2 mmol/L. None of the dogs in the study developed clinical signs related to hypocalcemia according to the information recorded in the medical record.

Discussion

The results of the present study indicated that preoperative serum iCa or PTH concentrations are not predictive of postoperative hypocalcemia in dogs undergoing parathyroidectomy for primary hyperparathyroidism. During the first 24 hours after surgery, iCa concentration decreased significantly over time in a linear fashion regardless of whether the patient's iCa concentration reached a nadir defined as hypocalcemia. Preoperative iCa concentrations and the slope of the decrease of iCa concentrations during the first 24 hours were not predictive of which patients would become hypocalcemic during 5 days after surgery.

The patient population in the present study was similar to those previously reported with respect to age at initial evaluation, sex distribution, and clinical signs.5,7,9–12 In our study population, unlike other reported populations, Keeshonds were not overrepresented.5,7,9–12 This is likely because of the low overall population of Keeshonds in our geographic area. As for previous reports,5,7,9–12 histologic analysis in most of these dogs was consistent with a parathyroid adenoma. We had 1 biopsy report of parathyroid hyperplasia, and once the abnormal gland was removed, the iCa concentration returned to normal. We did not find that preoperative iCa concentrations corresponded with the development of hypocalcemia in the postoperative period. Previous literature suggests supplementing calcium in patients with preoperative calcium concentrations > 14 mg/dL following parathyroidectomy1; however, there is no scientific evidence to support this recommendation. Calcium and vitamin D supplementation immediately following parathyroidectomy do not prevent serum calcium concentration decreases below reference limits in the postoperative period.1 Feldman1 recommends monitoring patients for 5 days after surgery even with calcium and vitamin D supplementation especially if the preoperative iCa concentration was > 14 mg/dL. Historically, some clinicians provide supplemental calcium to patients following parathyroidectomy regardless of postoperative calcium concentrations in an effort to avoid or prevent complications from hypocalcemia and to reduce expenses related to hospitalization and frequent blood testing. If calcium and vitamin D supplementation are instituted immediately after surgery, it is recommended to monitor the calcium concentrations and keep the values normal to low normal to allow stimulation of the remaining parathyroid glands.1 In the present study, only 4 dogs were supplemented with calcium and vitamin D on the basis of clinician decision; however, none of the dogs developed any clinical signs related to hypocalcemia, even the dogs that had an iCa concentration < 1.2 mmol/L that did not receive supplementation. According to the medical records, none of the dogs in the present study developed clinical signs of hypocalcemia after surgery, even those with low iCa concentrations. This may suggest that patients should be supplemented when they have clinical signs of hypocalcemia, rather than solely on the basis of iCa concentration. However, it should also be noted that if iCa concentrations are consistently decreasing, calcium supplementation should be provided despite clinical signs in an effort to avoid a severe hypocalcemic event.

During the first 24 hours following parathyroidectomy, iCa concentration decreases significantly over time in a linear fashion. Because the slopes of the regression were not different between the hypocalcemic and nonhypocalcemic groups in the present study, the slope of the regression during the first 24 hours after surgery is not predictive as to which patients will develop an iCa concentration < 1.2 mmol/L. We did not perform a regression past 24 hours because we were using the first 24 hours as an early predictor for development of hypocalcemia. Data collected in the medical record were not consistent enough to be able to establish a linear regression past 24 hours. Ionized calcium concentrations decrease in a linear fashion, like PTH concentrations, within the first 24 hours after surgery.1,10,13,15 After the first 24 hours, PTH concentrations seem to reach a plateau10,13; however, iCa concentration continues to decrease after 24 hours following surgery. This may be due to a mechanism unrelated to the effects of PTH. We suggest that it is unlikely that monitoring PTH concentrations after surgery will help in the prediction of postoperative hypocalcemia. Calcium excretion by the kidneys might remain elevated after surgery because of polyuria. Potentially monitoring calcium concentrations in the urine may provide better information concerning calcium decay and prediction of calcium concentrations. Perhaps iCa concentrations have a delay in increase following an increase in PTH concentrations. The interaction between calcium and degradation of PTH may be more intricate than previously thought.1

In the present study, we found that preoperative PTH concentrations were not predictive of hypocalcemia in either group. Parathyroid gland PTH secretion is chiefly controlled by iCa negative feedback and not by PTH concentrations in the blood. This may explain why PTH concentrations are not predictive of hypocalcemia. Currently, there are no data in the veterinary literature regarding PTH concentrations and the development of postoperative hypocalcemia. Parathyroid hormone concentrations are used almost exclusively for diagnosis of primary hyperparathyroidism but not for treatment. In humans, PTH concentrations are monitored intraoperatively to determine whether complete or partial excision of the parathyroid gland has been performed.15–17 These studies15–17 show that the PTH concentrations obtained during surgery correlate well with the amount of parathyroid tissue removed. Parathyroid hormone concentrations were not measured after surgery in the present study.

There are several limitations to the present study. Because PTH concentration measurements after surgery were not available, we could not evaluate the correlation between PTH concentrations and iCa concentrations. All patients had multiple iCa concentration measurements; however, the number of measurements and time periods were not consistent. The number of patients enrolled in the study was low, which could have also influenced our results. Power calculations were performed to help evaluate our data. The lowest power was 56%, which is still acceptable if we consider the biological and clinical importance of the data. The equipment used to measure both serum iCa and PTH concentrations was not standardized. Each piece of equipment has its own reference range, so a standardized reference range for iCa and PTH was not provided. Also, because of the retrospective nature, duration of clinical signs prior to surgical treatment was not consistently available. The duration of clinical signs is more likely to influence the rate of atrophy of the remaining parathyroid gland and therefore influence the rate of recovery of the remaining parathyroid gland following surgery. An additional limitation is the amount of time iCa concentration is monitored following surgery. In the present study, we evaluated iCa concentration for 7 days following surgery. Even though, on the basis of PTH half-life, most hypocalcemia will be observed within 2 days following parathyroidectomy, in some clinical instances, hypocalcemia can be detected for a longer duration and should be considered if clinical signs become evident. On the basis of the present study, the development of hypocalcemia following parathyroidectomy cannot be predicted with preoperative concentration of PTH or iCa nor the slope of the decrease of iCa concentration within the first 24 hours. Future studies should examine variables other than iCa concentration in an effort to predict which patients will need calcium and vitamin D supplementation following parathyroidectomy.

ABBREVIATIONS

iCa

Ionized calcium

PTH

Parathyroid hormone

References

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