An Algorithm Informed by the Parathyroid Hormone Level Reduces Hypocalcemic Complications of Thyroidectomy

The algorithm was applied in 135 patients, and 288 patients were managed conventionally. Conventionally managed patients received calcium replacement in response to serially drawn serum calcium levels and/or clinical manifestations of hypocalcemia. Demographic characteristics of the comparison groups are shown in Table 1. Length of hospitalization was significantly shorter in the algorithm population (1.10 ± 0.48 days vs. 2.72 ± 2.1 days; p < 0.0001). When the indication for surgery was considered, non-algorithm patients were more likely to undergo surgery for thyroid cancer (56.2% vs. 45.1%; p < 0.05). Algorithm patients were less likely to have critically low calcium levels during hospitalization (Fig. 2). Of the total cases during the study period, 91% were managed by 5 surgeons, all of whom did more than 35 operations. The mean number of episodes of critical hypocalcemia was not significantly different when comparing high-volume (>35 cases) to low-volume (<35 cases) surgeons (0.229 vs. 0.230; p = 0.51). The protective impact of the algorithm was more pronounced among patients undergoing TTx for cancer, 30% of whom developed critically low calcium levels when managed conventionally. In a multivariate logistic regression controlling for age, sex, race, insurance status (Medicare vs. private), co-morbidity (excluding thyroid cancer), length of hospitalization, and thyroid cancer status, only algorithm status predicted risk of having at least one low or critically low calcium value. Specifically, non-algorithm patients had a 2.17× greater risk of having a low calcium value during hospitalization compared with algorithm patients (95% CI 1.20–3.92; p < 0.01).

In algorithm patients, the 1-h PTH level correlated positively with the morning calcium level on postoperative day 1 (Fig. 3). Given the PTH cut-points assigned to different branches of the algorithm, we also examined the relationship between the morning calcium level and the PTH category (normal, low-normal, low; Fig. 4). Twenty-one percent (28/133) of algorithm patients had low 1-h PTH levels, of which 28.6% (8/28) developed critically low calcium levels. Sixty-one percent (81/133) had normal 1 h PTH levels, with 5% (4/81) of those individuals developing critically low serum calcium. A low postoperative PTH level predicted low (n = 45) or critically low (n = 8) postoperative calcium levels with a sensitivity of 93% and a specificity of 98%. A normal 1-h PTH was associated with higher mean calcium compared with either the low-normal or low PTH groups (p < 0.0001). Calcium values in the low versus low-normal PTH groups were not significantly different.

The use of intraoperative or postoperative PTH levels to predict hypocalcemia following TTx remains controversial. Several groups have found that PTH levels cannot reliably predict postoperative hypocalcemia [14, 15]. Lombardi et al. [16] reported that parathyroid hormone measurements less than 10 pg/ml levels alone 4 h after surgery were unable to accurately predict hypocalcemia in 13.4% of their study population, 2.1% of whom were symptomatic. Other investigators support the use of PTH in identifying patients likely to develop hypocalcemia following thyroidectomy [5‐13]. McLeod et al. [17] showed that postoperative PTH levels less than 12 pg/ml had a 100% sensitivity and 92% specificity for predicting hypocalcemia. This was corroborated by the work of Sywak et al. [18], which demonstrated a sensitivity of 90% and a specificity of 84% of PTH levels from 3–10 pg/ml drawn 4 h after surgery for predicting postoperative hypocalcemia (as defined by corrected calcium levels ≤2.0 mmol/l). Similarly, in a study looking at the experiences of five separate Australian institutions, Grodski and Serpell [19] demonstrated a sensitivity, specificity and positive predictive value of 70.7%, 92.6%, and 71.6%, respectively, for low PTH levels (<10 ng/l) 4 h after surgery in predicting postoperative hypocalcemia (<2.00 mmol/l). This led to the inclusion of the routine measurement of PTH postoperatively in the Australian Endocrine Surgeons Guidelines for patients undergoing total thyroidectomy [20]. In a 2008 meta-analysis of 27 papers, Grodski and Serpell [19] reiterated this recommendation, reporting that postoperative PTH at any time within 24 h of total thyroidectomy can be used to accurately predict the development of hypocalcemia and anticipate the need for calcium replacement, albeit with class C evidence. In this same vein, our findings support the use of PTH to identify those patients in whom postoperative hypocalcemia may be anticipated.

Our practice is to administer oral calcitriol to all patients with low and low-normal postoperative PTH levels. The efficacy of this drug treatment is supported by a number of previous studies [21‐23]. Tartaglia et al. [24] showed in 2005 that oral administration of calcium and calcitriol after thyroidectomy significantly decreases the risk of postoperative hypocalcemia. Calcitriol induces a fourfold increase in the uptake of oral calcium [25], reducing by half the dosage required to maintain physiologic levels in the postoperative period. This requires less frequent dosing and alleviates much of the nausea and constipation associated with large amounts of oral calcium, ultimately leading to superior patient compliance. Additionally, since a generic form became available in 2001, calcitriol is inexpensive ($1.20 per 0.25 mcg pill, TEVA Pharmaceuticals, Petach Tikva, Israel). When used judiciously in a sliding scale fashion, calcitriol does not lead to overtreatment (to date, this practice has not resulted in any episodes of hypercalcemia in our experience). For these reasons, we emphasize the use of calcitriol in combination with lower doses of oral calcium in lieu of large doses of oral calcium alone. In a separate but related study, we found that algorithmic management results in a significantly decreased length of hospital stay, reduced costs associated with multiple lab draws, and a reduced need for IV calcium administration. Furthermore, implementation of the algorithm reduced the number of hospital readmissions for postoperative complications to zero. These combined benefits yielded an average savings of $1,631 (74%) per patient in our hospital system [26].

We noted a statistically significant difference in the percentages of patients undergoing TTx for a cancer versus non-cancer diagnosis between the two study samples. Given the need to conduct a more aggressive operation in the treatment of malignancy, we postulated that an increased frequency of postoperative hypoparathyroidism would be observed in this patient population. The hypothesis was borne out in our data, which demonstrated a greater prevalence of critically low calcium levels among patients undergoing TTx for cancer, with a rate of 30% in those managed conventionally. This increased risk was present regardless of postoperative management, suggesting that, at present, our algorithm may be not aggressive enough to prevent hypocalcemia in this patient subset. In a randomized analysis of patients undergoing TTx with central lymph node dissection for papillary cancer, Roh et al. [22] demonstrated a postoperative hypocalcemia (<8.0 mg/dl) rate of 44% in patients who received neither oral calcium supplementation nor calcitriol. This rate decreased to 24% with administration of oral calcium, and 8.2% with a combination of oral calcium and calcitriol. The implication is that patients undergoing TTx for cancer are particularly vulnerable to postoperative hypoparathyroidism and anticipatory measures should be routinely employed.

The major limitation of postoperative PTH measurement is the possibility that these values may be spuriously normal or high in a patient that subsequently develops unanticipated critically low calcium levels. Among the 133 algorithm patients in our study, 81 (61%) had normal 1-h PTH levels, and only 5% (4/81) went on to develop critically low morning calcium levels. Therefore, though we acknowledge that spuriously normal PTH levels are occasionally found, these occurrences are rare. Notably, appropriate and timely intervention was taken in all algorithm patients who ultimately required IV calcium supplementation. The routine measurement of serum calcium on the morning following operation is an additional safeguard that permits identification of patients with hypoparathyroidism, even among those not correctly identified by the postoperative PTH level. Furthermore, all patients are discharged on continued calcium supplementation for 2 weeks, regardless of inpatient lab results (a low dose of 1,000 mg calcium carbonate twice daily with no calcitriol is used for patients with completely normal PTH and calcium levels). This affords a third tier of protection against the development of hypocalcemia should it occur in a delayed fashion following discharge, thus preventing hospital readmissions.

This study is limited by its retrospective, nonrandomized design. Despite these weaknesses, our data favor implementation of an algorithmic approach to calcium management after total thyroidectomy that is informed by measurement of postoperative PTH level.