**3. Definition of severe hypocalcemia post-parathyroidectomy and risk factors**

Previously, the critical value of hypocalcemia (CVH) was defined as Ca levels ≤6.0 mg/dL within 48 h of total parathyroidectomy, indicating the possibility of life threatening complications [14] or as profound and prolong hypocalcemia (hungry bone syndrome) with corrected serum Ca levels of ≤8.4 mg/dL lasting for 4 or more days, that occurred anytime within 1 month following the parathyroidectomy [15]. Bone hungry syndrome occurred frequently around 25–27.4% after total parathyroidectomy for secondary hyperparathyroidism [4, 15] and CVH around 15.3% [14].

In a recent study, we included 322 patients who were successfully treated with TPX & BT plus AT. They were divided into two groups. Group A (mild hypocalcemia) patients had serum Ca levels ≥6.5 mg/dL at 18 h post-operation and needed ≤4 g i.v. Ca gluconate to keep Ca levels ≥6.5 mg/dL during the post-operative period (7 days). Group B (severe hypocalcemia) patients had serum Ca levels <6.5 mg/dL at 18 h post-operation or needed >4 g of i.v. Ca gluconate during the post-operative period to keep Ca levels ≥6.5 mg/dL. Surgery was considered successful when iPTH levels were lowered to <72 pg./mL within 1 week after surgery [16]. The rate of severe hypocalcemia was 23.3% in our study. It appeared that our study included a larger sample size than previous series did [14, 15, 17–20]; thus, our results were more dependable, but a few risk factors we identified were different from those reported previously.

Using the ROC curve analysis of Ca levels at 18 h post-operation for predicting hypocalcemia that needed i.v. Ca gluconate, the maximal Youden index was 0.415 and the optimal cutoff value was 7.6 mg/dL, with sensitivity of 0.72 (95% CI 0.590–0.839), specificity of 0.695 (95% CI 0.620–0.748), and area under the curve 0.749 ± 0.032 (mean ± SE) (95% CI 0.686–0.812) (**Figure 1**); patients who met this criterion should be treated with i.v. Ca gluconate. Previous reports suggested that Ca levels of 7.5–8.0 mg/dL at 18 h post-operation could predict severe hypocalcemia, and our results support this finding [18, 20].

Preoperatively, patients were younger in Group B [50 (40–46)] [median (interquartile range)] than in Group A [58 (52–64)] (*p <* 0.001); serum P, Alk-ptase, and iPTH levels were significantly higher, but serum Ca levels were significantly lower in Group B than those in Group A (**Table 1**). Same findings were reported previously [14, 15]. There were no significant differences between the two groups in terms of sex, symptoms, body weight, and duration of dialysis (**Table 1**). The amount of blood loss during surgery was not significantly different between the two groups. The operation time, total weight of removed parathyroid glands, duration of post-operative hospitalization (days), and total amount of i.v. Ca gluconate administered were significantly more, but calcium levels at 18 h post-operation were significantly lower in Group B than in Group A (*p* = 0.014, *p* = 0.035, *p* < 0.001, *p* < 0.001, and *p* < 0.001, respectively) (**Table 2**).

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

patients with SHPT [1].

concurrent use of calcimimetics [4].

intolerance along with hypocalcemia [6].

the costs of vitamin D and P-binders [7].

with ESRD and suffering from uncontrolled SHPT [4].

**2. Parathyroidectomy rates, indications, and methods**

Due to toxicity, aluminum-based P-binders have been replaced by those containing Ca salts. At high doses, Ca-based P-binders may elevate the risk of vascular calcification. Ca-free P-binders with dietary P restriction appear to lower fibroblast growth factor-23 and improve cardiovascular and renal outcomes in

Despite the availability of several P-binders, the ideal P-binder that combines high efficacy, low pill burden, minimal side effects (including gastro-intestine), and low cost is still not available [2], and the effect on survival is unclear [3]. In EDRD patients, vitamin D may improve abnormal mineral homeostasis; however, a steady escalation of vitamin D analog dose is not feasible due to hypercalcemia, hyperphosphatemia, and/or parathyroid gland resistance, despite the

Calcimimetics such as cinacalcet therapy are currently a class of agents that activate

the Ca sensing receptor and potentiate the effect of extracellular Ca. Literature supports cinacalcet therapy to improve patients' outcomes, especially with regard to vascular calcifications and presumably the very lethal condition of calciphylaxis [5]. Additional clinical evidence suggests that cinacalcet in combination with low-dose vitamin D is more effective in lower PTH than calcitriol alone. However, cinacalcet is administered orally and has been associated with gastrointestinal

In addition, poor adherence has been observed among dialysis patients selfadministering cinacalcet [5]. Cost effectiveness is another consideration; the addition of cinacalcet contracts an additional US\$3000–4000 per year on the top of

Parathyroidectomy was required in about 10% of patients after 10 years and 20% after 20 years in dialysis patients [8]. The parathyroidectomy rate was 8.8/1000 patient-years from 1991 to 2009 in the Swedish dialysis and transplant population [9]. A trend toward a dip in parathyroidectomy rate was found during the era of cinacalcet. This change in treatment strategy was accompanied with increased preoperative

The overall rate of parathyroidectomy in the United States was approximately 5.4/1000 patients between 2002 and 2011. The rate decreased from 2003 (7.9/1000 patients), reached a nadir in 2005 (3.3/1000 patients), increased again through 2006 (5.4/1000 patients), and remained stable since that time. Rates of in-hospital

In-hospital mortality has seldom happened in Kaohsiung Chang Gung Memorial Hospital during 30 years in over 2000 patients undergoing parathyroidectomy plus autotransplantation for secondary hyperparathyroidism, owing to routine cardiac 2D-echography, thallium-201 myocardial imaging, and EKG examinations before surgery [12]. In recent 5 years, sestamibi parathyroid scintigraphy is also routinely

The indications for parathyroidectomy are symptoms of bone pain, skin itching, general weakness, insomnia, and soft tissue calcification with Ca levels ≥10.2 mg/dL, P levels ≥4.7 mg/dL, alkaline phosphatase (Alk-ptase) levels ≥94 IU/L, intact parathyroid hormone (iPTH) levels ≥800 pg./mL, and bone mineral density (T-score) ≤ −2.5

PTH levels reflecting delayed surgery and increased disease severity [10].

mortality after parathyroidectomy decreased from 1.9% in 2003 to 0.8% in

If calcimimetics side effects are intolerable, some researchers have reported that parathyroidectomy may be more cost-effective than cinacalcet in some patients

**100**

2011 [11].

performed preoperatively.

#### **Figure 1.**

*Using receiver operating characteristics (ROC) curve, maximal Youden's index = 0.415, sensitivity = 0.72, 1-specificity = 0.305, area under curve = 0.749 ± 0.032 (SE), 95% confidence interval = 0.686–0.812, and optimal cutoff calcium value = 7.6 mg/dL (at 18 h post-operation) to predict severe hypocalcemia.*

We believe that younger patients have better bone-formation abilities than older patients; thus, they are more likely to have severe hypocalcemia after parathyroidectomy [15, 21, 22].

In our study, severe hypocalcemia occurred in 75 patients (23.3%), which is lower than the rates (27.4–97%) reported previously, likely owing to the definition of severe hypocalcemia [15, 20–22].

We found that mean preoperative Ca levels were lower in Group B than in Group A but Alk-ptase levels in Group B were higher than in Group A (**Table 3**). The cause was not very clear, but this had also been reported previously [15, 20–22].

Before patient discharge, Ca levels in Group B were lower than in Group A, but Alk-ptase levels in Group B were higher than in Group A (**Table 3**). Although it was unclear whether serum Ca levels in patients with severe hypocalcemia remained significantly lower throughout the year after operation, as reported previously [15], we found that all patients in our study could maintain Ca levels >8.0 mg/dL after 3 months with the use of oral Ca carbonate <3 g/day and calcitriol <0.5 μg/day. We speculated that the autotransplanted parathyroid tissue might start to function 1–3 weeks later, as reported previously [23].

Preoperative P levels were higher in Group B than in Group A, which had rarely been reported previously [24].

**103**

*\* Using X2*

**Table 1.**

glands (g)

Ca levels 18 h after operation

*Using Student't test. Using Mann-Whitney U test.*

*\**

**Table 2.**

*-test. Using Mann-Whitney U test.*

*All data = median (interquarter range) (IQR).*

Total weight of removed parathyroid

*Data = median (interquarter range) (IQR). Data = mean±SD (standard deviation).*

*hypocalcemia (Group A) and severe (Group B) hypocalcemia groups.*

Days of postoperative hospitalization 5 (5–5)

*between mild (Group A) and severe (Group B) hypocalcemia groups.*

*Alk-tase = alkaline phostaphatase. iPTH = intact parathyroid hormone.*

*Severe Hypocalcemia after Total Parathyroidectomy Plus Autotransplantation for Secondary…*

**Mild hypocalcemia**

Age 58 (52–64) 50 (40–64) <0.001 Sex M/F 96/151 37/38 0.111\* Skin itching (+/-) 161/86 54/21 0.328\* Bone pain (+/-) 176/71 53/22 1.0\* General weakness (+/-) 121/126 32/43 0.358\* Insomnia (+/-) 154/93 44/31 0.590\* Body weight (kg) 57.1 (49.9–64.9) 59.2 (52.5–69.9) 0.122 Duration of hemodialysis (years) 10 (6.8–13)(N=207) 8.0 (5.8–11.3)(N=58) 0.205 Duration of peritoneal dialysis (years) 6.0 (4.3–8.8)(N=40) 7.0 (5.0-9.5)(N=17) 0.629 Ca [7.9-9.9 mg/dL] 10.4 (10–10.9) 10.3 (9.5–10.7) 0.007 P [2.4-4.7 mg/dL] 5.6 (4.6–6.7) 6.4 (5.7–7.1) <0.001 Alk-ptase [28-94 IU/L] 141 (99–228) 227 (169–420) <0.001 iPTH [14-72 pg/mL] 1298 (1025–1750) 1740 (1295–2359) <0.001

**Group B (N=75) Severe hypocalcemia**

**Group B (N=75) Severe hypocalcemia**

> 5 (5–8) 6.4 ± 2.5

3.3 (2.3–4.8) 3.8 (2.8–5.4) 0.035

8.2 (7.5–8.8) 7.2 (6.6–7.8) <0.001

**p**

**p**

<0.001 <0.001\*

hyperparathyroidism. Preoperative Alk-ptase levels were higher in Group B than in Group A. We found that preoperative Alk-ptase levels were an independent risk factor for severe hypocalcemia, similar to previous reports [14, 15, 17–19, 24]. After TPX & BT plus AT, Alk-ptase levels increased progressively, reflecting increased bone formation, which peaked at 2 weeks [15] and decreased gradually

*Blood loss during surgery, operation time, total weight of removed parathyroid glands, days of postoperative hospitalization and total intravenous (i.v.) Ca gluconate and Ca levels at 18 h post-operation. Comparison* 

*Age, sex, symptoms, body weight, duration of dialysis and preoperative serum calcium (Ca), phosphorus (P), Alkaline-phosphatase (Alk-ptase) and intact parathyroid hormone (iPTH) levels. Comparison between mild* 

> **Group A (N=247) Mild hypocalcemia**

Blood loss (cc) 15 (10–20) 17.5 (10–21) 0.560 Operation time (min) 131 (117–156) 145 (122–166) 0.014

5.0 ± 1.1

Total i.v. Ca gluconate (g) 0 (0–0) 12 (8–18) <0.001

*DOI: http://dx.doi.org/10.5772/intechopen.92976*

**[Normal ranges] Group A (N=247)**

High Alk-ptase levels are characteristic of bone diseases involving increased osteoblastic activity, bone formation, and resorption in secondary *Severe Hypocalcemia after Total Parathyroidectomy Plus Autotransplantation for Secondary… DOI: http://dx.doi.org/10.5772/intechopen.92976*


*\* Using X2 -test.*

*Using Mann-Whitney U test.*

*All data = median (interquarter range) (IQR).*

*Alk-tase = alkaline phostaphatase. iPTH = intact parathyroid hormone.*

### **Table 1.**

*Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*

We believe that younger patients have better bone-formation abilities than older patients; thus, they are more likely to have severe hypocalcemia after parathyroid-

We found that mean preoperative Ca levels were lower in Group B than in Group A but Alk-ptase levels in Group B were higher than in Group A (**Table 3**). The cause

Before patient discharge, Ca levels in Group B were lower than in Group A, but Alk-ptase levels in Group B were higher than in Group A (**Table 3**). Although it was unclear whether serum Ca levels in patients with severe hypocalcemia remained significantly lower throughout the year after operation, as reported previously [15], we found that all patients in our study could maintain Ca levels >8.0 mg/dL after 3 months with the use of oral Ca carbonate <3 g/day and calcitriol <0.5 μg/day. We speculated that the autotransplanted parathyroid tissue might start to function

Preoperative P levels were higher in Group B than in Group A, which had rarely

In our study, severe hypocalcemia occurred in 75 patients (23.3%), which is lower than the rates (27.4–97%) reported previously, likely owing to the definition

*Using receiver operating characteristics (ROC) curve, maximal Youden's index = 0.415, sensitivity = 0.72, 1-specificity = 0.305, area under curve = 0.749 ± 0.032 (SE), 95% confidence interval = 0.686–0.812, and optimal* 

*cutoff calcium value = 7.6 mg/dL (at 18 h post-operation) to predict severe hypocalcemia.*

was not very clear, but this had also been reported previously [15, 20–22].

High Alk-ptase levels are characteristic of bone diseases involving increased osteoblastic activity, bone formation, and resorption in secondary

**102**

ectomy [15, 21, 22].

**Figure 1.**

of severe hypocalcemia [15, 20–22].

1–3 weeks later, as reported previously [23].

been reported previously [24].

*Age, sex, symptoms, body weight, duration of dialysis and preoperative serum calcium (Ca), phosphorus (P), Alkaline-phosphatase (Alk-ptase) and intact parathyroid hormone (iPTH) levels. Comparison between mild hypocalcemia (Group A) and severe (Group B) hypocalcemia groups.*


*Using Student't test.*

*Using Mann-Whitney U test.*

*Data = median (interquarter range) (IQR).*

*Data = mean±SD (standard deviation).*

#### **Table 2.**

*Blood loss during surgery, operation time, total weight of removed parathyroid glands, days of postoperative hospitalization and total intravenous (i.v.) Ca gluconate and Ca levels at 18 h post-operation. Comparison between mild (Group A) and severe (Group B) hypocalcemia groups.*

hyperparathyroidism. Preoperative Alk-ptase levels were higher in Group B than in Group A. We found that preoperative Alk-ptase levels were an independent risk factor for severe hypocalcemia, similar to previous reports [14, 15, 17–19, 24].

After TPX & BT plus AT, Alk-ptase levels increased progressively, reflecting increased bone formation, which peaked at 2 weeks [15] and decreased gradually

#### *Mineral Deficiencies - Electrolyte Disturbances, Genes, Diet and Disease Interface*


#### **Table 3.**

*Serum calcium (Ca), phosphate (P), alkaline phosphatase (Alk-ptase) and intact parathyroid hormone (iPTH) levels at the day of discharge. Comparison between mild (Group A) and severe (Group B) hypocalcemia groups.*


*Using binary logistic regression test. Ca = calcium levels.*

*Alk-ptase = alkaline phosphatase.*

#### **Table 4.**

*Risk factors of severe hypocalcemia after total parathyroidectomy plus auto transplantation.*

to normal levels at 3 months post-operation (**Table 4**). Before patients were discharged in our series, the mean Alk-ptase level was still higher in Group B than in Group A showing that oral Ca carbonate and calcitriol should be continually administered for 2 weeks to 3 months, according to serum Ca levels [15].

Preoperatively, high iPTH levels were a clear indicator of the severity of renal hyperparathyroidism and bone disease. Preoperatively, high iPTH levels increased both bone formation and bone resorption; after parathyroidectomy, bone resorption would decrease and bone formation would increase; thus, severe hypocalcemia could develop after surgery [14, 22, 24].

We found that the total weight of the removed parathyroid glands was more in Group B than in Group A, as was the operation time. The total weight of parathyroid glands and the operation time contributed to severe hypocalcemia, might be due to advance disease and extensive dissection during surgery, but were rarely reported before [20, 25, 26].

Multi-variant binary logistic regression test showed that young age, low preoperative Ca levels, high preoperative Alk-ptase levels, and long operation time were independent risk factors for severe hypocalcemia, with associated odds ratio of 0.956, 0.595, 1.003, and 1.010, respectively (*p* = 0.001, *p* = 0.007, *p* < 0.001, and *p* = 0.016, respectively) (**Table 4**).

In our study, Ca levels were negatively correlated with P levels (*r* = −0.255, *p* < 0.001), and Alk-ptase levels were positively correlated with iPTH levels (*r* = 0.449, *p* < 0.001); therefore, preoperative Ca and Alk-ptase levels were finally identified as independent risk factors for severe hypocalcemia combined with young age and long operation time.

**105**

**Figure 2.**

*Severe Hypocalcemia after Total Parathyroidectomy Plus Autotransplantation for Secondary…*

Cozzolino et al. [27, 28] proposed a dose corresponding to the rate of 1–2 mg/kg/h for i.v. Ca gluconate, which could be increased or decreased by 25–50% from the initial value. Loke et al. [17] developed a titration regimen in which a 10% Ca gluconate infusion was started at 4.5 mL/h when serum Ca levels were < 8 mg/dL and then increased to 6.5 mL/h and finally to 9.5 mL/h if Ca levels continually declined. The algorithms they proposed were too complicated for clinical applications, and therefore, we modified it into our clinical algorithm (**Figure 2**). We adopted the clinical algorithm developed by Cozzolino et al. [28],

**4. Treatment of severe hypocalcemia with our algorithm**

*The clinical algorithm for the treatment of hypocalcemia after total parathyroidectomy plus* 

*autotransplantation for secondary hyperparathyroidism.*

*DOI: http://dx.doi.org/10.5772/intechopen.92976*

with some modifications.

*Severe Hypocalcemia after Total Parathyroidectomy Plus Autotransplantation for Secondary… DOI: http://dx.doi.org/10.5772/intechopen.92976*
