Intravenous Ca Research Articles

MO815: Cinacalcet Does not Prevent Severe Hypocalcemia After Parathyroidectomy in Dialysis-Dependent Patients

Abstract BACKGROUND AND AIMS Surgical treatment of secondary hyperparathyroidism (SHPT) is often followed by the rapid development of hypocalcemia, which is also known as hungry bone syndrome. We aimed to evaluate if preoperative use of cinacalcet may help to prevent severe hypocalcemia after parathyroidectomy (PTx) for SHPT in dialysis-dependent patients during the early postoperative period. METHOD The retrospective analysis included 616 patients who underwent PTx (either subtotal or total PTx with autotransplantation of parathyroid tissue) for SHPT between 2011 and 2019 in the single tertiary care center of endocrine surgery. Data on severe hypocalcemia development were available for 559 of the patients, 172 of them received cinacalcet before surgery. The median age of the patients was 49 (IQR 40–56) years and the median dialysis duration was 94 (IQR 56–142) months. Preoperative parathyroid hormone level was 153 pmol/L (IQR 105–223), total serum Ca was 2.44 mmol/L (IQR 2.24–2.61) and alkaline phosphatase was 283 IU/l (IQR 157–645). Severe postoperative hypocalcemia was defined as a serum ionized Ca level <0.9 mmol/L on the second or third day post-PTx. We also assessed need for intravenous (IV) calcium supplementation and the duration of in-hospital stay (≤7 days or >7 days) as surrogate markers of hungry bone syndrome severity. RESULTS Among patients treated with cinacalcet, 55.8% (n = 96) received 30 mg/day, 33.1% (n = 57)received 60 mg/day, 10.5% (n = 18) received 90 mg/day and 0.6% (n = 1) received 120 mg/day. Prevalence of severe hypocalcemia was less in patients who received 90 or more mg of cinacalcet a day, although this difference did not reach statistical significance (P = .1038) (Figure 1A). Use of cinacalcet (yes/no) was not associated with the risk of severe postoperative hypocalcemia: RR = 1.047 [95% confidence interval (95% CI) 0.946–1.146], OR = 1.229 (95% CI 0.801–1.886), P = .3837. A total of 54% of the patients were administered with IV calcium. Preoperative use of cinacalcet did not reduce the risk of IV calcium supplementation need: RR = 0.93 (95% CI 0.79–1.09), OR = 0.86 (95% CI 0.61–1.21); P = .3749. Among patients supplemented with IV calcium, medians of total Ca amount did not differ between those who received pre-PTx cinacalcet and those who did not: 6 (IQR 3–15) g versus 6 (IQR 4–10) g, respectively, P = .3981. Patients who received 60 mg of cinacalcet a day or more were more likely to require higher amounts of total IV Ca (Figure 1B), but this was not statistically significant [RR = 1.4 (95% CI 0.83–2.4); P = .2138]. In terms of length of hospital stay, we did not find differences between patients received 30, 60 and ≥ 90 mg of cinacalcet a day (P = .1285) (Figure 1C). Use of cinacalcet was not associated with prolonged (>7 days) in-hospital stay: RR = 0.863 (95% CI 0.708–1.04), OR = 0.765 (95% CI 0.546–1.081); P = .1417. CONCLUSION We found no evidence of a protective effect of preoperative cinacalcet use, neither on the prevalence nor on the severity of hypocalcemia development after PTx for SHPT in dialysis patients.

Extreme Secretion of PTHrP From a Pancreatic Neuroendocrine Tumor, A Shift From Severe Hypercalcemia to Hypocalcemia

Background: PTHrP-secreting pancreatic neuroendocrine tumors (PNET) are a recognized cause of malignancy associated hypercalcemia. Herein, we report a case of severe hypercalcemia due to an extreme elevation of PTHrP from a PNET, where after treatment of the hypercalcemia, symptomatic hypocalcemia occurred. Clinical Case: A 59 year-old-woman with a recurrent PNET with liver metastases undergoing an evaluation for multi-visceral transplant presented with acute confusion, nausea and vomiting. Diagnostic testing identified an extreme elevation of total calcium (Ca) [>20.1 mg/dL (8.5 - 10.2)] from two different samples [serum albumin 4.1 g/dL (3.9 - 4.9)]. The total Ca level one month earlier was 8.3 mg/dL with a serum albumin of 3.1 g/dL. Total Ca measurements were performed with the Ca Gen.2 assay on a cobas c702 chemistry analyzer (Roche Diagnostics). Results greater than the analytical measurement range (0.8 – 20.1 mg/dL) were diluted with saline and confirmed (22.6 mg/dL). A Radiometer ABL 800 Flex blood gas analyzer was used to determine the ionized Ca concentration [2.94 mmol/L (1.08 - 1.30)]. Upon presentation the serum creatinine (Cr) was 2.07 mg/dL (0.58 - 0.96); eGFR utilizing the MDRD equation 24 mL/min/1.73m2; baseline serum Cr 0.78 mg/dL. Her serum 25-OH vitamin D was 31 ng/mL (31.0 - 80.0), PTH 12 pg/mL (15 - 65), phosphate 4.3 mg/dL (2.7 - 4.8) and 1, 25-OH vitamin D 39.1 (15.0 - 60.0). PTHrP measurements were performed by ARUP Laboratories via liquid chromatography tandem mass spectrometry (LC-MS/MS) and resulted in a reported value of >2500 pmol/L (0.0 - 3.4). Her symptoms resolved and the corrected Ca gradually decreased to 8 mg/dL after treatment with IV fluids, calcitonin 200 units sc every 12 hours for 48 hours, 60 mg IV pamidronate, and five sessions of hemodialysis. Within thirteen days of receiving pamidronate, her corrected Ca slowly increased to 12mg/dL; thus, she received a single dose of 120 mg sc denosumab. Nine days later, the patient developed symptomatic hypocalcemia (7.3 mg/dL) manifested by paresthesia in the hands and feet and perioral numbness. She then received multiple doses of oral and intravenous Ca along with 50,000 units of oral ergocalciferol twice weekly. The corrected Ca normalized (8.1 mg/dL) and symptoms resolved. The patient was discharged with plans for future treatment of her underlying malignancy. Conclusion: This is the first report of a PNET producing an extreme elevation of PTHrP of higher than 2500 pmol/L, resulting in a concordant extreme elevation of total calcium within a month of documented normocalcemia. Treatment of hypercalcemia with denosumab may result in the development of hypocalcemia requiring treatment.

Histologic Distribution and Characteristics on MR Imaging of Ultrasmall Superparamagnetic Iron Oxide in Ethyl-nitrosourea-induced Endogenous Rat Glioma.

Purpose:(1) To evaluate the enhancement patterns of an ultrasmall superparamagnetic iron oxide contrast agent (USPIO-CA) compared with those of a gadolinium-based contrast agent (Gd-BCA). (2) To compare the histologic distribution of USPIO-related iron particles (USPIO-IPs) with the USPIO-enhancement area in the early vascular and in the cellular imaging phase (E- and L-phase, respectively) after intravenous CA administration.Methods:We performed USPIO-enhanced MRI of N-ethyl-N-nitrosourea (ENU)-induced endogenous rat glioma, including spin-echo (SE) T1-weighted images (T1WIs) and gradient-recalled-echo (GRE) T2-weighted images (T2WIs), before and at 3–6 h after USPIO-CA administration for E-phase images. For L-phase images, MRI was performed at 16–19 and 62–69 h after administration. Two observers determined the USPIO-enhancement area on E-phase images and Gd-enhancement areas. We compared the USPIO-enhancement size (USPIO-ES) and Gd-ES on SE T1WIs, and the hypo-intense USPIO-ES on GRE T2WIs and Gd-ES using the Wilcoxon signed-rank test. In addition, two raters visually evaluated the correspondence between the histologic distribution of USPIO-IPs and the USPIO-enhancement area on corresponding GRE T2WIs at each phase using a 3-rating scale.Results:Significantly smaller hyper-intense, hypo-intense and combined hyper-/hypo-intense areas were observed on USPIO-enhanced SE T1WIs compared with Gd-enhanced images (all P < 0.001). The hypo-intense USPIO-ES on GRE T2WIs was significantly smaller than the Gd-ES (P = 0.001). The distribution of USPIO-IPs on histopathological specimen and USPIO-enhancement on GRE T2WIs exhibited poor agreement in 5 of 9 tumors with enhancement from rats sacrificed early. The distribution of microglia containing USPIO-IPs corresponded with the pattern of USPIO-enhancement in the 2 tumors with late enhancement.Conclusion:The enhancement pattern and size of USPIO-CA in a rat glioma model were statistically different from those of Gd-BCA. Our histological data suggests that USPIO-enhanced MRI offers vascular bed imaging in E-phase and might depict the intra-tumoral distribution of immune effector cells in L-phase.

Effects of maintaining eucalcemia following immunoactivation in lactating Holstein dairy cows

Periparturient hypocalcemia is a common metabolic disorder and it is ostensibly associated with negative health and production outcomes. Acute infection also markedly decreases circulating Ca, but the reasons for and consequences of it on physiological and immunological parameters are unknown. Objectives were to evaluate the effects of maintaining eucalcemia on production, metabolic, and immune variables following an intravenous lipopolysaccharide (LPS) challenge. Twelve multiparous lactating Holstein cows (717 ± 20 kg of body weight; 176 ± 34 d in milk; parity 3 ± 0.2) were enrolled in a study containing 2 experimental periods (P); during P1 (3 d), cows consumed feed ad libitum and baseline values were obtained. At the initiation of P2 (4 d), cows were randomly assigned to 1 of 2 treatments: (1) LPS administered (LPS-Con; 0.5 μg/kg of body weight LPS; n = 6) or (2) LPS administered + eucalcemic clamp (LPS-Ca; 0.5 μg/kg of body weight LPS; Ca infusion; n = 6). Cows were fasted for the first 12 h during P2. After LPS administration, ionized Ca was determined every 15 min for 6 h and every 30 min for an additional 6 h and intravenous Ca infusion was adjusted in LPS-Ca cows to maintain eucalcemia. Blood ionized Ca was decreased 23% for the first 12 h postbolus in LPS-Con cows, and by design, Ca infusion prevented hypocalcemia. To maintain eucalcemia for the 12 h, 13.7 g of Ca was infused. The total Ca deficit (including Ca not secreted into milk) accumulated over the 12 h was 10.4 and 20.2 g for the LPS-Con and LPS-Ca treatments, respectively. Mild hyperthermia (0.8°C) occurred for ∼6 h post-LPS administration relative to P1. From 6 to 7 h postbolus rectal temperature from LPS-Ca cows was increased (0.6°C) relative to LPS-Con cows. On d 1 of P2, milk yield decreased (61%) in both treatments relative to P1. Relative to LPS-Con cows, milk yield decreased (15%) in LPS-Ca cows during P2. Overall, circulating LPS-binding protein continuously increased postbolus, and at 24 h LPS-binding protein levels in LPS-Ca cows were increased (80%) relative to LPS-Con cows. During P2, serum amyloid A increased (4-fold) in both treatments relative to P1. Administering LPS initially decreased circulating neutrophils, then cell counts progressively increased with time. Calcium infusion decreased neutrophil counts (40%) from 9 to 12 h postbolus relative to LPS-Con cows. Neutrophil function, as assessed by oxidative burst and myeloperoxidase production, did not differ due to treatment. In summary, maintaining eucalcemia (via intravenous Ca infusion) during an immune challenge appeared to intensify inflammation and adversely affect lactation performance.

Effect of subclinical and clinical hypocalcemia and dietary cation-anion difference on rumination activity in periparturient dairy cows

Rumination involves a complex series of muscle contractions that bring a bolus of ingesta to the mouth for further mastication before it is swallowed again. Healthy cows ruminate 8 to 9 h/d. Hypocalcemia is known to disrupt nerve and muscle function. Our hypothesis was that hypocalcemia in periparturient cows would reduce rumination activity. Twenty-six Holstein cows entering their third lactation or greater were fed a control diet [dietary cation-anion difference (DCAD) = +196 mEq/kg of dry matter (DM)] or a low DCAD diet supplemented with anions (DCAD = -9 mEq/kg of DM) prepartum. Periparturient plasma Ca concentration and rumination rate were determined. Four of 12 control cows developed clinical milk fever, necessitating intravenous Ca therapy. Rumination rate decreased in all cows around the time of calving. Rumination rate on the first and second day of lactation was highly correlated with the cow's plasma Ca concentration on the first day of lactation. In one of our statistical models, a normocalcemic cow was defined as a cow whose plasma Ca concentration remained above 2.00 mM. Cows were retrospectively classified as normocalcemic, subclinically hypocalcemic, or clinically hypocalcemic (milk fever). Only 4 cows were considered normocalcemic, and all had been fed the low DCAD diet. Normocalcemic cows spent more time ruminating on the first day after calving than subclinically hypocalcemic cows or cows with milk fever. Cows with milk fever had a lower rumination rate than normocalcemic cows through d 3 of lactation. Rumination activity in cows with milk fever was almost nondetectable in the hours before and after intravenous Ca treatment for an extended period, despite the return of muscle function that allowed the cows to stand and eructate following treatment. Other statistical models using different definitions of normocalcemia gave qualitatively similar results. Diet had a great effect on plasma Ca concentration and rumination rate. Even when cows with clinical milk fever were removed from the control cow data set, cows on the low DCAD diet had significantly greater plasma Ca concentrations in the first 36 h after calving and a higher rumination rate on d 1 of lactation (248 ± 26 min) than control cows (158 ± 32 min).

Intravenous calcium infusion in a calving protocol disrupts calcium homeostasis compared with an oral calcium supplement

Hypocalcemia is a common postpartum condition in dairy cows, which negatively affects health and production. Intravenous Ca infusions are commonly included in calving protocols to prevent or mitigate the effect of hypocalcemia in multiparous cows. Thus, we sought to contrast the effect of intravenous Ca infusion against voluntary oral Ca intake on Ca metabolism. Serum total Ca (tCa) and whole-blood ionized Ca (iCa) were monitored in 24 multiparous Holstein cows after parturition. Precalving diets were formulated with a positive dietary cation-anion difference of 172 mEq/kg of DM and contained 4.1 g of Ca/kg of DM. At parturition, cows were blocked by calving sequence and calcemic status as either normocalcemic (cutoff threshold of iCa ≥1.10 mmol/L) or hypocalcemic (cutoff threshold of iCa <1.10 mmol/L). Cows in each block were randomly assigned to 1 of 2 treatments: either an oral source of Ca (Ca-Oral; n = 12) or an intravenous source of Ca (Ca-IV; n = 12). Cows in the Ca-Oral group were offered a 20-L commercial Ca suspension (48 g of Ca) for voluntary consumption. The supplement contained Ca carbonate, Ca formate, Ca propionate, and other minerals and vitamins (Farm-O-San Reviva, Trouw Nutrition, Amersfoort, the Netherlands). Cows in the Ca-IV group received a 450-mL intravenous Ca solution (13 g of Ca) that contained 298 mg/mL of Ca gluconate, 33 mg/mL of magnesium chloride, and 82 mg/mL of boric acid (AmosCAL, Kommer-Biopharm BV, Heiloo, the Netherlands). Both treatments were initiated within 25 ± 10 min after calving. The oral Ca suspension was offered to cows in a 25-L bucket and was available for 10 min. All cows in the Ca-Oral group voluntarily consumed the entire 20 L of the Ca suspension within 5 min. Blood samples for Ca analyses were collected at 0 (before treatment initiation), 1, 3, 10, and 18 h relative to treatment, and at 0700 and 1900 h for the next 2 consecutive days, to represent the 24-, 36-, 48-, and 60-h sampling time points. In Ca-IV cows, both iCa and tCa concentrations peaked at 1 h (1.54 mmol/L for iCa and 2.85 mmol/L for tCa) and declined to a nadir at 24 h following treatment initiation (0.94 mmol/L for iCa and 1.74 mmol/L for tCa). Although whole-blood iCa and serum tCa were higher at 1 and 3 h in Ca-IV cows, concentrations of iCa were greater for Ca-Oral cows at 18, 24, and 36 h and for tCa at 24 and 36 h. Our data indicate that intravenous Ca infusion immediately induced a state of hypercalcemia followed by lower whole-blood iCa and serum tCa concentrations 24 h later compared with oral Ca.

Effect of Continuous Intravenous Calcium Loading on Fibroblast Growth Factor 23 in Normal and Uremic Rats.

Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with CKD. However, the mechanisms underlying stimulation of FGF23 remain to be investigated. We examined whether hypercalcemia induced by continuous intravenous (CIV) calcium (Ca) infusion regulates FGF23 levels in normal rats (Normal) and 5/6 nephrectomized uremic rats (Nx). Microinfusion pumps were implanted in the Normal and Nx rats for CIV Ca infusion, and blood, urine, kidney, and tibia were collected. The results showed an increase in serum Ca-stimulated FGF23 independently of serum phosphate (P) and creatinine levels in Normal and Nx rats. FGF23 mRNA from the tibia was also increased by the Ca infusion. Despite high FGF23 levels after Ca infusion, urinary P excretion was decreased. Renal α-Klotho expression was significantly reduced by Ca infusion. These results suggest that intravenous Ca loading might stimulate FGF23 production from bone in normal and uremic rats. Reduction of renal P excretion suggests that the bioactivity of FGF23 is inhibited, and the decrease in renal α-Klotho expression might have a role in this pathological process. In conclusion, CIV Ca loading increased FGF23 in normal and uremic rats, and renal α-Klotho is necessary to maintain the bioactivity of FGF23 as a phosphaturic factor.

Intravenous Calcium-/Zinc-Diethylene Triamine Penta-Acetic Acid in Patients With Presumed Gadolinium Deposition Disease: A Preliminary Report on 25 Patients.

The aim of this study was to report the use of intravenous calcium (Ca)-/zinc (Zn)-diethylene triamine penta-acetic acid (DTPA) for the treatment of 25 symptomatic patients diagnosed with gadolinium deposition disease (GDD). Written informed consent was obtained. Twenty-five patients (18 women; mean age, 46.8 ± 15.3 years) with a diagnosis of GDD were included. All patients had received at least 1 administration of a gadolinium (Gd)-based contrast agent. Patients received 3 treatment sessions with Ca-/Zn-DTPA, 15 with treatments spaced 1 month apart, and 10 with treatments spaced 1 week apart. In all cases, every treatment consisted of an application of Ca-DTPA and Zn-DTPA separated by 24 hours. Measurements of 24-hour urine Gd content before dosing and on the first and second days of therapy were performed. Symptomatic improvement of patients was determined by use of a 10-point scale of patient symptoms. Serum electrolytes were quantified. Gadolinium content increased in the urine, with an overall mean of 30.3-fold increase in the monthly regimen (P < 0.001) and 12.9-fold in the weekly regimen (P < 0.001). Eleven patients experienced transient worsening of at least some of their symptoms, termed a "flare-up" phenomenon, in most of whom symptoms improved or receded. Overall, symptoms improved in 13 patients, unchanged in 10, and worse in 2. Significant clinical improvement was present for headache, brain fog, and bone pain for the monthly regimen and arm pain and leg pain for the weekly regimen. There were no significant changes in major serum electrolytes. Three courses of intravenous Ca-/Zn-DTPA therapy results in significantly increased urine content of Gd after treatment and moderate symptomatic improvement.

Persisting Hypocalcemia After Surgical Parathyroidectomy: The Differential Effectiveness of Calcium Citrate Versus Calcium Carbonate With Acid Suppression

The effectiveness of oral calcium (Ca) may be contingent on a patient׳s factors beyond compliance, such as proton-pump inhibitor use and the choice of calcium supplements. A 32-year-old Hispanic male with end-stage renal disease on peritoneal dialysis underwent successful surgical parathyroidectomy (intact parathyroid hormone level: 2,328pg/mL; postsurgical: 287-69pg/mL [normal: 8.5-72.5]). His postoperative course was complicated by severe and recurrent hypocalcemia as outpatient and he needed repeated admissions for intravenous Ca gluconate. Initially, severe hypocalcemia (corrected Ca: 4.8-5.6mg/dL; nadir ionized Ca: 0.57-0.69mmol/L) was attributed solely to medical noncompliance with oral Ca carbonate (3750mg, 3×/day between meals) and calcitriol (2-4mcg/day). Recognizing coexisting treatment with proton-pump inhibitor, oral Ca supplement was changed to calcium citrate (2,850mg, 3×/day) with prompt resolution of hypocalcemia (corrected Ca: 8.1-8.3mg/dL). This current case and the included literature review emphasize the disproportionate effectiveness of Ca citrate in subjects with achlorhydria.

Can serum isotope levels accurately measure intestinal calcium absorption compared to gold-standard methods?

BackgroundLow fractional calcium absorption (FCA) contributes to osteoporosis but is not measured clinically, as the gold-standard method requires administration of two calcium tracers and a subsequent 24-h urine collection. We evaluated alternate methods to measure FCA, compared to the gold standard method.MethodsWe administered two stable calcium isotope tracers (~8 mg oral 44Ca and ~3 mg intravenous 42Ca) with breakfast to 20 fasting post-menopausal women (Cohort 1) 59 ± 7 years old with vitamin D insufficiency. We measured subsequent calcium isotope concentrations in 24-h urine samples and serum collected 1, 3 and 5 h post tracer administration during an inpatient research stay. We assessed the candidate serum estimates in a second cohort of 9 women with similar characteristics. Methods of measuring FCA were compared using correlation coefficients and Bland-Altman tests.ResultsFCA estimated from a 3-h serum sample correlated highest with the levels from the 24-h urine collection (ρ 0.78, p < 0.001), but explained only 58 % of the variance in FCA. The total variance explained by 3-h estimates improved to 61 % with incorporation of glomerular filtration rate (GFR). FCA estimates from the 3-h serum measurement were assessed in a second group of nine women (Cohort 2) 60 ± 7 years old. In this cohort, however, FCA estimated by 3-h serum isotope levels did not correlate with gold-standard FCA measurements, whether determined with (ρ 0.02, p = 0.97) or without GFR values (ρ 0.03, p = 0.93). By contrast, FCA in Cohort 2 correlated best with 5-h serum isotope levels (ρ 0.75, p = 0.02).ConclusionsWe conclude that serum isotope levels correlate with true fractional calcium absorption, but do not reliably estimate FCA when analyzed using Bland-Altman tests, compared to gold-standard methods.Trial registrationClinicalTrials.gov.Identifier: NCT00933244

Bioavailability of enteric-coated microencapsulated calcium during pregnancy: a randomized crossover trial in Bangladesh

Prenatal calcium and iron supplements are recommended in settings of low dietary calcium intake and high prevalence of anemia. However, calcium administration may inhibit iron absorption. To overcome calcium-iron interactions, we developed a multi-micronutrient powder containing iron (60 mg), folic acid (400 μg), and calcium carbonate granules microencapsulated with a pH-sensitive enteric coating to delay intestinal release. We aimed to establish in vivo evidence that enteric-coated (EC) calcium is bioavailable in pregnant women and to explore the dose-responsiveness of fractional calcium absorption (FCA) in pregnancy. This was a randomized crossover trial in pregnant women (26-28 wk of gestation) in Dhaka, Bangladesh. Participants were allocated to 1 of 3 dose groups (500, 1000, or 1500 mg elemental Ca). FCA was estimated in random order for EC and non-EC (control) granules by a dual-stable-isotope method ((44)Ca-labeled granules and intravenous (42)Ca) on the basis of the relative recovery of (44)Ca compared with (42)Ca in urine over 48 h. Forty-nine participants with FCA for both EC and non-EC granules were included in the primary analyses. FCA geometric means were as follows: 21.8% (500 mg), 9.2% (1000 mg), and 11.7% (1500 mg) for non-EC granules compared with 3.3% (500 mg), 1.2% (1000 mg), and 2.1% for EC granules. Cumulative 48-h FCA of EC calcium was 85% lower (P < 0.001) than that of non-EC calcium, after adjustment for dose. In comparison to 500 mg, the FCA for the 1000-mg dose was 61% lower (P < 0.001) and was 42% lower (P = 0.002) for the 1500-mg dose, after adjustment for formulation. A pH-sensitive enteric coating substantially reduced calcium absorption from a prenatal multi-micronutrient powder. In its current formulation, this novel supplement is not suitable for clinical use. FCA was highly dose-dependent, such that doses of 1000 and 1500 mg delivered only negligibly more bioavailable calcium than the 500-mg dose. This trial was registered at clinicaltrials.gov as NCT01678079.

Blood calcium dynamics after prophylactic treatment of subclinical hypocalcemia with oral or intravenous calcium

Total serum Ca dynamics and urine pH levels were evaluated after prophylactic treatment of subclinical hypocalcemia after parturition in 33 multiparous Jersey × Holstein crossbreed cows. Cows were blocked according to their calcemic status at the time of treatment [normocalcemic (8.0–9.9mg/dL; n=15) or hypocalcemic (5.0–7.9mg/dL; n=18)] and randomly assigned to 1 of 3 treatments: control [no Ca supplementation (n=11)]; intravenous Ca [Ca-IV (n=11), 500mL of 23% calcium gluconate (10.7g of Ca and 17.5g of boric acid as a solubilizing agent; Durvet, Blue Springs, MO)]; or oral Ca [Ca-Oral (n=11), 1 oral bolus (Bovikalc bolus, Boehringer Ingelheim, St. Joseph, MO) containing CaCl2 and CaSO4 (43g of Ca) 2 times 12h apart]. Total serum Ca levels were evaluated at 0, 1, 2, 4, 8, 12, 16, 20, 24, 36, and 48h, and urine pH was evaluated at 0, 1, 12, 24, 36, and 48h after treatment initiation. Total serum Ca levels were higher for Ca-IV than for control and Ca-Oral cows at 1, 2, and 4h after treatment initiation, but lower than Ca-Oral cows at 20, 24, and 36h and lower than control cows at 36 and 48h. At 1h after treatment initiation, when serum Ca levels for Ca-IV cows peaked (11.4mg/dL), a greater proportion of Ca-IV (n=8) cows had total serum Ca levels >10mg/dL than control (n=0) and Ca-Oral (n=1) cows. At 24h after treatment initiation, when Ca-IV cows reached the total serum Ca nadir (6.4mg/dL), a greater proportion of Ca-IV (n=10) cows had serum Ca levels <8mg/dL than control (n=5) and Ca-Oral (n=2) cows. Treatment, time, and treatment × time interaction were significant for urine pH. Mean urine pH was lower for Ca-Oral cows (6.69) than for control (7.52) and Ca-IV (7.19) cows. Urine pH levels at 1h after treatment were lower for Ca-IV cows compared with both control and Ca-Oral cows, a finding likely associated with the iatrogenic administration of boric acid added as a solubilizing agent of the intravenous Ca solution used. At 12, 24, and 36h, urine pH levels were lower for Ca-Oral cows compared with both control and Ca-IV cows. This was expected because the oral Ca supplementation used (Bovikalc) is designed as an acidifying agent. Wide fluctuations in blood Ca were observed after prophylactic intravenous Ca supplementation. The implications for milk production and animal health, if any, of these transient changes in total serum Ca have yet to be evaluated.

AB0926 Traditional Chinese Medicine-Induced Toxic Epidermal Necrolysis in an Old Patient with Sle

BackgroundToxic epidermal necrolysis (TEN) is a fulminant bulluous dermatitis with widespread erythema and severe exfoliative epidermal sloughing of skin affecting 20-100% of the total body surface area. TEN is often...

Circulating FGF23 levels in response to acute changes in plasma Ca(2+).

The regulation of fibroblast growth factor 23 (FGF23) synthesis and secretion is still incompletely understood. FGF23 is an important regulator of renal phosphate excretion and has regulatory effects on the calciotropic hormones calcitriol and parathyroid hormone (PTH). Calcium (Ca) and phosphate homeostasis are closely interrelated, and it is therefore likely that Ca is involved in FGF23 regulation. It has recently been reported that dietary Ca influenced FGF23 levels, with high Ca increasing FGF23. The mechanism remains to be clarified. It remains unknown whether acute changes in plasma Ca influence FGF23 levels and whether a close relationship, similar that known for Ca and PTH, exists between Ca and FGF23. Thus, the aim of the present study was to examine whether acute hypercalcemia and hypocalcemia regulate FGF23 levels in the rat. Acute hypercalcemia was induced by an intravenous Ca infusion and hypocalcemia by infusion of ethylene glycol tetraacetic acid (EGTA) in normal and acutely parathyroidectomized rats. Intact plasma FGF23 and intact plasma PTH and plasma Ca(2+) and phosphate were measured. Acute hypercalcemia and hypocalcemia resulted as expected in adequate PTH secretory responses. Plasma FGF23 levels remained stable at all plasma Ca(2+) levels; acute parathyroidectomy did not affect FGF23 secretion. In conclusion, Ca is not a regulator of acute changes in FGF23 secretion.

Placental vitamin D receptor (VDR) expression is related to neonatal vitamin D status, placental calcium transfer, and fetal bone length in pregnant adolescents

The purpose of the study was to identify determinants of placental vitamin D receptor (VDR) expression and placental calcium (Ca) transfer among pregnant adolescents. Placental tissue was obtained in 94 adolescents (≤18 yr) at term. In 12 of these teens, stable Ca isotopes were given intravenously ((42)Ca) and orally ((44)Ca) early in labor. Placental VDR expression was assessed via Western blot and validated by RT-PCR. Maternal-to-fetal Ca transfer was calculated as the enrichment in cord blood at delivery relative to maternal serum enrichment 2 h postdosing. Isotopic study outcomes were examined in relation to fetal long bone length, placental VDR, serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and parathyroid hormone (PTH) in maternal circulation and cord blood at delivery. Placental VDR expression was inversely associated with neonatal 25(OH)D (P=0.012) and positively with neonatal 1,25(OH)2D (P=0.006). Placental VDR was a positive predictor of fetal femur length Z score (P=0.018; R(2)=0.06) and was positively correlated with maternal-to-fetal transfer of intravenous (42)Ca (P=0.004; R(2)=0.62). The fetus may regulate placental VDR expression given the significant associations with neonatal vitamin D metabolites. The association between placental VDR and fetal long bone length may indicate a role for VDR in fetal bone development, potentially by mediating transplacental Ca transfer.

Risk assessment for severe hypocalcemia requiring hospitalization with denosumab.

115 Background: Skeletal-related events (SRE) pose clinical risks to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) that can be mitigated with denosumab. Hypocalcemia is a side effect, however risk factors are not well described. Methods: An IRB waiver was obtained to review medical records for all mCRPC pts receiving denosumab at MSKCC between March-August 2011 for baseline labs, calcium (ca) and vitamin D nadirs, details of hospitalizations, concurrent therapies, and comorbidities. Comparisons between groups were made using Fisher’s exact test and the Wilcox rank sum test. Results: Nine of sixty pts (15%) treated with 1-2 doses of denosumab developed severe symptomatic hypocalcemia (median nadir 6.5 mg/dL) requiring hospitalization for intravenous (IV) ca replacement. Ca/Vitamin D was recommended to all pts. Ca recovered in 17 days in those who did return to baseline levels (n=5). However, four of nine (44%) pts required repeated hospitalizations for IV ca, never recovered to baseline ca levels, and died of advanced disease within 3 months. Median vitamin D 25-OH was 22.5 ng/ml for hospitalized pts, and PTH was 198 pg/ml at ca nadir. Conclusions: Denosumab was associated with severe hypocalcemia sufficient to require hospitalizations for IV ca replacement in 15% of pts with mCRPC. PSA, Ca, Alk Phos, and current chemotherapy were associated with severe hypocalcemia requiring hospitalization for IV ca. Clinicians are cautioned regarding potential risk factors including advanced disease, vitamin D insufficiency, and possibly comorbidities affecting calcium absorption. [Table: see text]

Validation of a simple isotope method for estimating true calcium fractional absorption in adolescents

We validated a single oral isotope method for estimating fractional calcium absorption determined by double isotope methods in adolescents. Developed equations with an oral isotope including a single blood draw or spot urine collection can be used to evaluate fractional calcium absorption in adolescents which allows flexibility in developing protocols. This study was designed to develop and validate a simpler, less expensive single oral isotope method for determining fractional calcium (Ca) absorption in adolescents. We used our database of 31 observations from ten white and 12 black adolescent girls aged 10-15years who participated in metabolic and kinetic studies. Tracer data following oral ((44)Ca) and intravenous (IV, (42)Ca) administration of calcium stable isotopes and samples in serum and urine from various time points up to 4days were used to develop methods using multiple regression analysis based on a single measurement of enriched stable isotope/tracee defined as tracer/tracee (TT) in serum (TT(serum)) or urine (TT(urine)). Reference values for fractional calcium absorption were from oral/IV stable isotope ratios in 24-h serum or urine and full kinetic modeling. The strongest equation using a single blood sample had R (2) = 0.94 (p < 0.001): fractional Ca absorption = 1.3340(4-h TT(serum))(0.7872) BSA(1.7132)e ((-0.01652 PMA)), where BSA is body surface area and PMA is post-menarcheal age. The strongest equation using a single urine sample had R (2) = 0.95 (p < 0.001): fractional Ca absorption = 2.3088 (5-12h TT(urine))(0.8208) BSA(1.5260)e ((-0.01850 PMA)). Equations were also developed with Tanner score. An external data set of Asian adolescent boys and girls was used to validate the equations. Equations using an oral isotope and a single blood draw or urine collection for determining fractional calcium absorption were successfully validated in healthy, non-obese white and black adolescent girls aged 10-15years. The equations well-predicted fractional calcium absorption in Asian adolescent boys and girls.

Hypocalcemia in Infants and Children

Hypocalcemia in Infants and Children

41Ca and Accelerator Mass Spectrometry to Monitor Calcium Metabolism in End Stage Renal Disease Patients

Monitoring bone resorption with measurements of bone density and biochemical markers is indirect. We hypothesized that bone resorption can be studied directly by serial measurements of the ratio (41)Ca/Ca in serum after in vivo labeling of calcium pools with (41)Ca. We report the preparation of an intravenous (41)Ca dose suitable for humans, an analytical method for determining (41)Ca/Ca isotope ratios in biological samples, and studies in human volunteers. (41)Ca was formulated and aliquoted into individual vials, and to the extent possible, the (41)Ca doses were tested according to US Pharmacopeia (USP) guidelines. A 10 nCi dose of (41)Ca was administered intravenously to 4 end stage renal disease (ESRD) patients on hemodialysis and 4 healthy control individuals. Distribution kinetics were determined over 168 days. Calcium was isolated with 3 precipitation steps and a cation-exchange column, and (41)Ca/Ca ratios in serum were then measured by accelerator mass spectrometry. The dosing solution was chemically and radiologically pure, contained <0.1 endotoxin unit/mL, and passed USP sterility tests. Quantification of (41)Ca/Ca ratios was linear from 6 x 10(-14) to 9.1 x 10(-10). The run-to-run imprecision (as CV) of the method was 4% at 4.6 x 10(-11) and 6% at 9.1 x 10(-10). The area under the curve of (41)Ca in the central compartment vs time was significantly less for ESRD patients than for controls (P < 0.005). Isotope ratios spanning 5 orders of magnitude can be measured by accelerator mass spectrometry with excellent precision in the range observed in samples collected from patients who have received 10 nCi of (41)Ca. The (41)Ca at this dose caused no adverse effects in 8 volunteers. This is the first report of the use of (41)Ca to monitor differences in bone turnover between healthy individuals and ESRD patients.

Safety and Efficacy of Large Volume Leukapheresis for Allogeneic Hematopoietic Progenitor Cell Transplantation- the University of Miami Experience.

Purpose: To report our experience with large volume leukapheresis (LVL) for allogeneic hematopoietic progenitor cell (HPC) transplantation, evaluating its safety and efficacy in 69 consecutive healthy donors.Methods: Donor medical records from 1995–2004 were reviewed. These consisted of 38 males, 31 females, age range 16–65 (median: 37). All were mobilized with G-CSF, based on a dose of 7.5 mcg/kg/day (median: 600 mcg, range 300–960 mcg) for four days prior to outpatient LVL (Cobe spectra). Vascular access was femoral vein in 59 and antecubital veins in 10 donors. Pre- and post-LVL determinations included: WBC count, hemoglobin, hematocrit, platelet count, serum potassium, and calcium (Ca++). Oral KCL and oral/intravenous Ca++ were given as indicated by laboratory values and symptoms. Catheter-related complications and blood product requirements associated with collection were assessed. Final CD34/kg recipient body weight (rec. BW) and recipient engraftment data was evaluated.Results: LVL was well tolerated by all donors undergoing a total of 74 procedures.Data/LVL ProcedureMeanRangeProcedures per patient11–2Blood volume processed (L)24.215.0–34.4Time (minutes)273180–386Flow rate (ml/min)9265–100ACD–A used (ml)1008636–1449Heparin used (units)3000Not applicableCD34/kg rec. BW8.21.36–33.9Adverse reactions were minor and occurred in 40% of the donors. Local parasthesias accounted for majority (86%) of the adverse events. Bone pain secondary to G-CSF accounted for the remainder of the cases and was well controlled with analgesics. Oral electrolyte supplements were administered in 61% of the donors. Eleven (15.9%) required intravenous Ca++ during collection. There were no catheter-related complications and no requirement for blood products during or after collection. Target values of 2 x 106 CD34/kg rec. BW was obtained in 68 cases (98.6%). Engraftment was achieved in 92% of the cases (6 died prior to engraftment). There were no early or late graft failures. Median time to ANC recovery was 10 days (range 8–25 days). Self-sustained platelet count was achieved in a median of 13 days.Conclusion: LVL was a safe and efficacious method of allogeneic HPC collection. The use of a lower G-CSF dose for mobilization is more economical and well tolerated. This dose allows for adequate collection of CD34 positive cells. These cells support the sustained recovery from high-dose chemotherapy for allogeneic transplantation.