Correction Of Hypocalcemia Research Articles

Hypocalcemic effect of zoledronic acid or other bisphosphonates may contribute to their antiangiogenic properties

Bisphosphonates, effectively used for metastatic bone disease and hypercalcemia, may evidentially have antiangiogenic properties. However, mechanism(s) of antiangiogenic effects of bisphosphonates are not fully understood. Their most pronounced effect is on metabolism of calcium, which is a main point of intersection for many distinct molecular signaling pathways that promote and modulate angiogenesis. An elevation of Ca 2+ plays a role in the mitogenic and secretory effects of growth factors. Some preclinical clues imply that antiangiogenic effects of bisphosphonates are related to its well-known hypocalcemic activity. Consequently, it may not be right to routinely recommend vitamin D and calcium supplementation to correct hypocalcemia unless it is symptomatic.

Acute Pancreatitis in Children.

There are no drugs that cure or abate pancreatitis. The treatment of patients with mild and moderate episodes of pancreatitis (85%) is supportive and expectant. Central issues include the removal of the initiating process (if possible), relief of pain, and maintenance of fluid and electrolyte balance. Endoscopic retrograde cholangiopancreatography may be required for stone extraction in patients with biliary pancreatitis. Surgery is rarely required. The aims of treatment for patients with severe disease includes treatment of local, systemic, and septic complications in addition to those for mild and moderate disease. Homeostasis is maintained by the correction of hypocalcemia, anemia, hypoalbuminemia, electrolyte imbalances, and hypoxemia. A large number of medications have been used unsuccessfully in an attempt to halt the progression of the autodigestive process within the pancreas and to reduce pancreatic secretions. Nutritional support with either enteral or parenteral feeding is given. Intravenous antibiotics or selective bowel decontamination decrease mortality in patients with severe episodes of pancreatitis. The treatment for these individuals is often prolonged. Surgical treatment of traumatic pancreatitis with ductal rupture includes repair or resection. At times, simple drainage is performed and definitive surgery is deferred until later. Surgical treatment of severe pancreatitis includes debridement of necrotic and infected tissue. The emerging consensus appears to be that necrosectomy and local lavage or open management with planned re-exploration offers better survival than the conventional therapy of resection plus drainage alone.

Predialysis management of divalent ion metabolism

Disordered divalent ion metabolism has its origins in the earliest stages of renal impairment. Early intervention is essential to minimize its effects, especially in the light of recent reports demonstrating an association between serum phosphate and relative risk of mortality in dialysis patients. As the age and comorbidity of patients accepted for renal replacement therapy increases, the complexity of their management also increases. A dedicated "predialysis" enables a multidisciplinary team to intervene in an orderly and appropriate fashion to delay progression, modify comorbidity, prevent uraemic complications and prepare the patient mentally and physically for dialysis and renal transplantation. Part of this process involves the identification of patients at high risk of the skeletal and biochemical complications of renal osteodystrophy. Correction of hypocalcemia, acidosis, hyperphosphatemia and rising PTH levels should be achieved quickly. Oral calcitriol therapy is frequently necessary, and requires careful monitoring and supervision.

Correction of hypocalcaemia in the critically ill: What is the haemodynamic benefit?

The prevalence of hypocalcaemia is known to be elevated in critically ill patients, but the expected benefit from calcium repletion in hypocalcaemic patients has not been well defined. The objective of the present study was therefore prospective determination of the cardiovascular response to calcium administration in critically ill patients with hypocalcaemia. A total of 17 patients found to have ionized hypocalcaemia (Ca2+ < 1.05 mmol/l) from a group of 32 patients who were invasively monitored as part of their ICU management. Slow intravenous injection of 1 g of calcium chloride. Calcium administration was followed by an increase in mean arterial pressure from 77 +/- 8 to 90 +/- 12 mmHg (P < 0.01). There was no significant change in cardiac filling pressures or heart rate. Cardiac index and systemic vascular resistance increased slightly but not significantly (from 2.67 +/- 0.92 to 2.81 +/- 1.25 1/min.m2 and from 2133 +/- 647 to 2378 +/- 817 dynes.s.cm-5 m-2, respectively). Left ventricular stroke work index increased from 23 +/- 8 to 32 +/- 13 g.m/m2 (P < 0.01). These changes were maintained for 60 min. The correction of hypocalcaemia can result in a significant increase in arterial pressure that can persist for at least 1 h. Despite an associated improvement in left ventricular function, cardiac index and oxygen delivery do not increase significantly.

Hypomagnesemic hypocalcemia in chronic renal failure.

Hypomagnesemic hypocalcemia in chronic renal disease is a rare finding. Controversy remains regarding the role of decreased magnesium in producing impaired parathyroid hormone (PTH) secretion versus target organ unresponsiveness to PTH. We describe six patients with severe chronic renal disease in whom hypocalcemia and hypomagnesemia were detected. Five patients had chronic interstitial nephropathy; all of them showed renal magnesium wasting. One patient had chronic glomerulonephritis and a malabsorption syndrome and showed a low rate of urinary excretion of magnesium. The administration of magnesium increased calcium levels in all patients. We have found elevated PTH levels in absolute terms, which, however, were inappropriate to correct hypocalcemia; the PTH levels increased in three patients and not in the other three after magnesium replacement. We conclude that in patients with tubulointerstitial nephropathies, chronic renal losses of magnesium can produce hypomagnesemic hypocalcemia.

A prospective, randomized, double-blind comparison of calcium chloride and calcium gluconate therapies for hypocalcemia in critically ill children

Disturbances of ionized calcium levels have been reported in sick neonates, l and we have found a high rate of occurrence of ionized hypocalcemia, 2 which was associated with a significantly increased mortality rate in critically ill nonneonatal pediatric patients. Calcium chloride and calcium gluconate are two of the standard salt preparations that are used to correct hypocalcemia; the former is usually preferred because it is in the ionized form and therefore provides more readily available ionized calcium for use. In this study, critically ill pediatric patients with ionized hypocalcemia received either calcium chloride or calcium gluconate in a randomized manner. The purposes of this study were (1) to determine whether calcium chloride and calcium gluconate provide equal bioavailability of ionized calcium and (2) to assess whether there were any differences in physiologic effects after administration of the two salts. METHODS Patient selection. All patients admitted to the Le Bonheur Children's Medical Center intensive care unit were eligible for participation in this study if they were found to have hypocalcemia. Patients were enrolled in the study after informed consent was obtained in compliance with the investigational review boards of the University of Tennessee and LBCMC. Exclusion criteria were (1) calcium administration before arrival in the ICU and (2) no documentation of

Hypocalcemic Heart Failure in End-Stage Renal Disease

A 37-year-old woman presented with hypocalcemic heart failure complicating end-stage renal disease. Heart failure persisted despite conventional therapy but improved after correction of hypocalcemia. Continuous monitoring of left ventricular function by radionuclide study during calcium replacement showed dramatic improvement. Our case showed that hypocalcemia could be a rare but reversible cause of frank heart failure in uremic patients.

Diminished Aldosterone Responses to Angiotensin II and Adrenocorticotropin in Hypocalcemic Subjects: Restoration of Responsiveness with Normocalcemia

ACTH-, angiotensin II (AII)-, and K+-mediated aldosterone responses in vitro are dependent on extracellular and intracellular Ca concentrations. This study examined in vivo the relationship of changes in ambient serum calcium (serum Ca) to ACTH- and AII-mediated aldosterone release in hypoparathyroid subjects. Plasma aldosterone (PA) responses to graded dose infusions of ACTH and AII were examined in hypoparathyroid (HypoPTH) patients before (n = 8) and after correction of hypocalcemia (n = 6) and compared to responses in 20 normotensive normocalcemic subjects. ACTH and AII were infused for 90 min at rates increasing from 12.5 to 50 mIU/30 min and 0.5 to 2.0 ng/kg X min, respectively. Pretreatment mean serum Ca was 6.8 +/- 0.2 (+/- SEM) mg/dl, and it rose to 9.3 +/- 0.2 mg/dl after 3-8 weeks of vitamin D administration. In the untreated HypoPTH patients, basal mean PA (5.4 +/- 1.3 ng/dl) was lower (P less than 0.01) than in the normal subjects (10.6 +/- 0.6 ng/dl) or treated HypoPTH patients (9.5 +/- 1.8 ng/dl). There was a marked reduction in PA responses to ACTH at all doses in the untreated HypoPTH patients compared to the normal subjects. With normalization of serum Ca in four patients, the mean peak PA response to ACTH (25.1 +/- 6.0 ng/dl) was not significantly different from normal (28.9 +/- 1.7 ng/dl). During graded dose AII infusion in five untreated HypoPTH patients, mean PA levels increased from 6.9 +/- 1.2 to 11.6 +/- 2.2 ng/dl; when the serum Ca was normal, the corresponding values were 8.7 +/- 1.8 and 20.2 +/- 3.61 ng/dl. There was a positive correlation (r = 0.475; P less than 0.05) between basal PA and serum Ca levels. In addition, maximum changes in mean arterial pressure in response to AII infusions were significantly greater after correction of hypocalcemia. These observations indicate that in HypoPTH patients, extracellular Ca concentrations can influence humoral aldosterone response to ACTH and AII and pressor responses to AII.

Altered red cell sodium transport in hypoparathyroidism: relation to serum calcium.

We studied Na transport in red blood cells (RBC) from six patients with hypoparathyroidism (HYPO; 3 postsurgical and 3 idiopathic) and 13 normal subjects. In HYPO, the effect of treatment-induced increases in serum Ca2+ on RBC Na transport also was examined. Na efflux mediated by the ouabain-sensitive Na,K pump and furosemide-sensitive Na,K cotransport (CoT) was examined by flux methodology in RBCs Na loaded to 5 levels of intracellular Na (Nai; 5-90 mM/liter cells) by the p-chloromercuribenzene method. The pump-mediated Na efflux was similar in untreated HYPO patients and normal subjects. Correction of hypocalcemia by vitamin D and oral calcium produced a mean increase in serum Ca2+ from 6.62 +/- 0.23 (+/- SEM) to 8.73 +/- 0.32 mg/dl. In HYPO patients treated with vitamin D and oral calcium, an increasing serum Ca2+ level was associated with significant (P less than 0.01) reductions in pump activity. Further, there was an inverse correlation (r = 0.813; P less than 0.001) between serum Ca2+ and pump-mediated Na efflux rate. RBC Na efflux through the CoT pathway was markedly reduced (P less than 0.05-0.01) in HYPO patients compared to normal subjects at all levels of Nai. Treatment-induced increases in serum Ca2+ had no effect on the reduced RBC CoT function in HYPO. Thus, changes in ambient serum Ca2+ can modulate the activity of the RBC Na,K pump in HYPO, with increases in Ca2+ inhibiting pump function. The markedly decreased RBC CoT activity was not related to associated hypertension or altered renal function and may represent a primary phenomenon in HYPO. These alterations in RBC Na transport may account for the higher Na, in RBCs of HYPO patients.

Ionized calcium during CPR in the canine model

The purpose of our study was to determine ionized calcium levels during cardiopulmonary resuscitation (CPR). Following placement of ascending aortic catheters in 15 adult mongrel dogs, ventricular fibrillation was induced electrically. After five minutes without therapy, mechanical external CPR was instituted. Animals received either standard CPR (S-CPR, n = 8) or simultaneous compression and ventilation CPR (SCV-CPR, n = 7) for 30 minutes. Ionized calcium levels were obtained prior to fibrillation and every five minutes during CPR. Mean ionized calcium levels during CPR (1.27 +/- 0.06 mmol/L) did not differ significantly from prearrest levels (1.27 +/- 0.07 mmol/L) at any point during CPR. This was true when the dogs were analyzed together (P = 0.1293) and when the animals receiving S-CPR (P = 0.4465) and SCV-CPR (P = 0.5470) were analyzed by groups. Defibrillation was attempted in all animals and resulted in electromechanical dissociation in three. None of these dogs was hypocalcemic either prior to arrest or during CPR, and none developed an effective rhythm with the administration of calcium. Furthermore, three of the four animals receiving calcium developed markedly elevated ionized calcium levels. Hypocalcemia apparently does not occur during CPR. The beneficial effect of calcium in reported cases cannot be explained routinely by correction of hypocalcemia. Further studies are needed to define the role of calcium administration, if any, in CPR.

Hypocalcemic heart failure

Hypocalcemia is a relatively uncommon but reversible cause of congestive heart failure. A 39-year-old woman with hypocalcemia due to untreated hypoparathyroidism presented with congestive heart failure and a left ventricular ejection fraction of 25 percent. She had no evidence of underlying cardiac disease. The serum calcium level was normalized within one week, associated with complete clearing of the signs and symptoms of heart failure and a twofold increase to 50 percent in the ejection fraction. This is the first patient without underlying myocardial disease in whom significant improvement of left ventricular function has been quantitatively assessed prior to and following correction of hypocalcemia.

Bone response to phosphate and vitamin D metabolites in the hypophosphatemic male mouse.

The hypophosphatemic male mouse (Hyp/y), the proposed model for human vitamin D-resistant rickets (VDRR), is characterized by chronic hypophosphatemia, dwarfism, and rachitic and osteomalacic bone lesions. We have reported that treatment of Hyp/y mice with phosphate salts (Pi) heals rickets but does not correct the defective endosteal bone mineralization. In an attempt to cure osteomalacia, mutant male animals were treated with Pi combined with 25-hydroxyvitamin D3 (25OHD3, 1 microgram/kg/day), 24,25-dihydroxyvitamin D3 [24,25(OH)2D3, 0.5 microgram/kg/day], or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3, 0.05--0.25 microgram/kg/day] infused constantly for 3 weeks. The biochemical and skeletal effects of treatment were assessed by analytical methods and bone histomorphometry. The results show that only 1,25(OH)2D3 produced a dose-dependent elevation of serum calcium and phosphorus, and greatly improved bone mineralization at doses high enough to increase serum calcium and phosphorus concentrations within or above the normal range. Better improvement of bone mineralization was obtained when Pi was combined to 1,25(OH)2D3. In conjunction with the correction of hypocalcemia, Pi + 1,25(OH)2D3 suppressed the stimulation of bone turnover induced by Pi supplementation. The results show that, as in VDRR children, 1,25(OH)2D3 produces beneficial effects on bone lesions in Hyp/y mice, mainly through enhancement of mineral availability. However, the persistence of osteomalacia despite correction of serum mineral concentrations suggests that there is a specific bone cell resistance to mineral and/or hormonal influences in Hyp/y mice.

Somatostatin and insulin secretion in man. IV. The role of calcium.

In this study we evaluated the influence of changes in serum calcium concentration upon somatostatin-mediated inhibition of insulin secretion in man. For this purpose, we investigated the effect of somatostatin in a group of subjects with hypoparathyroidism before and after correction of hypocalcemia and in normal subjects made hypercalcemic by exogenous calcium administration. In the presence of hypocalcemia, somatostatin caused an almost total inhibition of glucose-induced insulin secretion. In addition, somatostatin significantly decreased glucose tolerance in those hypocalcemic patients who exhibited normal tolerance under basal conditions [glucose utilization (kG), 1.44 +/- 0.13 before vs. 0.68 +/- 0.14 during somatostatin; P < 0.02]. Glucose tolerance was unaltered in those subjects who had a decreased glucose tolerance under basal conditions (kG, 1.01 +/- 0.1 before vs. 0.88 +/- 0.16 during somatostatin; P = NS). Under normocalcemic conditions, the insulin response to glucose and glucose tolerance were significantly greater than values measured during hypocalcemia. However, somatostatin blunted the insulin response to glucose and significantly decreased glucose utilization. These inhibitory effects of somatostatin upon insulin secretion and glucose tolerance were not reversed by a concurrent infusion of calcium (serum calcium, 6.9 +/- 0.3 meq/liter) in a group of normal subjects. Our data confirm the reduced insulin secretion and glucose tolerance in hypoparathyroidism and demonstrate that the suppressive effect of somatostatin upon glucose-stimulated insulin secretion is independent of changes in serum calcium concentration over a wide range.

Limit by hypherphosphatemia ofthe usefulness of vitamin D metabolites (1 α-hydroxycholecalciferol and 25-hydroxycholecalciferol) in the treatment of renal osteodystrophy

Nineteen patients who had been on maintenance hemodialysis for 33 months ,(± 13) with conditions optimized to prevent renal osteodystrophy (3 times week, a dialysate calcium of 7.0 mg/dl, oral calcium supplement and aluminum hydroxide to correct hypocalcemia and hyperphosphatemia, but with no vitamin D supplement) were treated with 1-alpha-HCC and 25-HCC (daily dosage of 1 and 50 μg respectively) for one year. This treatment was stopped every time the predialytic plasma levels of calcium and/or phosphate rose above 11.0 and 7.0 mg/di respectively in spite of an Increase in the prescribed dosage of aluminum hydroxide, and was resumed after normalization of plasma calcium and/or phosphate at reduced doses. The effect of vitamin D therapy was mainly assessed by histomorphometric evaluation of bone biopsies performed before initiating the treatment and 6 to 12 months later. Initially, no patient had histological evidence of osteomalacia as assessed by osteoid thickness Index, in spite of low plasma 25-HCC levels in 10 15 patients. 14 19 had hyperparathyroidism with extended active resorption surfaces (ARS) which were positively correlated with plasma PTH levels. During treatment, no patient developed osteomatacia. ARS Improved in 6 patients, worsened in 7 and remained unchanged In the 6 others, including 3 with initially normal values. When comparing worsened versus Improved patients, the aggravation of osteltis fibrosa was associated with increasing levels of plasma phosphate and pPTH. It is concluded that addition of vitamin D derivatives to optimal dialysis condlitions seems of questionable value because : 1) optimal dialysis conditions alone adequately prevent osteomalacla and most radiological osteitis fibrosa ; 2) vitamin D metabolite therapy may make plasma phosphate control more difficult which contributes to worsening of residual hyperparathyrodism.

Increased Growth after Long-Term Oral 1α,25-Vitamin D3in Childhood Renal Osteodystrophy

We evaluated oral 1,25-vitamin D3 for as long as 26 months in six prepubescent children with renal osteodystrophy previously treated with vitamin D2. Therapy was given at 14 to 41 ng per kilogram per day to correct hypocalcemia and reverse bone disease. Serum levels of 1,25-vitamin D3 were initially reduced at 15 +/- 5 pg per milliliter (mean +/- S.E.M.) and after treatment rose to 54 +/- 13. Serum calcium rose from 7.5 +/- 1.6 mg per deciliter (mean +/- S.D.) to 9.8 +/- 0.6 after one month (P less than 0.02). Alkaline phosphatase activity fell from 536 +/- 298 to 208 +/- 91 IU per liter after 12 months (P less than 0.05). Serum immunoreactive parathyroid levels fell from 900 +/- 562 microliter eq per milliliter 411 +/- 377. Healing of rickets and subperiosteal erosions was found. Remineralization of bone was demonstrated by the photon absorption technic. In four patients growth velocity, evaluated for 12 months before and after therapy, increased from 2.6 +/- 0.8 to 8.0 +/- 3.2 cm per year. Growth velocity per year increased from less than third percentile in each to the 10th to 97th percentile after therapy. Height increment ranged from 27 to 113 per cent of that expected for change in chronologic age and 40 to 114 per cent expected for change in bone age after therapy. This trial demonstrates that oral 1,25-vitamin D3 can reverse renal bone disease and increase growth in uremic children.