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Three Part Question

[In patients presenting with hypocalcemia to the emergency department] is the [administration of intravenous calcium gluconate as effective as calcium chloride] at [increasing calcium levels]?

Clinical Scenario

A 22 year old woman with a history of hypoparathyroidism presents to the emergency department with recurrent grand mal seizures. Her ionized calcium level is 0.7 mmol/L (2.8 mg/dL). You prefer to administer intravenous calcium gluconate over calcium chloride because it causes less tissue necrosis if extravasated. Also, calcium gluconate is better tolerated through a peripheral IV. However, you recall that calcium gluconate might possess a slower onset of action because it requires hepatic metabolism to release the elemental and active form of calcium.

Search Strategy

Medline 1966-08/16 using OVID interface, Cochrane Library (2016), and Embase
[exp calcium gluconate/ AND exp calcium chloride/ AND exp hypocalcemia/]

Search Outcome

12 studies were identified; three clinical trials addressed the clinical question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Thomas J Martin, M.D., Yoogoo Kang, M.D., Kerri M Robertson, M.D., F.R.C.P., Mohamed A. Virji, M.D., July 1990 USA	24 Adult patients undergoing liver trasplant were monitored with frequent blood samples through an arterial line during adminstraction of calcium gluconate or calcium chloride.	Randomized prospective	Increase in Ca++ concentration following administration of CaGluc or CaCl2 in essentially anhepatic patients.	Ca++ concentration increased rapidly in both formulations. At 1 min, CaCl2 group had an increase of 0.98 +/- 0.14mM and CaGluc had an increase of 1.05 +/-0.10mM. Both groups showed equal gradual decline over the subsequent 10 min. Ca++ concentration was similar in the two groups of patients over the observation period.	Patients were anesthetized and undergoing liver transplant with co-morbidities related to this disease state. Patients were anhepatic and possessed normal ionized calcium levels. Only single dose regimens were used of Calcium gluconate.
Charles J. Cote, M.D., Lambertus J. Drop, M.D., Alfred L. Daniels, M.S., David C. Hoaglin, Ph.D. 1987 USA	Pediatric patients scheduled for burn wound excision and grafting as well as conditioned dogs under halothane anesthesia received calcium chloride and calcium gluconate.	Randomized Prospective	In pediatric patients and dogs, rate and dissociation of Cal++ was compared and analyzed.	No significant difference in the ionization of CaGluc and CaCl2 was noted when given as a ratio of 1:3 respectively. Both formulations resulted in a rapid and equivalent change in Ca++ concentration. No short-term advantage of one formulation over another.	No adult patients were used in the study. Dogs were used in the study. Calcium was administered in subjects with normal ionized calcium states. Patients were not critically ill. Factors of tissue damage and pH were not evaluated.
Cynthia W. Broner, MD, Gregory L Stidham, MD, David F. Westenkirchner, MD and DOnald C Watson, MD December 1990 USA	Critically ill non-neonatal pediatric patients	Prospective, Randomized, Double-Blind Comparison	Critically ill pediatric patients with hypocalcemia.	The mean increase in ionized calcium level in the CaCl2 group was 0.19 mmol/L and for the CaGluc group 0.09 mmol/L. All patients who recieved CaCl2 showed increase in Ionized Calcium levels. Two patients in the CaGluc group showed no increase in ionized Calcium. CaCl2 appears to have greater bioavailability.	No adult patients were enrolled in the study. Study involved only critical ill pediatric patients.

Comment(s)

Patients presenting to the Emergency department with hypocalcemia require urgent or emergent transfusion of calcium. Calcium gluconate and calcium chloride are two commonly used compounds for correction of hypocalcemia. Concern over tissue necrosis with the use of calcium chloride may preclude its use in these cases, but the delayed rise in serum calcium in calcium gluconate may preclude its use. Concern for bioavailability, dissociation and hepatic metabolism also contribute to the use of one modality over another. The rise in ionized or bioavailable calcium reflects the correction of this chemical element en vivo. Evaluating the risk of providing calcium chloride over calcium gluconate may provide evidence that the risk of this chemical formulation outweighs the benefits of the presumed rapid rise in serum calcium. Calcium gluconate and calcium chloride also are used in cardiac stabilization in patients with hyperkalemia. If the serum concentration of calcium rises equally in calcium gluconate and calcium chloride, then the use of calcium gluconate would be preferred due to the lower risk of side effects including tissue necrosis from extravasation.

Clinical Bottom Line

The risk of tissue necrosis due to extravasation of CaCl2 is well established and calcium gluconate is known to better tolerated through a peripheral IV. Therefore, finding benefit of CaCl over CaGluc requires additional benefits for CaCl when considering administration through a peripheral IV. Martin, et al. and Cote et al. showed that calcium gluconate and calcium chloride show equal rise in calcium concentrations concluding that bioavailability are equal in these two chemical formulations. However, they assess patients with normal ionized calcium levels and therefore may underestimate the true bioavailablity of calcium in patients with ionized hypocalcemia. Broner et al. focused on critically ill pediatric patients with documented low ionized calcium levels. The use of calcium chloride for correction of ionized calcium was superior to calcium gluconate in this study. The physiology of a critically ill child may increase the bioavailability of Ca++ in CaCl2. Therefore, we are left with the risk of calcium chloride versus the accelerated improvement of ionized calcium. Calcium gluconate shows improvement of ionized calcium levels that is delayed in comparison. This is most noted in critically ill pediatric patients. Clinical judgement remains prudent in selecting the appropriate agent in the correction of hypocalcemia in emergency department patients.

References

1. Martin TJ, et al. Ionization and Hemodynamic Effects of Calcium Chloride and Calcium Gluconate in the Absence of Hepatic Function Anesthesiology July 1990; 62-65
2. Cote CJ, et al. 1987 Calcium Chloride Versus Calcium Gluconate: Comparison of Ionized and Cardiovascular Effects in Children and Dogs Anesthesiology 1987; 465-470
3. Broner CW, et al. December 1990 A Prospective, Randomized, Double-Blind Comparison of Calcium Chloride and Calcium Gluconate Therapies for Hypocalcemia in Critically Ill Children The Journal of Pediatrics December 1990; 986-989