Medicines Q&As Q&A 373.1 How is acute hypocalcaemia treated in adults? Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Date prepared: 13th September 2011 Background There are no national guidelines for the treatment of acute hypocalcaemia, and practice varies widely across hospital Trusts. Following a thorough search of the literature, this guidance has been prepared and adopted in Leeds Teaching Hospitals NHS Trust. The use of calcium for other indications has not been considered. Reference ranges for serum calcium concentrations vary between laboratories. For the purpose of this document, the reference range used for adjusted calcium is 2.2 - 2.6 mmol/L. Intestinal calcium absorption is enhanced by 1,25-dihydroxyvitamin D3 (1,2) and the concentration of serum calcium is maintained within a narrow normal range under the influence of parathyroid hormone and 1,25-dihydroxyvitamin D3 (2-5). Mild hypocalcaemia is usually asymptomatic (4). Symptoms of hypocalcaemia generally correlate with the rate and magnitude of calcium depletion (2,3). It has been suggested that patients are less likely to be symptomatic if the serum calcium concentration has declined slowly (3). Features of hypocalcaemia may include: (2-7) Paraesthesia Tremors Muscle weakness Chvostek and Trousseau signs Muscle cramps Tetany Laryngospasm Bronchospasm Prolonged QT interval Hypotension Cardiac arrhythmias Seizures Coagulation irregularities Nausea, vomiting, diarrhoea Changes in mental state, e.g. confusion, irritability, anxiety Hypocalcaemia has been associated with the following conditions: (1-5,7,8) Septic shock Severe acute pancreatitis Rhabdomyolysis Chronic renal insufficiency Hypomagnesaemia Hypoparathyroidism Pseudohypoparathyroidism Post parathyroidectomy Malignant disease Inadequate dietary calcium intake Calcium malabsorption Vitamin D deficiency Massive blood transfusion Drug-induced: including some anticonvulsants, bisphosphonates, calcitonin, phosphate, colchicine overdose, foscarnet, citrated blood transfusions, radio contrast dye, ketoconazole and some antineoplastic agents From the National Electronic Library for Medicines. www.nelm.nhs.uk 1 Medicines Q&As Answer The cause of the hypocalcaemia should be established and if possible steps taken to correct it before calcium is administered, as in many cases the hypocalcaemia will reoccur if the underlying cause is not treated (9). Although this document offers guidance, the dose of calcium to correct hypocalcaemia should be determined on an individual patient basis. Oral calcium replacement Asymptomatic, mild hypocalcaemia is usually treated with oral calcium supplements (1,2) at a dose of 10 to 50 mmol daily for simple deficiency states and adjusted to the patient’s individual requirements (10). Calcium carbonate is the most frequently supplied calcium salt (11) and is well tolerated by most patients (3). In mild, asymptomatic hypocalcaemia, intravenous calcium replacement is not thought to be of any greater benefit than oral replacement and carries the risk of administration site reactions (12). Intravenous calcium replacement In severe acute hypocalcaemia or hypocalcaemic tetany, 2.2 to 4.5 mmol calcium (as gluconate) is administered as a slow intravenous injection over 5 to 10 minutes with ECG monitoring throughout the injection and afterwards (13-15). Note there is a risk of cardiac arrhythmias if the calcium is administered too quickly (3,13,14). The injection is usually followed with a calcium infusion to prevent recurrence (2,10,13). Practice varies, but a suggested regimen is 22.5 mmol calcium (as gluconate) in 1 litre sodium chloride 0.9% and administered at 50ml/hour (10,13,16). 10ml/kg of the above described preparation is estimated to increase serum calcium concentrations by 0.3 0.5 mmol/L (16). Calcium gluconate and calcium chloride are the most commonly used intravenous calcium preparations. Some prefer calcium chloride to calcium gluconate for parenteral administration, because retention of calcium from the chloride salt is thought to be greater than from the gluconate salt, and results in a more predictable increase in extracellular ionised calcium concentration. However, calcium chloride is considered to be the most irritant of the calcium salts (10). In September 2010, the MHRA published an alert regarding the use of calcium gluconate in small volume containers and the risk of aluminium exposure (17). Monitoring requirements Monitor electrolytes and urea (2,8). Parathyroid hormone and vitamin D levels should ideally be checked before initiating treatment for hypocalcaemia (8,16). If the patient has sepsis or renal failure, metabolic acidosis may accompany the hypocalcaemia. Calcium must be replaced to achieve serum levels close to normal range before the acidosis can be corrected. Failure to do this may result in convulsions or cardiac arrest (2,9). Serum magnesium concentrations should be monitored (2,4,8,16). If hypocalcaemia is secondary to hypomagnesaemia, correction of the magnesium may lead to spontaneous normalisation of calcium concentrations after a lag period of about 2 days (7). Without replenishing the magnesium, any increase in calcium concentrations may be transient (7,16). Cautions and contraindications of calcium use Calcium salts are contraindicated in patients with ventricular fibrillation or hypercalcaemia and should be used with great caution in patients who are taking cardiac glycosides as calcium enhances the effects of digoxin on the heart and may precipitate digitalis intoxication (4,8,10,15,16,18,19). If administered too quickly, parenteral calcium solutions can cause cardiac arrhythmias and hypotension (3,13,14). ECG monitoring should be performed during intravenous administration of calcium, especially in patients with a history of cardiac disease or those at risk of arrhythmias (4,13,14,). Calcium salts should be used with caution in patients with calcium renal calculi or in patients with diseases associated with hypercalcaemia such as sarcoidosis and some malignancies (10,18). From the National Electronic Library for Medicines. www.nelm.nhs.uk 2 Closer monitoring of serum calcium concentrations should be performed in patients with renal impairment (20). If parenteral calcium is used to treat hypocalcaemia when hyperphosphataemia is present (for example some acute cases of rhabdomyolysis), damaging precipitation of calciumphosphate in soft tissues can result (3). Adverse effects of calcium therapy Hypercalcaemia, gastrointestinal irritation and constipation have all been reported following calcium administration (10,18). A high dietary intake of calcium has long been suspected as contributing to the risk of renal calculi and calcium should be used with caution in patients at risk of renal calculi (18). Rapid intravenous injection of calcium salts may cause venous irritation (10,13,15,18), symptoms of hypercalcaemia, as well as a chalky taste (10,18), hot flushes, and peripheral vasodilatation (10,15). Hypotension, bradycardia, cardiac arrhythmias, syncope, and cardiac arrest have occurred following rapid intravenous administration of calcium salts (18). Soft-tissue calcification has followed the use of calcium salts parenterally (10,15). Care should be taken to avoid extravasation. Summary There is no national guidance on the treatment of hypocalcaemia, and practice varies widely between hospital Trusts. The guidance in this document reflects practice at Leeds Teaching Hospitals NHS Trust. The cause of the hypocalcaemia should be established and if possible, steps taken to correct it before calcium is administered Mild, asymptomatic hypocalcaemia is usually treated with oral calcium replacement at a dose of 10 to 50 mmol calcium daily for simple deficiency states and adjusted to the patient’s individual requirements. In severe acute hypocalcaemia or hypocalcaemic tetany, 2.2 to 4.5 mmol calcium is administered as a slow intravenous injection over 5 to 10 minutes and is usually followed by a calcium infusion to prevent recurrence. Intravenous calcium administration has been associated with adverse effects including serious venous irritation, hypotension, bradycardia, cardiac arrhythmias and cardiac arrest especially if calcium is administered too quickly. Care should be taken to avoid extravasation. Monitor urea and electrolytes including magnesium as only transient rises in serum calcium concentrations will be seen if concurrent hypomagnesaemia is not adequately treated. Check parathyroid hormone and vitamin D levels before initiating treatment for hypocalcaemia. Limitations This Q&A is designed for adult patients only. This guidance is not suitable for chronic hypocalcaemia, patients with complex medical problems, or those with renal impairment. The dose and route of calcium to correct hypocalcaemia should be determined on an individual patient basis. There are no national guidelines for the treatment of acute hypocalcaemia, and practice varies widely across Hospital Trusts. Disclaimer Medicines Q&As are intended for healthcare professionals and reflect UK practice. Each Q&A relates only to the clinical scenario described. Q&As are believed to accurately reflect the medical literature at the time of writing. The authors of Medicines Q&As are not responsible for the content of external websites and links are made available solely to indicate their potential usefulness to users of NeLM.You must use your judgement to determine the accuracy and relevance of the information they contain. See NeLM for full disclaimer. 3 References 1. Ariyan CE and Sosa JA. Assessment and Management of Patients with Abnormal Calcium. Critical Care Medicine. 2004;32(4)S146-S154 2. Bushinsky DA, Monk RD. Electrolyte Quintet: Calcium. The Lancet. 1998; 352: 305–11 3. Tohme JF and Bilezikian JP. Diagnosis and Treatment of Hypocalcaemic Emergencies. The Endocrinologist. 1996;6:10-18 4. Compston, JE. Investigation of Hypocalcaemia. Clinical Endocrinology. 1995; 42: 195-198 5. Goldhill DR. Calcium and Magnesium. Care of the Critically Ill. 1997;13(1):112-115 6. Forsythe RM, Wessel CB, Billiar TR et al. Parenteral Calcium for Intensive Care Unit Patients (Review). A Cochrane Review. The Cochrane Library. 2009. Issue 3 7. Dickerson RN, Morgan LM, Croce MA et al. Treatment of Moderate to Severe Acute Hypocalcaemia in Critically Ill Trauma Patients. Journal of Parenteral and Enteral Nutrition. 2007; 31(3):228-233 8. Dickerson RN. Guidelines for the Intravenous Management of Hypophosphatemia, Hypomagnesemia, Hypokalemia, and Hypocalcemia. Hospital Pharmacy. 2001;36(11):1201-1208 9. Leeds Teaching Hospitals NHS Trust. Clinical Guideline for the Treatment of Hypocalcaemia in Adults. In house document. Review date August 2013. 10. Sweetman S (ed.). Martindale. The Complete Drug Reference, online edition. The Pharmaceutical Press, London. http://medicinescomplete.com. (Date accessed 09/09/2011) 11. Steichen O. Use of Oral Calcium to Treat Hypocalcaemia (letter). British Medical Journal. 2008;336:1392 12. Chen HC. Intravenous Calcium Replacement for Asymptomatic Hypocalcemia of Critical Illness. The Endocrinologist. 2001;11:364-367 13. Martin J (Editor). British National Formulary. No. 61 March 2011. The British Medical Association and the Royal Pharmaceutical Society of Great Britain. Available online at www.bnf.org 14. Medusa Injectable Medicines Guide. Available at http://medusa.wales.nhs.uk (Date accessed 17/06/2011) 15. Summary of Product Characteristics. Electronic Medicines Compendium. Datapharm Communications Ltd. (Hameln Ltd Calcium Gluconate Injection BP). http://emc.medicines.org.uk/ (date accessed 24/1/2010; date last updated: 09/08/2010) 16. Cooper, MS, Gittoes, NJL. Diagnosis and Management of Hypocalcaemia. British Medical Journal. 2008;336:1298-1302 17. Medicines and Healthcare products Regulatory Authority. Public Assessment Report Calcium gluconate 10% injection in 10ml glass containers: risk of aluminium exposure. September 2010. Available at http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarnings andmessagesformedicines/CON093935 18. McEvoy GK (ed.). AHFS Drug Information 2009, online edition. American Society of Health-System Pharmacists, Bethesda, USA. http://medicinescomplete.com. (Date accessed 17/06/2011) 19. Baxter K (ed). Stockley’s Drug Interactions, online edition. The Pharmaceutical Press, London. http://medicinescomplete.com. (Date accessed 17/06/2011) 20. Ashley, C and Currie, A (Eds). The Renal Drug Handbook, 3rd Edition (2009). Radcliffe Medical Press, Oxford. Quality Assurance Prepared by Lucy Hennessy, Leeds Medicines Information Centre Date Prepared 13th September 2011 Checked by David Abbott, Leeds Medicines Information Centre 4 Date of check 13th September 2011 External QA check by Chris Proudlove Date of check 14th September 2011 Search strategy Embase [terms used: calcium (exp), calcium deficiency (exp), limited to English, Human and Adult.] Medline [terms used: calcium (exp), calcium deficiency (exp), limited to English, Human and Adult] In-house Database/resources eMC 5