Special Comments - Neonatal Intensive Care Drug Manual

Evidence summary
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Hypocalcaemia:
Hypocalcaemia may be defined as a serum total calcium concentration <1.875 mmol/L (7.5 mg/dL) or ionized calcium < 1.2 mmol/L.[1] Calcium concentrations decrease transiently after birth.[2-4] Early neonatal hypocalcaemia occurs within the first 3 days of life and is common in premature infants with 26% to 50% having levels < 1.75 mmol/L (7 mg/dL).[2-4] Most infants will be asymptomatic, with hypocalcaemia detected only on routine chemistries. They may present with symptoms of neuromuscular irritability including tremulousness, tetany, exaggerated startle response, seizures and laryngospasm, and nonspecific symptoms such as apnea.[1, 3]
Efficacy:
Treatment of hypocalcaemia: In normocalcaemic infants, a randomised trial of calcium chloride 10% (2.5 mg/kg) vs calcium gluconate 10% (7.5 mg/kg) reported an equal effect on calcium concentrations.[5] However, in 49 critically ill, hypocalcaemic infants (age 1 day to 17 years), calcium chloride 0.136 mEq/kg per dose resulted in a greater increase in ionised calcium and blood pressure than calcium gluconate 0.136 mEq/kg per dose. The group receiving calcium chloride had an increase in MAP of nearly 6 mm Hg (p <0.05). No change in blood pressure was seen in the group receiving calcium gluconate.[6] In 104 newborns with late symptomatic hypocalcaemia after artificial feeding with a full-cream evaporated milk were randomly allocated to calcium gluconate 10% 10 ml orally vs phenobarbitone 75 mg 6-hourly orally for 48 hours vs magnesium sulphate 50% 0.2 mL/kg intramuscularly on two occasions 12 hourly. The plasma calcium levels rose in all groups, but infants treated with magnesium sulphate had higher plasma-calcium concentrations after 48 hours’ treatment and fewer convulsions during and after the treatment period.[7]
Prevention of hypocalcaemia: In preterm and sick newborn infants, the addition of calcium gluconate 10% at 4 ml/kg/day [0.93 mmol/day calcium] to maintenance fluids for 120 hours resulted in a reduction in hypocalcaemia incidence (15% vs 48% ionised Ca <0.7 mmol/l) but an increased incidence of extravasation with tissue damage (35% vs 10%). The benefit of intravenous calcium was short lived and associated with a significant risk of local tissue necrosis.[8]
Recommendation:
Routine addition of calcium to maintenance fluids cannot be recommended in high risk babies.[8](LOE II GOR C)
Treatment of newborns with acute or symptomatic hypocalcaemia is accomplished best by the intravenous infusion of calcium salts - 10% calcium gluconate (9.3 mg/mL of elemental calcium) is used most commonly. In asymptomatic newborns, treatment is indicated when the total serum calcium concentration < 1.5 mmol/L (6 mg/dL) in the preterm infant and less than <1.75 mmol/L (7 mg/dL) in the term infant. Calcium supplementation can be given either by the intravenous or oral route, depending on the clinical status of the infant. [1] [Expert opinion].
Treatment in cardiac arrest: Calcium is not commended for use in neonatal resuscitation by ILCOR or ANZCOR.[9, 10] Evidence from three LOE 2 studies in children and five LOE 5 adult studies failed to document an improvement in survival to hospital admission, hospital discharge, or favourable neurological outcome when calcium was administered during cardiopulmonary arrest in the absence of documented hypocalcaemia, calcium channel blocker overdose, hypermagnesaemia or hyperkalaemia. [11, 12] [Expert Consensus Opinion]
ANZCOR Paediatric recommendation: Calcium may be used as an inotropic or vasopressor but it has no place in the management of an arrhythmia unless it is caused by hyperkalaemia, hypocalcaemia, hypermagnesaemia or calcium channel blocker. It should not be given routinely at a cardiac arrest and is associated with worse outcome. [11] [Expert Consensus Opinion]
Arrhythmia caused by hyperkalaemia, hypocalcaemia or hypermagnesaemia, or hypotension caused by calcium channel blocker: In a case series, extremely premature infants with arrhythmia secondary to hyperkalaemia were all initially successfully treated with an intravenous bolus of calcium (dose not reported). [13, 14]
ANZCOR Paediatric guideline: Calcium (0.15 mmol/kg) is the antidote to hypotension caused by a calcium channel blocker.[9] The intravenous or intraosseous dose is 0.2mL/kg of 10% calcium chloride or 0.7mL/kg of 10% calcium gluconate. [11] [Expert Consensus Opinion]
Exchange transfusion: Exchange transfusion with blood stored in citrate causes a fall in ionised calcium concentrations.[15, 16] Current supplies of Australian Red Cross Blood Service whole blood contain citrate, whereas packed red cells contain saline, adenine, glucose and mannitol. A quasi-random trial of 30 infants undergoing exchange transfusion for hyperbilirubinaemia with CPD stored whole blood with intervention group receiving 1 mL 10% calcium gluconate for every 100 mL blood reported the intervention group had a significant increase in total and ionised calcium whereas control group had a fall in total and ionised calcium. However, the difference was not clinically important.[17] Conclusion: A systematic review concluded there is no good-quality evidence to support or reject continual use of calcium during exchange transfusion with citrated blood.[18]
Safety:
The addition of calcium gluconate 10% at 4 ml/kg/day [0.93 mmol/day calcium] to intravenous maintenance fluids increased incidence of extravasation with tissue damage (35% vs 10%).
Calcium gluconate solution in glass containers contains almost 200 times more aluminium than calcium gluconate in plastic containers, due to the solution leaching aluminium from the glass. The Paediatric Medicines Expert Advisory Group recommended that these products should no longer be used for repeated or prolonged treatment of children or those with impaired renal function. [19]
Calcium can slow the heart rate and precipitate arrhythmias. In cardiac arrest, calcium may be given by rapid intravenous injection. In the presence of a spontaneous circulation give it slowly. Do not give calcium solutions and sodium bicarbonate simultaneously by the same route to avoid precipitation.[20]
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References
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1. Hyman SJ, Novoa Y, Holzman I. Perinatal Endocrinology: Common Endocrine Disorders in the Sick and Premature Newborn. Endocrinology and Metabolism Clinics of North America. 2009;38:509-24.
2. Altirkawi K, Rozycki HJ. Hypocalcemia is common in the first 48 h of life in ELBW infants. Journal of Perinatal Medicine. 2008;36:348-53.
3. Rosli A, Fanconi A. Neonatal hypocalcaemia. 'Early type' in low birth weight newborns. Helvetica Paediatrica Acta. 1973;28:443-57.
4. Tsang RC, Oh W. Neonatal hypocalcemia in low birth weight infants. Pediatrics. 1970;45:773-81.
5. Cote CJ, Drop LJ, Daniels AL, Hoaglin DC. Calcium chloride versus calcium gluconate: comparison of ionization and cardiovascular effects in children and dogs. Anesthesiology. 1987;66:465-70.
6. Broner CW, Stidham GL, Westenkirchner DF, Watson DC. A prospective study, randomized, double-blind comparison of calcium chloride and calcium gluconate therapies for hypocalcemia in critically ill children. Journal of Pediatrics. 1990;117:986-9.
7. Turner TL, Cockburn F, Forfar JO. Magnesium therapy in neonatal tetany. Lancet. 1977;1:283-4.
8. Khan MAG, Upadhyay A, Chikanna S, Jaiswal V. Efficacy of prophylactic intravenous calcium administration in first 5 days of life in high risk neonates to prevent early onset neonatal hypocalcaemia: A randomised controlled trial. Archives of Disease in Childhood: Fetal and Neonatal Edition. 2010;95:F462-F3.
9. Australian Resuscitation Council. New Zealand Resuscitation Council. Medication or fluids for the resuscitation of the newborn infant. ARC and NZRC Guideline 2010. Emerg Med Australas. 2011;23:442-4.
10. Wyllie J, Perlman JM, Kattwinkel J, Wyckoff MH, Aziz K, Guinsburg R, Kim HS, Liley HG, Mildenhall L, Simon WM, Szyld E, Tamura M, Velaphi S, Neonatal Resuscitation Chapter C. Part 7: Neonatal resuscitation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015;95:e169-201.
11. Australian Resuscitation Council. New Zealand Resuscitation Council. Medications and fluids in paediatric advanced life support. ARC and NZRC Guideline 2010. Emerg Med Australas. 2011;23:405-8.
12. de Caen AR, Kleinman ME, Chameides L, Atkins DL, Berg RA, Berg MD, Bhanji F, Biarent D, Bingham R, Coovadia AH, Hazinski MF, Hickey RW, Nadkarni VM, Reis AG, Rodriguez-Nunez A, Tibballs J, Zaritsky AL, Zideman D, Paediatric B, Advanced Life Support Chapter C. Part 10: Paediatric basic and advanced life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2010;81 Suppl 1:e213-59.
13. Kilbride HW, Cater G, Warady BA. Early onset hyperkalemia in extremely low birth weight infants. J Perinatol. 1988;8:211-4.
14. Vemgal P, Ohlsson A. Interventions for non-oliguric hyperkalaemia in preterm neonates. Cochrane Database Syst Rev. 2012:CD005257.
15. Maisels MJ, Li TK, Piechocki JT, Werthman MW. The effect of exchange transfusion on serum ionized calcium. Pediatrics. 1974;53:683-6.
16. Smits-Wintjens VE, Rath ME, van Zwet EW, Oepkes D, Brand A, Walther FJ, Lopriore E. Neonatal morbidity after exchange transfusion for red cell alloimmune hemolytic disease. Neonatology. 2013;103:141-7.
17. Locham KK, Kaur K, Tandon R, Kaur M, Garg R. Exchange blood transfusion in neonatal hyperbilirubinemia-role of calcium. Indian pediatrics. 2002;39:657-9.
18. Ogunlesi TA, Lesi FE, Oduwole O. Prophylactic intravenous calcium therapy for exchange blood transfusion in the newborn. Cochrane Database Syst Rev. 2017;10:CD011048.
19. Medicines and Healthcare products Regulatory Agency (MHRA) report. Calcium gluconate 10% in 10 mL glass containers: risk of aluminium exposure. http://www.mhra.gov.uk/safety-public-assessment-reports/CON105682. 2010.
20. Soar J, Nolan JP, Bottiger BW, Perkins GD, Lott C, Carli P, Pellis T, Sandroni C, Skrifvars MB, Smith GB, Sunde K, Deakin CD, Adult advanced life support section C. European Resuscitation Council Guidelines for Resuscitation 2015: Section 3. Adult advanced life support. Resuscitation. 2015;95:100-47.
21. Calcium chloride – Micromedex. Accessed online 24/3/2016.
22. Calcium gluconate – Micromedex. Accessed online 24/3/2016.
23. Australian Injectable Drugs Handbook, 6th Edition, Society of Hospital Pharmacists of Australia 2014. Accessed on 24/3/2016.
24. Calcium equivalents. http://www-users.med.cornell.edu/~spon/picu/calc/cacalc.htm. Accessed on 7 06 2016.
25. Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. 1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). Journal of pediatric gastroenterology and nutrition. 2005;41 Suppl 2:S1-87.
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