Investigation and Management of Acute Hypocalcaemia
Flowchart
Introduction

This guideline is intended to provide doctors with a clear structure for the initial investigations and management of children who present with hypocalcaemia. It incorporates recently published guidance and consensus.
Scope

Paediatricians working across Wessex. Children with hypocalcaemia should be discussed with the lead for paediatric endocrinology at each DGH (Wessex Paediatric Endocrinology Network) during working hours
Purpose
​​
The aim of the guideline is to provide an agreed clinical approach to managing hypocalcaemia, provide an overview of the wide spectrum of underlying disorders that can result in hypocalcaemia and guide clinicians to the appropriate investigations including those that should be carried out prior to initiating treatment. 
Definitions
Calcium
99% of body calcium is contained in bones. Calcium circulates in plasma in three fractions: ionised, non-ionised and protein bound (mainly to albumin). Ionised calcium constitutes about 50% total circulating calcium and must be maintained within narrow limits (1.1-1.3 mmol/l) for optimal neuromuscular function. Gas machines will give a value for the ionised calcium (iCa). Most of the remaining calcium (about 40%) is bound to albumin, with a typical normal range of 2.2-2.6mmol/l. Conditions associated with hypoalbuminaemia will reduce the total calcium without a change in ionised calcium.
 
Corrected calcium for albumin level can be calculated with the following formula:
 
Ca corr = Ca total + (40-alb) x 0.02

Calcium homeostasis
The maintenance of serum calcium levels in the normal range by a complex process involving Vitamin D, parathyroid hormone (PTH) and the calcium sensing receptor.
 
Hypocalcaemia itself is not a diagnosis and requires thorough investigation to establish the cause. It can be defined as a corrected calcium level that is below normal values for age. 
 
Hypocalcaemia can also be defined as per clinical presentation:
  • Biochemical (asymptomatic)
  • Mildly symptomatic (distal paraesthesia) usually levels < 2.0mmol/l
  • Severely symptomatic (tetany, seizures, arrhythmias) usually levels <1.8 mmol/l​
Clinical Features of Hypocalcaemia

  • Hypocalcaemic tetany 
  • Paraesthesia of hands and feet
  • Perioral numbness
  • Muscle cramps
  • Carpopedal spasm
  • Focal or generalised seizures
  • Cardiac arrhythmias (prolonged QTc, conductive abnormalities with bradycardia)
  • Some patients may have more non-specific symptoms such as fatigue, hyperirritability anxiety and depression
  • Infants may show non-specific symptoms of lethargy, vomiting or poor feeding
  • Patients with chronic hypocalcaemia may be asymptomatic even with severe hypocalcaemia (total corrected Ca <1.8 mmol/l)
Causes of Hypocalcaemia

A PTH measurement at the time of hypocalcaemia is key to determining the underlying aetiology. 

Hypocalcaemia associated with low PTH
 
  • Hypoparathyroidism
    • Parathyroid aplasia/hypoplasia or abnormal PTH production
    • Following neck surgery eg thyroidectomy
    • As part of 22q11 deletions (Di George syndrome)
      • 10p13 deletion
      • CHARGE syndrome
    • X linked/AR/AD hypoparathyroidism 
    • Syndrome of hypoparathyroidism, deafness, renal dysplasia (HDR)
    • Sanjad-Sakati syndrome (hypoparathyroidism, retardation, dysmorphism; HRD)
    • Type 1 autoimmune polyendocrinopathy
    • Infiltrative lesions such as Wilson’s disease, thalassaemia
    • Mitochondrial DNA mutations e.g. Kearns Sayre syndrome
 
  • Hypomagnesaemia (congenital – rare, acquired – malabsorption, drugs, burns). 
 
Hypocalcaemia associated with inappropriately normal PTH 

  • Abnormalities of the calcium-sensing receptor
 
Hypocalcaemia associated with high PTH 

  • Iatrogenic – excessive phosphate intake eg high phosphate containing milks, TPN.
  • Vitamin D deficiency - nutritional insufficiency, malabsorption
  • Impaired vitamin D metabolism
    • Enzyme deficiency—defects of the 1 alpha hydroxylase gene. (vitamin D dependent rickets type I)
    • End organ resistance to vitamin D (vitamin D dependent rickets type II)
  • Pseudohypoparathyroidism Type 1a – Albright’s hereditary osteodystrophy phenotype
  • Chronic renal failure
  • Osteopetrosis (rare neonatal)
Important Points to Guide the Examination

a) Signs suggestive of acute hypocalcaemia include:
  • Seizures
  • Muscle cramps 
  • Latent tetany may be detected by positive Chvostek’s and Trousseau’s signs
  • Trousseau’s sign: induction of carpopedal spasm by inflation of a sphygmomanometer above systolic blood pressure for three minutes.
  • Chvostek’s sign: contraction of ipsilateral facial muscle elicited by tapping the facial nerve just anterior to the ear.
 
b) Clinical signs of rickets
  • Swollen wrists
  • Prominent costochondral junction (rachitic rosary)
  • Bow legs or Knock knees
  • Craniotabes
 
c) Signs suggestive of chronic hypocalcaemia include:
  • Dry skin, coarse hair, brittle nails
  • Enamel hypoplasia with dental caries
  • Cataract, papilloedema
  • Extrapyramidal signs from basal ganglia calcification.
 
d) Check for features of syndromes associated with hypocalcaemia
  • Pseudohypoparathyrodism type 1a – e.g. subcutaneous ossification
  • 22q deletion (DiGeorge syndrome) – e.g. congenital heart disease
Investigation of Hypocalcaemia

A key clinical practice point is to take blood for PTH at the time of hypocalcaemia and before institution of therapy. The PTH level at the time of hypocalcaemia is diagnostically important to aid diagnosis and subsequent management (section 3). 
Blood
Urine
Other
  • Calcium (corrected and ionised)
  • PTH (send urgently to lab)
  • Phosphate 
  • 25 hydroxy vitamin D 
  • Magnesium 
  • Bicarbonate 
  • Alkaline phosphate
  • Renal profile
  • LFTs​
  • Save serum sample 
 
Consider : Calcium, phosphate, PTH, 25OHD in parents (especially for neonatal presentations) – e.g. calcium sensing receptor mutations may be autosomal dominant 
  • Calcium/ Creatinine ratio 
  • Phosphate
  • pH 
  • protein
  • glucose 
  • 12-lead ECG - Look for Prolonged QTc
  • CXR to look for evidence of cardiomegaly
  • XR hand and wrist (if rickets suspected)
Acute Management of Severe Hypocalcaemia

Severely symptomatic (Tetany, Seizures, Arrhythmias, Stridor):
 
  • Assess and stabilise ABC
  • If seizures, treat with anticonvulsants as per status epilepticus guideline
  • Continuous cardiac monitoring
  • Establish good venous access and take above bloods
  • A slow bolus intravenous correction of hypocalcaemia is indicated followed by an infusion of calcium if the patient is severely symptomatic. 
An intravenous bolus of 10% calcium gluconate 0.5 ml/kg (0.11 mmol/kg) to a maximum of 20 ml over 10 minutes should be administered (maximum rate 0.5 mmol/minute), followed by a continuous intravenous infusion over 24 h of 0.5 -1.0 mmol/kg (maximum 8.8 mmol)

  • consider transfer to Paediatric HDU, cardiac monitoring
  • contact local anaesthetic team and PICU to establish central access for calcium infusion
 
Central access is required for calcium infusions.

Calcium gluconate undiluted has high osmolality and may cause venous irritation and tissue damage in cases of extravasation. In an emergency situation if central venous access is unavailable, a bolus of diluted Calcium gluconate may be given using a large peripheral IV line. Monitor the insertion site closely using a recognised phlebitis scoring tool. Re-site cannula at first signs of inflammation.

Intravenous calcium injection and IV calcium infusion preparation
 
Neonate and child 1 month - 18 years:
 
Dilute with sodium chloride 0.9% or glucose 5%.
 
Dilute to a concentration of 0.045mmol in 1mL (a 1 in 5 dilution, that is, dilute each 1mL calcium gluconate 100mg per 1mL with 4mL diluent). Concentrations greater than 0.045mmol in 1mL should be given via a central venous access device.
Example calculations:

Infusion rate (neonate and child up to 2 years)

Calculate the infusion rate using the following equation:
 
Calcium gluconate infusion rate (mL/hour) = Dose (mmol/kg/day) x patient weight (kg)/24 (hours) x concentration (mmol/mL)
 
For example: To administer a dose of 1mmol/kg/day of calcium gluconate to a 10kg child using a solution diluted to 0.045mmol/mL:
 
Calcium gluconate infusion rate =1 (mmol/kg/daily) x 10 (kg)/ 24 (hours) x 0.045 (mmol/mL) = 9.3mL/hour
Infusion rate (child 2-18 years) 

​Calculate the infusion rate using the following equation:
 
Calcium gluconate infusion rate (mL/hour) = Dose (mmol over 24 hours)/24 (hours) x Concentration (mmol/mL)
 
For example: To administer a dose of 8.8mmol over 24 hours to a 6 year old child using a
solution diluted to 0.045mmol/mL:
 
Calcium gluconate infusion rate = 8.8 (mmol over 24 hours)/ 24 (hours) x 0.045 (mmol/mL) = 8.1mL/hour

Give calcium through an intravenous line with no other infusions running. Phosphate and bicarbonate will cause precipitation.

Treat hypomagnesemia  

Hypomagnesemia will usually respond to oral Mg treatment Mg glycerophosphate 0.2mmol/kg every 8 hours (When over 40 kg the maximum dose is 8mmol every 8 hours). In severe symptomatic hypocalcaemia with Mg less than 0.5 mmol/L consider treatment with IV magnesium sulphate – see SORT guideline.  

Ongoing management
​
  • Discuss case with network centre lead for paediatric endocrinology at each DGH during working hours (appendix A)
  • Repeat Ca level after first bolus and at 4 - 6 hours to ensure improvement, then 12 hourly as indicated by trend of Ca levels
  • Stopping the calcium infusion suddenly is likely to result in a rapid fall of serum calcium levels due to uptake into bone, aim to wean off over 24-48 hours or sooner if oral treatment has been initiated.
  • Aim to keep corrected calcium > 1.9 mmol/L and ensure that oral treatment is tolerated.

At this point start to wean calcium infusion rate gradually over the following 48 hrs (suggested weaning rate is by 25% every 12 hours with 12-hourly calcium levels to guide any adjustment to this rate).
  • Aim to maintain calcium in low normal range (2-2.2 mmol/L) (to limit risk of hypercalciuria if underlying cause hypoparathyroidism)
  • Closely monitor cannula site during infusion because of risk of extravasation.
 
Asymptomatic but severe biochemical hypocalcaemia (corrected Ca < 1.8 mmol/L or ionised Ca < 0.9)

  • Perform ECG and measure QTc
  • If prolonged QTc (> 0.44 seconds) or history suggestive of sudden drop in Ca treat with calcium infusion as above.
  • If asymptomatic with normal QTc (likely in chronic Hypocalcaemia) use oral treatment (see below)
  • Continuous ECG monitor is recommended until corrected Ca+ > 1.8 mmol/l
  • If symptoms develop or a sudden further drop in Ca while on oral supplement, start on intravenous Ca infusion as above.
 
Oral calcium and vitamin D  therapy 

  • Commence therapy after taking investigations (see section 3)
 
Calcium supplement: doses as per BNFC. Doses can be adjusted as per response aiming for corrected Ca levels 2-2.2 mmol/L
  • Age 1 month – 4 years: 0.25 mmol (10 mg) per kg four times daily
  • Age 5 – 12 years: 0.2 mmol (8 mg) per kg four times daily
  • Age 12–18 years: 10 mmol (400 mg) four times daily ​

Examples of Calcium preparations (see BNFc):
  • Liquid: Calcium –Sandoz syrup 2.7mmol/5mls
  • Effervescent tablets:
    • ​Calcit (calcium carbonate 1.25g) – providing 500mg or 12.5mmol Ca2+ per tablet when dissolved in water.
    • Sandocal 400 tablets (calcium lactate gluconate 930mg, calcium carbonate 700mg) - providing calcium 400mg or 10mmol per tablet when dissolved in water.
  • Chewable tablets:
    • Adcal - fruit flavoured - calcium carbonate 1.5g (calcium 600mg or 15mmol per tablet)
    • Calcichew - orange flavoured calcium carbonate 1.25g (calcium 500mg or 12.5 mmol/tablet)
 
Optimise calcium content of diet:
 
See the British Dietetic Association (BDA) factsheet on Calcium (available at www.bda.uk.com) for information on how the recommended daily calcium intake can be achieved.

Vitamin D supplements:

Commence all patients on Vitamin D supplements pending the results of 25(OH) Vitamin D.

There is data to show that (colecalciferol) vitamin D3 is more bioavailable than (ergocalciferol) vitamin D2 , therefore vitamin D3 is recommended as the preferred treatment although treatment with vitamin D2 is effective.
The doses of vitamin D below are based on what are currently recommended in the British National Formulary for Children (BNFC) and National Osteoporosis Society guidance:

  • under 1 month 1,500 units daily
  • 6 months 3,000 units daily
  • 6 months - 12 years 6,000 units daily
  • 8 weeks 12 -18 years 10,000 units daily
 
If not tolerating oral vitamin D or concerns regarding possible malabsorption an intramuscular dose of ergocalciferol can be given as follows:

  • 1-6 months: 15 000 units
  • 6 month-12 years: 25 000 units
  • 12 years: 40 000 units
 
Examples of vitamin D preparations (please discuss with your hospital pharmacy):
  • Invita D3 2,400 IU/ml oral drops (1 drop = 67 units)
  • InVita D3 25,000 IU oral solution (snap ampoules)
  • Fultium D3 drops 2740 IU/ml, 3 drops = 200 units
 
Please be aware some preparations contain nut oils. Fultium D3 drops and Invita D3 snap ampoules contain coconut oil and palm kernel oil, and olive oil respectively. They are suitable for patients with peanut allergies. They are also suitable for vegetarians, and are Kosher and Halal. Tablets or capsule preparations are also available for example: 800 unit (Desunin or Fultium D3), 20,000 units (Aviticol, Fultium D3, Plenachol)

Alfacalcidol/Calcitriol should NOT be used to treat vitamin D deficiency

​1α hydroxylated preparations (e.g. alfacalcidol or calcitriol) should NOT be used in the routine management of vitamin D deficiency. Their use is limited to treating significant hypocalcaemia, disorders of malabsorption, renal disease and rare diseases of calcium and phosphate regulation and would need to be discussed with the network centre lead at each DGH and the Regional Paediatric Endocrine team at Southampton
Implementation

The guideline will be displayed on the PIER website and can be accessed by all healthcare professionals working within Wessex. This guideline will be disseminated to network centre leads within the Wessex Paediatric Endocrine Network
Process for Monitoring Effectiveness

Compliance with the guideline will be audited and results disseminated to the Wessex Paediatric Endocrine Network. A service evaluation of parental satisfaction of initial management will be undertaken.
References
  1. Calcium and Bone Disorders in Children and Adolescents. A Practical Approach to Hypocalcaemia in Children Nick Shaw Department of Endocrinology, Birmingham Children’s Hospital, Birmingham, UK. Endocr Dev. Basel, Karger, 2015, vol 28, pp 84-100.
  2. The investigation of hypocalcaemia and rickets J Singh, N Moghal, S H S Pearce, T Cheetham Arch Dis Child 2003;88:403–407
  3. Practical Neonatal Endocrinology. Cambridge clinical Guides. Amanda Ogilvy-Stuart and Paula Midgley 2008.
  4. Vitamin D deficiency in children NICE 2016
  5. Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management in Children and Young People. National Osteoporosis society. December 2018
  6. Electrolyte replacement guidelines SORT - https://www.sort.nhs.uk/Media/Guidelines/Electrolytereplacementguidelines.pdf
  7. MEDUSA Injectable medicines guide Version 6 (5/2/2019): calcium gluconate
  8. British Dietetic Association (BDA) factsheet on Calcium (www.bda.uk.com)
  9. UK standards for Paediatric Endocrinology (BSPED and RCPCH)
Document Version: 
1.0

Lead Author: 
Dr Eleri Williams, Consultant Paediatrician, Winchester
Approving Network:
Wessex Endocrine Network

Date of Approval: 
October 2019

Review Date:
​October 2022