WASD

ABC of Intravenous Fluids, Electrolyte Disorders and AKI Management in Adults

MANAGEMENT OFHYPOCALCAEMIA

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Hypocalcaemia is a serum (albumen-adjusted) total calcium, (s[Ca]) ,2.20mmol/L (normal range 2.2–2.6mmol/L)[1–4]. Severe hypocalcaemia, if untreated, can lead to serious neurological and cardiovascular complications[1– 4].

Causes: (commonly caused by Hypothyroidism and VD defi ciency)[1–8]

iPTH: Inappropriately low or normal ,1.5pmol/L

Hypoparathyroidism (the commonest in-patie nt cause)[1–3]: Post-surgery is the commonest cause[1,5,6]; usually secondary to total

thyroidectomy[5]. Hypocalcaemia is transient or permanent[4]. Auto-immune[1,2,4]. Genetic (rare)[1,2,4,6]. Irradiation, storage or infi ltrative diseases of the PTG (rare) Hypomagnesaemia (can cause PTH end organ-resistance and impaired

PTH secretion)[1,4,8], see hypomagnesaemia chapter

iPTH: High.1.5pmol/L

Vitamin D defi ciency (VD) (The commonest community cause[1–4]) Reduced intake1reduced exposure to UVL, malabsorption[1,4,6]. Functional VD defi ciency: decreased 25- (liver) or 1-hydroxylation

(kidney)[1,3,4,6].

[Severe VD defi ciency can cause rickets and osteomalacia]

PTH resistance[1–4,8]: target organs (kidney/bone) resistance to PTH: (Pseudohypoparathyroidism, hypomagnesaemia)

Renal disease (low calcitriol and hyperphosphatemia)[4,8].

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ABC of Intravenous Fluids46

Extravascular deposition: Hyperphosphatemia: Ca-PO4 is deposited mostly in bone, but also in

extra-skeletal tissues[4], as in TLS, Rhabdomyolysis and CKD[3,4,8]. Acute pancreatitis[3–5,8].

Sepsis or severe illness: impaired PTH secretion/end organ resistance and reduced calcitriol production[2,4,7,8].

Widespread osteoblastic metastasis: possible in carcinoma prostrate; breast[2,4,8].

PTH: Normal

Drugs[1–4]

Inhibitors of bone resorption (OCIs): (bisphosphonates, calcitonin, denosumab), especially if VD defi cient[2–4].

Cinacalcet[4], consider PPI-associated hypomagnesaemia[5]. Ca Chelation: Citrate in massive blood transfusion [2–5,7]. It reduces sCa1

but not s[Ca][4].

Symptoms and Signs[1–9]

Asymptomatic or non-specifi c if mild and/or chronic. Prominent when the decrease in s[Ca] occurs rapidly or is large [1–5,8,9]. Neuromuscular Excitability: paresthesia, carpopedal spasm, severe cases can progress to

tetany, seizures Neuropsychiatric Symptoms: depression, cognitive impairment Bone: pain and fractures (if osteomalacia present) CVS: Prolonged QT and ventricular fi brillation or heart block in severe cases. Other: dry skin, cataract.

Investigations (the diagnosis is often clear from the history and physical examination [4])

Do all necessary tests before starting treatment[1,3]. s[Ca] (adjusted for albumin), ALP, UEs, s[PO4], s[Mg] iPTH: the single most important diagnostic test[1,4]. Selective tests[1,4], based on history and physical examination, to determine the cause:

a. Low or normal iPTH: indicates hypoparathyroidism. b. High iPTH: UEs deranged (CKD); if UEs normal check: 1. 25HCC – VD defi ciency if low; if normal: suggest pseudohypoparathyroidism[1,2]. 2. High ALP/low PO4 suggest VD defi ciency/osteomalacia[1].

Poor correlation between the ionised (free) serum calcium (sCa21) and s[Ca], especially in states of low albumin or acid/base imbalances:a. Pseudohypocalcaemia: in hypoalbuminaemic states the s[Ca] is low but the sCa21 is normal[1,2,4].

Hence, the albumin-correction equation[1,2,4,8].b. The adjusted calcium calculation is not valid in acidosis or alkalosis: the affi nity of calcium

to albumin is increased in alkalosis; acute respiratory alkalosis can be associated withreduced sCa21, but not s[Ca] and development of symptoms – paraesthesia. Consider checking sCa21 [1,2,4,8].

Abbreviations: iPTH5intact PTH; PTG5Parathyroid Gland, UVL5Ultra-Violet Light, TLS5Tumour Lysis Syndrome, OCIs5Osteoclast Inhibitors.

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Management of Hypocalcaemia47

Treatment choice depends on the biochemical severity and rate of onset of hypocalcaemia, in addition to the symptoms and the underlying cause. Managing hypocalcaemia is based mainly on clinical experience and accepted practice rather than controlled trials[1,2,4].

s[Ca] (mmol/L) Treatment [1–10]

(Chronic) Mild, asymptomatics[Ca] 2.0–2.2

Treatment:Oral calcium1Oral VD

Prompt identifi cation and treatment of the underlying cause Oral calcium: give 25–50mmol (2000mg) elemental Ca/day[2–5]

(e.g. Ca carbonate 1250mg 2 tab BD[3], alternatively Sandocal 1000mg bd[5]), before meals[8]. Monitor s[Ca] as per monitoring section below

Add: Cause-specifi c treatment

Hypoparathyroidism

Hypoparathyroidism: give Calcitriol 0.5μg or alfacalcidol 1μg od – increase dose every 4–7 days to achieve a s[Ca] in the lower end of the reference range to avoid hypercalc iuria[1,2,5,6,8].

Post-thyroidectomy, repeat calcium 24hrs later, if s[Ca][5]: .2.1: discharge and re-check s[Ca] within one week 1.9–2.1: increase Sandocal™ 1000 to three BD – 1.9–2.1 for .72hrs post-operatively despite Ca supplementation: start

1-alfacalcidol 0.25μg/day (or calcitriol) with close monitoring

Post-parathyroidectomy: judicious pre-operative preparation will avoid the development of hungry bone syndrome[5,8]. Close monitoring, treat hypocalcaemia as per its severity, see guidance.

Ergocalciferol (VD2) and cholecalciferol (VD3) are ineff ective, as PTH is needed for the 1α-hydroxylation[1,4]. This is also true in advanced CKD because of 1α-hydroxylase defi ciency[4].

Recombinant PTH is not a standard care measure because of its cost, subcutaneous use, and long term safety is not established[4].

Vitamin D defi ciency

Give VD, either VD2 or VD3 at 1000–2000u daily. Combined Ca-VD 2tab (800u) od[1].

Symptomatic VD defi ciency or non-responders can be treated with VD (D2 or D3) 50 000 IU orally once a week for eight weeks[1,2].

Long-term maintenance is usually 1000iu/VD3/day.

Monitoring

Initially, s[Ca] levels should be monitored weekly, until defi ciency is corrected and then monthly while optimal dose is determined, thereafter:

Monitor s[Ca]: every 3–6 months[2,4,5]. Monitor urine [Ca] annually. Hypercalciuria is the main side eff ect, if

detected reduce VD dose to avoid nephrocalcinosis[1,2,8].

Refer to endocrine, renal, or other teams as appropriate

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ABC of Intravenous Fluids48

(Acute) severe s[Ca]#1.9, and/or symptomatic:

CPS, tetany, seizures

Prolonged QT/ CCF

Treatment:IV Ca1 oral VD

1. Hospital admission/ECG monitoring – too rapid Ca infusion can induce hypotension and serious dysrhythmias[1–4,10]

2. Secure proper IV access – a large vein or CV line if access poor. 3. IV Calcium gluconate is the preferred form for peripheral IV calcium.

10–20ml of 10% calcium gluconate (2.25–4.5mmol), diluted in 50–100ml of 5% dextrose and infused slowly over 10–20 minutes[1–7,10]. Its eff ect lasts for only 2–3 hours.

4. Repeat treatment until symptoms clear[1,5]

Follow by slow, continuous IV infusion of a dilute solution of Ca to prevent recurrence of hypocalcaemia[1,3,8,10]. Use infusion pump

5. Dilute 100ml of calcium gluconate 10% (10 ampules) in 1 litre 5% D or 0.9% NS and infuse at 50ml/hour[1,3,4,7,10].

Monitor s[Ca], titrate rate of infusion to achieve s[Ca] at the lower end of the reference range[1,4,5]. [An infusion of 10ml/kg of this solution is estimated to increase s[Ca] by 0.3–0.5mmol/l[1]]

The usual maximum total daily dose is 15 ampoules of 10ml of 10% calcium gluconate (i.e. 33.75mmol Ca)

6. Phosphate and bicarbonate should not be infused with calcium to avoid precipitation of Ca salts[2,8].

7. NB. CaCl2 is more likely to cause phlebitis and tissue necrosis ifextra-vasated[1,2,4–6,9]; should be given via central vein[2,5]

Oral Ca supplements, as above, should be given concurrently[2,6].

8. If PTH is defi cient or non-functional calcitriol (preferred – more potent1 rapid onset of action) should be given at 1μg/day[1,2,4].

9. When patient is asymptomatic and s[Ca] at the target, monitor, apply treatment outlined in the fi rst box, as indicated1further management

Further Management

Hypomagnesaemia-associated hypocalcaemia: the association frequently co-exist due to malabsorption or poor dietary intake[8]. HoM causes PTH defi ciency and PTH resistance[1.2,4]. Correct hypomagnesaemia fi rst, unless the patient presents with severe symptoms[1,2,4,7]. Give IV MgSO4, 24mmol/24 hours in 500ml 0.9% NS or 5% D, to achieve normal s[Mg] level[5]. Monitor s[Mg]/s[Ca].

Hyperphosphataemia-related hypocalcaemia[2,4,7,8]: the increased Ca3PO4 product induces precipitation of Ca-PO4 in soft tissues resulting in hypocalcaemia. Thus, acute hypocalcaemia in TLS or Rhabdomyolysis should not be treated with Ca, unless symptomatic from hypocalcaemia (e.g. tetany or cardiac arrhythmia), until the hyperphosphatemia is corrected[4,8]. This is to avoid further calcium-phosphate precipitation in vasculature and soft tissue. Hemodialysis is often indicated in such patients[1,3,4,8].

Give disease-specifi c treatment as per treatment of mild, asymptomatic cases box above

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Management of Hypocalcaemia49

CKD-associated hypocalcaemia: correction of hyperphosphataemia and calcitriol defi ciency (secondary to reduced renal mass/increased FGF-23) is the primary goal.

Metabolic acidosis: replace s[Ca] to near normal range fi rst, before correcting the acidosis[3,8]. Failure to do this may result in convulsions or cardiac arrest[3,8].

Digoxin: IV calcium must be used cautiously as it may precipitate digitalis intoxication; calcium enhances the eff ects of digoxin on the heart[1–3,8].

Hungry Bone Syndrome (HBS): It follows parathyroidectomy. The sudden drop in PTH level results in acute mineralisation of osteoid. This causes a rapid drop in serum calcium (Ca), magnesium and phosphate. HBS can result in seizures and tetany. Associated hypomagnesaemia can be severe, prolonged and symptomatic; accompanied by hypophosphatemia[8,9]. It may require high doses IV Calcitriol (0.25-1mcg) and prolonged periods of high doses of Ca supplementation[8].Good preparation and giving Ca and calcitriol supplementation for several days pre-operatively prevents HBS[8].

REFERENCES [1] Cooper, M.S. and Gittoes, N.J.L. Diagnosis and management of hypocalcaemia. The British

Medical Journal (2008), Vol. 336, No. 7656, pp.1298–1302. doi: 10.1136/bmj.39582.589433.BE

[2] Fong, J. and Khan, A. Hypocalcemia: Updates in diagnosis and management for primary care. Canadian Family Physician (2012), Vol. 58, No. 2, pp.158–162.

[3] United Kingdom Medicines Information (UKMi) pharmacists for NHS healthcare professional 2011. How is acute hypocalcaemia treated in adults? Medicines Q&As.

[4] Uptodate: Etiology/Treatment of hypocalcemia in adults (Viewed 06.2015).

[5] Society for Endocrinology 2013. Emergency Endocrine Guidance. Acute Hypocalcaemia, in adult patients. https://www.endocrinology.org/policy/docs/13-02_EmergencyGuidance-AcuteHypocalcaemia_(inAdults).pdf

[6] Murphy, E. and Williams, G.R. Hypocalcaemia. Medicine (2009), Vol. 37, No. 9, pp.465–8.

[7] Ariyan, C.E. and Sosa, J.A. Assessment and Management of Patients with Abnormal Calcium. Critical Care Medicine (2004), Vol. 32, No. 4, pp.S146–S154.

[8] Bushinsky, D.A. and Monk, R.D. Electrolyte Quintet: Calcium. The Lancet (1998), Vol. 352,pp.305–11.

[9] Witteveen. J.E., van Thiel, S., Romijn, J.A. and Hamdy, N.A. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism: a systematic review of the literature. European Journal of Endocrinology (2013), Vol. 168, No. 3, pp.R45–53. doi: 10.1530/EJE-12-0528.

[10] British National Formulary August 2015 (Viewed 06.09.2015).

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