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AIIMS- NICU protocols 2010

Hypocalcemia in the Newborn

AIIMS- NICU protocols 2010 Hypocalcemia in the Newborn Ashish Jain*, Ramesh Agarwal, M Jeeva Sankar, Ashok
AIIMS- NICU protocols 2010 Hypocalcemia in the Newborn Ashish Jain*, Ramesh Agarwal, M Jeeva Sankar, Ashok
AIIMS- NICU protocols 2010 Hypocalcemia in the Newborn Ashish Jain*, Ramesh Agarwal, M Jeeva Sankar, Ashok

Ashish Jain*, Ramesh Agarwal, M Jeeva Sankar, Ashok Deorari, Vinod K Paul Division of Neonatology, Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi –110029 and *Department of Pediatrics, Hindu Rao Hospital, New Delhi

and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P
and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P
and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P
and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P
and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P
and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P
and *Department of Pediatrics, Hindu Rao Hospital, New Delhi Address for correspondence: Dr Ashok Deorari P

Address for correspondence:

Dr Ashok Deorari Professor Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 110029 Email: sdeorari@yahoo.com

Downloaded from www.newbornwhocc.org

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Abstract

Hypocalcaemia is a frequently observed clinical and laboratory abnormality in

neonates. Ionic calcium is crucial for many biochemical processes including

blood coagulation, neuromuscular excitability, cell membrane integrity, and

neuromuscular excitability, cell membrane integrity, and many of the cellular enzymatic activities. Healthy term
neuromuscular excitability, cell membrane integrity, and many of the cellular enzymatic activities. Healthy term

many of the cellular enzymatic activities. Healthy term infants undergo a

enzymatic activities. Healthy term infants undergo a physiological nadir in serum calcium levels by 24-48 hours

physiological nadir in serum calcium levels by 24-48 hours of age. This nadir

in serum calcium levels by 24-48 hours of age. This nadir may drop to hypocalcemic levels

may drop to hypocalcemic levels in high-risk neonates including infants of

levels in high-risk neonates including infants of diabetic mothers, preterm infants and infants with perinatal

diabetic mothers, preterm infants and infants with perinatal asphyxia. The

preterm infants and infants with perinatal asphyxia. The early onset hypocalcemia which presents within 72 hours

early onset hypocalcemia which presents within 72 hours requires treatment

which presents within 72 hours requires treatment with calcium supplementation for at least 72 hours. In
which presents within 72 hours requires treatment with calcium supplementation for at least 72 hours. In

with calcium supplementation for at least 72 hours. In contrast, late onset

for at least 72 hours. In contrast, late onset hypocalcemia usually presents after 7 days and

hypocalcemia usually presents after 7 days and requires longer term therapy.

Keywords: Hypocalcemia, Newborn, Therapy

hypocalcemia usually presents after 7 days and requires longer term therapy. Keywords: Hypocalcemia, Newborn, Therapy 2
hypocalcemia usually presents after 7 days and requires longer term therapy. Keywords: Hypocalcemia, Newborn, Therapy 2

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Introduction

During the last

trimester, calcium is actively transferred from mother to the

fetus

as

demonstrated

by

a

significantly

high

level

of total

calcium

concentration in

cord blood compared to maternal serum. 1 Parathyroid

hormone (PTH) and calcitonin (CT) do not cross the placental barrier. The PTH

calcitonin (CT) do not cross the placental barrier. The PTH related peptide (PTHrP) is the main
calcitonin (CT) do not cross the placental barrier. The PTH related peptide (PTHrP) is the main

related peptide (PTHrP) is the main regulator of the positive calcium balance

is the main regulator of the positive calcium balance across the placenta. Serum calcium (SCa) in

across the placenta. Serum calcium (SCa) in the fetus is 10-11 mg/dL at term

Serum calcium (SCa) in the fetus is 10-11 mg/dL at term (1-2 mg higher as compared

(1-2 mg higher as compared to mother).

10-11 mg/dL at term (1-2 mg higher as compared to mother). skeletal After birth the SCa
skeletal
skeletal

After birth the SCa levels in newborns depend on the PTH secretion, dietary

calcium

intake,

renal

calcium

reabsorbtion,

dietary calcium intake, renal calcium reabsorbtion, calcium stores, and vitamin D status. Hence, after delivery,

calcium

stores,

and

intake, renal calcium reabsorbtion, calcium stores, and vitamin D status. Hence, after delivery, calcium levels

vitamin D status.

Hence, after delivery, calcium levels start decreasing (the

Hence, after delivery, calcium levels start decreasing (the rate and extent of decrease is inversely proportional

rate and extent of decrease is inversely proportional to the gestation) and

reaches a nadir of 7.5-8.5 mg/dL in healthy term babies by day 2 of life. This

parathyroid
parathyroid

drop in postnatal SCa may be related to hypoparathyroidism, end organ

to
to

unresponsiveness

related to hypoparathyroidism, end organ to unresponsiveness hormone 2 , abnormalities of vitamin D metabolism,

hormone

2 ,

abnormalities

of

vitamin

D

metabolism, hyperphosphatemia, hypomagnesemia, and hypercalcitonemia 3

hyperphosphatemia, hypomagnesemia, and hypercalcitonemia 3 which occurs by 12-24 hours of age. PTH levels increase

which occurs by 12-24 hours of age. PTH levels increase gradually in the first

which occurs by 12-24 hours of age. PTH levels increase gradually in the first

48 hours of life and normal levels of SCa are regained by 3 rd day of life. 4 The

efficacy of the intestinal absorption of calcium and the renal handling matures

by 2 to 4 weeks. This transition phase is responsible for the increased risk of

early onset hypocalcemia in high-risk neonates.

Calcium homeostasis in newborn

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Body calcium exists in two major compartments: skeleton (99%) and extracellular fluid (1%).

Calcium in the extracellular fluid is present in three forms: (a) bound to albumin (40%) (b)

bound to anions like phosphorus, citrate, sulfate and lactate (10%) and (c) free ionized form

(50%) 5 . Ionized calcium is crucial for many biochemical processes including blood coagulation,

neuromuscular excitability, cell membrane integrity and function, and cellular enzymatic and

secretory activity.

and function, and cellular enzymatic and secretory activity. Measurement of the total serum Ca concentration alone
and function, and cellular enzymatic and secretory activity. Measurement of the total serum Ca concentration alone

Measurement of the total serum Ca concentration alone can be misleading

of the total serum Ca concentration alone can be misleading because the relationship between total and

because the relationship between total and ionized Ca is not always linear.

between total and ionized Ca is not always linear. Correlation is poor when the serum albumin

Correlation is poor when the serum albumin concentration is low or, to a lesser

when the serum albumin concentration is low or, to a lesser degree, with disturbances in acid-base

degree, with disturbances in acid-base status, both of which occur frequently in

in acid-base status, both of which occur frequently in premature or sick infants. With hypoalbuminemia, the

premature or sick infants. With hypoalbuminemia, the total Ca concentration

infants. With hypoalbuminemia, the total Ca concentration will be low while the ionized fraction will be

will be low while the ionized fraction will be normal unless some other factor is

ionized fraction will be normal unless some other factor is affecting Ca metabolism. More so, falsely
ionized fraction will be normal unless some other factor is affecting Ca metabolism. More so, falsely

affecting Ca metabolism. More so, falsely low ionic calcium levels may be

recorded in alkalosis and with heparin use.

levels may be recorded in alkalosis and with heparin use. for every 1.0 g/dL fall in

for every 1.0 g/dL fall in the plasma albumin concentration.

for every 1.0 g/dL fall in the plasma albumin concentration. In general, the plasma calcium concentration
for every 1.0 g/dL fall in the plasma albumin concentration. In general, the plasma calcium concentration

In general, the plasma calcium concentration falls by 0.8 mg/dL (0.2 mmol/L)

plasma calcium concentration falls by 0.8 mg/dL (0.2 mmol/L) Therefore, estimation of total calcium levels is

Therefore, estimation of total calcium levels is a poor substitute for

estimation of total calcium levels is a poor substitute for measuring the ionized levels. Definition Hypocalcemia

measuring the ionized levels.

Definition

Hypocalcemia is defined as total serum calcium of less than 7 mg/dL (1.75

mmol/L) or ionized calcium less than 4 mg/dL (1 mmol/L) in preterm infants

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and less

than 8 mg/dL (2 mmol/L; total) or <1.2 mmol/L

neonates. 6

(ionic) in term

The SCa concentration is usually reported in different ways viz. mg/dL, meq/L

and mmol/L The relationship between these units is related to the following

equations: mmol/L = [mg/dL x 10] ÷ molecular wt,

meq/L = mmol/L x

mmol/L = [mg/dL x 10] ÷ molecular wt, meq/L = mmol/L x valency. Since the molecular

valency. Since the molecular weight of calcium is 40 and the valence is +2, 1

molecular weight of calcium is 40 and the valence is +2, 1 mg/dL is equivalent to

mg/dL is equivalent to 0.25 mmol/L and to 0.5 meq/L. Thus, values in mg/dl

to 0.25 mmol/L and to 0.5 meq/L. Thus, values in mg/dl may be converted to molar

may be converted to molar units (mmol/L) by dividing by 4.

may be converted to molar units (mmol/L) by dividing by 4. Early onset neonatal hypocalcemia (ENH)Table
may be converted to molar units (mmol/L) by dividing by 4. Early onset neonatal hypocalcemia (ENH)Table

Early onset neonatal hypocalcemia (ENH)Table 1

by 4. Early onset neonatal hypocalcemia (ENH)Table 1 This condition is fairly common and seen within
by 4. Early onset neonatal hypocalcemia (ENH)Table 1 This condition is fairly common and seen within
by 4. Early onset neonatal hypocalcemia (ENH)Table 1 This condition is fairly common and seen within
by 4. Early onset neonatal hypocalcemia (ENH)Table 1 This condition is fairly common and seen within

This condition is fairly common and seen within the first 3-4 days of life in

following clinical settings:

Prematurity: This may be related to premature termination of trans-placental

supply, exaggeration of the postnatal drop to hypocalcemic levels, increased

calcitonin

hormone.

drop to hypocalcemic levels, increased calcitonin hormone. diminished and responsiveness to parathyroid target organ
diminished
diminished

and

levels, increased calcitonin hormone. diminished and responsiveness to parathyroid target organ Infant of

responsiveness

to

parathyroid

target

organ

Infant of diabetic mother (gestational and insulin dependent): This may be

mother (gestational and insulin dependent): This may be related to increased calcium demands of a macrosomic

related to increased calcium demands of a macrosomic baby. 7 Magnesium

This
This

fetus.

depletion in mothers with diabetes mellitus causes hypomagnesemic state in the

induces

functional

hypoparathyroidism

and

hypomagnesemia

hypocalcemia in the infant. A high incidence of birth asphyxia and prematurity in

infants of diabetic mothers are also contributing factors.

Perinatal asphyxia:

Delayed introduction of feeds, increased calcitonin

production, increased endogenous phosphate load, renal insufficiency, and

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diminished

parathyroid

hormone

secretion

all

may

contribute

to

hypocalcemia.

Maternal hyperparathyroidism:

This causes intrauterine hypercalcemia

suppressing

the

parathyroid

activity

in

the

fetus

resulting

in

impaired

parathyroid responsiveness to hypocalcaemia after birth. Hypocalcaemia may

be severe and prolonged.

after birth. Hypocalcaemia may be severe and prolonged. Intrauterine growth restriction (IUGR): Infants with IUGR
after birth. Hypocalcaemia may be severe and prolonged. Intrauterine growth restriction (IUGR): Infants with IUGR
after birth. Hypocalcaemia may be severe and prolonged. Intrauterine growth restriction (IUGR): Infants with IUGR

Intrauterine growth restriction (IUGR): Infants with IUGR may have

hypocalcemia if they are born preterm and/or have had perinatal asphyxia.

if they are born preterm and/or have had perinatal asphyxia. Small for gestational age is not

Small for gestational age is not an independent risk factor for ENH.

gestational age is not an independent risk factor for ENH . Iatrogenic: Any condition causing alkalosis
gestational age is not an independent risk factor for ENH . Iatrogenic: Any condition causing alkalosis

Iatrogenic: Any condition causing alkalosis increases the binding of the

Any condition causing alkalosis increases the binding of the calcium with albumin and causes decrease in

calcium with albumin and causes decrease in ionic calcium levels

with albumin and causes decrease in ionic calcium levels Screening is recommended in at risk neonates
with albumin and causes decrease in ionic calcium levels Screening is recommended in at risk neonates

Screening is recommended in at risk neonates

1.Preterm infants born before 32 wks

in at risk neonates 1.Preterm infants born before 32 wks 2. Infants of diabetic mothers on

2. Infants of diabetic mothers on iv fluids

before 32 wks 2. Infants of diabetic mothers on iv fluids 3.Infants born after severe perinatal

3.Infants born after severe perinatal asphyxia defined as Apgar score < 4 at 1

minute of age

asphyxia defined as Apgar score < 4 at 1 minute of age Time schedule for screening
asphyxia defined as Apgar score < 4 at 1 minute of age Time schedule for screening

Time schedule for screening

score < 4 at 1 minute of age Time schedule for screening At 24 and 48

At 24 and 48 hours of age in at risk babies

Clinical presentation:

1. Asymptomatic: ENH is usually asymptomatic unlike the late onset variety

and is incidentally detected.

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2.

Symptomatic:

The symptoms may be of neuromuscular irritability -

myoclonic jerks, jitteriness, exaggerated startle, and seizures. They may

represent

the

cardiac

involvement

like-

tachycardia,

heart

failure,

prolonged QT interval, decreased contractibility. More often they are non-

specific and not related to the severity of hypocalcemia. Apnea, cyanosis,

related to the severity of hypocalcemia. Apnea, cyanosis, tachypnoea, vomiting and laryngospasm are other symptoms
related to the severity of hypocalcemia. Apnea, cyanosis, tachypnoea, vomiting and laryngospasm are other symptoms

tachypnoea, vomiting and laryngospasm are other symptoms that are

noted.

vomiting and laryngospasm are other symptoms that are noted. <4.0 mg/dL). Ionized calcium is the preferred
vomiting and laryngospasm are other symptoms that are noted. <4.0 mg/dL). Ionized calcium is the preferred
vomiting and laryngospasm are other symptoms that are noted. <4.0 mg/dL). Ionized calcium is the preferred

<4.0 mg/dL). Ionized calcium is the preferred mode for diagnosis of

hypocalcemia.

calcium is the preferred mode for diagnosis of hypocalcemia. Diagnosis 1. Laboratory: Total or ionized serum
calcium is the preferred mode for diagnosis of hypocalcemia. Diagnosis 1. Laboratory: Total or ionized serum

Diagnosis

the preferred mode for diagnosis of hypocalcemia. Diagnosis 1. Laboratory: Total or ionized serum calcium (total

1. Laboratory: Total or ionized serum calcium (total <7 mg/dL or ionized

2. ECG: QoTc >0.22 seconds or QTc >0.45 seconds

2. ECG: QoTc >0.22 seconds or QTc >0.45 seconds QTc = QT interval in seconds R-R

QTc =

QT interval in seconds

or QTc >0.45 seconds QTc = QT interval in seconds R-R interval in seconds QoTc =
or QTc >0.45 seconds QTc = QT interval in seconds R-R interval in seconds QoTc =

R-R interval in seconds

seconds QTc = QT interval in seconds R-R interval in seconds QoTc = QoT interval in

QoTc = QoT interval in seconds R-R interval in seconds

seconds QTc = QT interval in seconds R-R interval in seconds QoTc = QoT interval in
seconds QTc = QT interval in seconds R-R interval in seconds QoTc = QoT interval in
seconds QTc = QT interval in seconds R-R interval in seconds QoTc = QoT interval in

(QT interval is measured from origin of q wave to end of T wave on ECG; QoT is

measured from origin of q wave to origin of T wave).

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A diagnosis of hypocalcemia based only on ECG criteria is likely to

yield a high false positive rate. Although these parameters

have good correlation with hypocalcaemia in low birth

weight

infants

(sensitivity

of

77%

and

specificity

of

94.7%) 8 , neonates suspected to have hypocalcemia by ECG

8 , neonates suspected to have hypocalcemia by ECG by criteria should have the diagnosis confirmed

by

criteria

should

have

the

diagnosis

hypocalcemia by ECG by criteria should have the diagnosis confirmed measurement of serum calcium levels. Treatment

confirmed

measurement of serum calcium levels.

the diagnosis confirmed measurement of serum calcium levels. Treatment of early onset hypocalcemia (1 ml of

Treatment of early onset hypocalcemia

serum calcium levels. Treatment of early onset hypocalcemia (1 ml of calcium gluconate (10%) gives 9
serum calcium levels. Treatment of early onset hypocalcemia (1 ml of calcium gluconate (10%) gives 9

(1 ml of calcium gluconate (10%) gives 9 mg of elemental calcium)

at

increased

risk

(10%) gives 9 mg of elemental calcium) at increased risk 1. Patients of hypocalcemia( prophylactic) :

1. Patients

of

hypocalcemia(

prophylactic):

increased risk 1. Patients of hypocalcemia( prophylactic) : asphyxia mL/kg/day Preterm infants ( 32 weeks), sick
asphyxia
asphyxia

mL/kg/day

Preterm infants ( 32 weeks), sick infants of diabetic mothers and those

with

severe

elemental

perinatal

receive

40

calcium

mg/kg/day

gluconate)

of

for

should

of

(4
(4

calcium

10%

calcium mg/kg/day gluconate) of for should of (4 calcium 10% prevention of early onset hypocalcemia. However

prevention of early onset hypocalcemia. However there is not sufficient

evidence for this practice. Infants tolerating oral feeds may receive this

practice. Infants tolerating oral feeds may receive this calcium orally q 6 hourly. Therapy should be
practice. Infants tolerating oral feeds may receive this calcium orally q 6 hourly. Therapy should be

calcium orally q 6 hourly. Therapy should be continued for 3 days. Oral

q 6 hourly. Therapy should be continued for 3 days. Oral 2. Patients calcium preparations have

2.

Patients

calcium preparations have high osmolality and should be avoided in

babies at higher risk of necrotizing enterocolitis.

diagnosed

to

have

asymptomatic

hypocalcemia(on

screening): Infants detected to have hypocalcemia on screening and

who

are

otherwise

asymptomatic

should

receive

80-mg/kg/day

elemental calcium (8 mL/kg/day of 10% calcium gluconate) for 48 hours.

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This may be tapered to 50% dose for another

24 hours and then

discontinued. Neonates tolerating oral feeds may be treated with oral

calcium (IV preparation may be used orally).

3.

Patients diagnosed to have symptomatic hypocalcemia: These

patients should receive a bolus dose of 2 mL/kg/dose diluted 1:1 with

should receive a bolus dose of 2 mL/kg/dose diluted 1:1 with 5% dextrose over 10 minutes

5% dextrose over 10 minutes under cardiac monitoring. When there is

over 10 minutes under cardiac monitoring. When there is severe hypocalcaemia with poor cardiac function, calcium

severe hypocalcaemia with poor cardiac function, calcium chloride 20

with poor cardiac function, calcium chloride 20 mg/kg may be given through a central line over

mg/kg may be given through a central line over 10-30 minutes (as

may be given through a central line over 10-30 minutes (as chloride in comparison to gluconate

chloride in comparison to gluconate does not require the metabolism by

comparison to gluconate does not require the metabolism by the liver for the release of free
comparison to gluconate does not require the metabolism by the liver for the release of free

the liver for the release of free calcium). This should be followed by a

the release of free calcium). This should be followed by a continuous IV infusion of 80

continuous IV infusion of 80 mg/kg/day elemental calcium for 48 hours.

IV infusion of 80 mg/kg/day elemental calcium for 48 hours. Continuous infusion is preferred to IV
IV infusion of 80 mg/kg/day elemental calcium for 48 hours. Continuous infusion is preferred to IV

Continuous infusion is preferred to IV bolus doses (1 mL/kg/dose q 6

hourly). Calcium infusion should be dropped to 50% of the original dose

infusion should be dropped to 50% of the original dose for the next 24 hours and

for the next 24 hours and then discontinued. The infusion may be

the next 24 hours and then discontinued. The infusion may be replaced with oral calcium therapy

replaced with oral calcium therapy on the last day. Normal calcium

values should be documented at 48 hours before weaning the infusion.

be documented at 48 hours before weaning the infusion. infusion All categories of hypocalcemia should be
be documented at 48 hours before weaning the infusion. infusion All categories of hypocalcemia should be

infusion

All categories of hypocalcemia should be treated for at least 72

is

preferred

to

IV

bolus

doses.

be treated for at least 72 is preferred to IV bolus doses. hours. Continuous Symptomatic hypocalcemia

hours.

Continuous

Symptomatic hypocalcemia should be treated with a continuous

infusion for at least 48 hours. (refer Algorithm 1)

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Algorithm 1

Management of early neonatal hypocalcaemia

Hypocalcemia

Total serum Cal <7 mg/dl

Asymptomatic 80 mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate )

mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate ) Taper to 40 mg/kg/day for
mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate ) Taper to 40 mg/kg/day for
mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate ) Taper to 40 mg/kg/day for
mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate ) Taper to 40 mg/kg/day for

Taper to 40 mg/kg/day for one day Then stop

gluconate ) Taper to 40 mg/kg/day for one day Then stop Symptomatic Bolus of 2 mL/kg
gluconate ) Taper to 40 mg/kg/day for one day Then stop Symptomatic Bolus of 2 mL/kg
gluconate ) Taper to 40 mg/kg/day for one day Then stop Symptomatic Bolus of 2 mL/kg

Symptomatic Bolus of 2 mL/kg calcium gluconate 1:1 diluted with 5 % dextrose over 10 minutes under cardiac monitoring

with 5 % dextrose over 10 minutes under cardiac monitoring Followed by continuous infusion 80 mg/kg/day
with 5 % dextrose over 10 minutes under cardiac monitoring Followed by continuous infusion 80 mg/kg/day

Followed by continuous infusion 80 mg/kg/day for 48 hrs (8 mL/kg/day of 10% calcium gluconate ) Document normal calcium at 48 hrs

10% calcium gluconate ) Document normal calcium at 48 hrs Then taper to 40 mg/kg/day for
10% calcium gluconate ) Document normal calcium at 48 hrs Then taper to 40 mg/kg/day for
10% calcium gluconate ) Document normal calcium at 48 hrs Then taper to 40 mg/kg/day for

Then taper to 40 mg/kg/day for one day Then stop

Prophylactic

taper to 40 mg/kg/day for one day Then stop Prophylactic Preterm< 32 wks, sick IDM, severe
taper to 40 mg/kg/day for one day Then stop Prophylactic Preterm< 32 wks, sick IDM, severe

Preterm< 32 wks, sick IDM, severe asphyxia

40 mg/kg/day for 3 days (4ml/kg/day of 10% calcium gluconate ) IV or oral if can tolerate per oral

10% calcium gluconate ) IV or oral if can tolerate per oral  Treatment is for

Treatment is for 72 hours

Continuous infusion is better than bolus

Symptomatic babies treatment is 48 hrs continuous infusion

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In case the hypoclcemia does not correct by the above by, 72 hours than investigate for causes of late hypocalcemia.- Refer Table 2 Precautions and side effects

Bradycardia and arrhythmia are known side effects of bolus IV calcium

administration. Hence, bolus doses of calcium should be diluted 1:1 with 5%

dextrose and given slowly (over 10 to 30 minutes) under cardiac monitoring.

slowly (over 10 to 30 minutes) under cardiac monitoring. An umbilical venous catheter (UVC) may be

An umbilical venous catheter (UVC) may be used for administration of calcium

catheter (UVC) may be used for administration of calcium only after ensuring that the tip is

only after ensuring that the tip is positioned in the inferior vena cava. Hepatic

the tip is positioned in the inferior vena cava. Hepatic necrosis may occur if the tip

necrosis may occur if the tip of the UVC lies in a branch of the portal vein.

if the tip of the UVC lies in a branch of the portal vein. Umbilical artery

Umbilical artery catheter (UAC) should never be used for giving calcium

catheter (UAC) should never be used for giving calcium injections. Accidental injection into the UAC may
catheter (UAC) should never be used for giving calcium injections. Accidental injection into the UAC may

injections. Accidental injection into the UAC may result in arterial spasms and

injection into the UAC may result in arterial spasms and intestinal necrosis. Skin and subcutaneous tissue

intestinal necrosis. Skin and subcutaneous tissue necrosis may occur due to

Skin and subcutaneous tissue necrosis may occur due to extravasation. Hence, IV sites where calcium is
Skin and subcutaneous tissue necrosis may occur due to extravasation. Hence, IV sites where calcium is
Skin and subcutaneous tissue necrosis may occur due to extravasation. Hence, IV sites where calcium is

extravasation.

Hence, IV sites where calcium is being infused should be checked at

least q 2 hourly to monitor for extravasation and avoid subcutaneous

2 hourly to monitor for extravasation and avoid subcutaneous tissue necrosis. Prolonged or resistant hypocalcemia therapy

tissue necrosis.

for extravasation and avoid subcutaneous tissue necrosis. Prolonged or resistant hypocalcemia therapy This condition
for extravasation and avoid subcutaneous tissue necrosis. Prolonged or resistant hypocalcemia therapy This condition

Prolonged or resistant hypocalcemia

tissue necrosis. Prolonged or resistant hypocalcemia therapy This condition should be considered in the following

therapy

This condition should be considered in the following situations:

Symptomatic hypocalcemia unresponsive to adequate doses of calcium

Infants needing calcium supplements beyond 72 hours of age

Hypocalcemia presenting at the end of the first week.

These infants should be investigated for causes of LNH (see below).

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Late onset neonatal hypocalcemia (LNH)

This condition is rare as compared to ENH. It usually presents at the end of the

first week of life. It is usually symptomatic in the form of neonatal tetany or

seizures. This is usually caused by high phosphate intake (iatrogenic). The

is usually caused by high phosphate intake (iatrogenic). The causes are listed in table 2. Examination

causes are listed in table 2.

Examination:

The causes are listed in table 2. Examination : Such babies should have an examination with
The causes are listed in table 2. Examination : Such babies should have an examination with
The causes are listed in table 2. Examination : Such babies should have an examination with

Such babies should have an examination with special emphasis on cataracts,

have an examination with special emphasis on cataracts, hearing, and any evidence of basal ganglia involvement

hearing, and any evidence of basal ganglia involvement (movement disorder).

evidence of basal ganglia involvement (movement disorder). Investigations These should be considered in LNH or if

Investigations

Investigations These should be considered in LNH or if the hypocalcemia does not respond to

These should be considered in LNH or if the hypocalcemia does not respond to

considered in LNH or if the hypocalcemia does not respond to adequate doses of calcium. The

adequate doses of calcium. The work up of such a case is very important to

of calcium. The work up of such a case is very important to determine the etiology.

determine the etiology. The same can be planned as per the table 3.

the etiology. The same can be planned as per the table 3. If hypocalcemia is present

If hypocalcemia is present with hyperphosphatemia and a normal renal

is present with hyperphosphatemia and a normal renal function, hypoparathyroidism should be strongly suspected

function, hypoparathyroidism should be strongly suspected

function, hypoparathyroidism should be strongly suspected Treatment of LNH The treatment of LNH is specific to

Treatment of LNH

should be strongly suspected Treatment of LNH The treatment of LNH is specific to etiology and

The treatment of LNH is specific to etiology and may in certain diseases be life-

long.

1. Hypomagnesemia: Symptomatic hypocalcemia unresponsive to adequate

doses of IV calcium therapy is usually due to hypomagnesemia. It may present

either as ENH or later as LNH. The neonate should receive 2 doses of 0.2 mL/kg

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of 50% MgSO 4 injection, 12 hours apart, deep IM followed by a maintenance

dose of 0.2 mL/kg/day of 50% MgSO 4 , PO for 3 days.

2. High phosphate load: These infants have hyperphosphatemia with near

normal calcium levels. Exclusive breast-feeding should be encouraged and top

feeding with cow’s milk should be discontinued. Phosphate binding gels should

milk should be discontinued. Phosphate binding gels should be avoided. 3 . Hypoparathyroidism 9 These infants

be avoided.

3.

discontinued. Phosphate binding gels should be avoided. 3 . Hypoparathyroidism 9 These infants tend to be

Hypoparathyroidism 9 These infants tend to be hyperphosphatemic and

9 These infants tend to be hyperphosphatemic and hypocalcemic with normal renal function. Elevated phosphate

hypocalcemic with normal renal function. Elevated phosphate levels in the

with normal renal function. Elevated phosphate levels in the absence of exogenous phosphate load (cow’s milk)

absence of exogenous phosphate load (cow’s milk) and presence of normal

phosphate load (cow’s milk) and presence of normal renal functions indicates parathormone inefficiency. It is
phosphate load (cow’s milk) and presence of normal renal functions indicates parathormone inefficiency. It is

renal functions indicates parathormone inefficiency.

It is important to realize

parathormone inefficiency. It is important to realize that if the phosphate level is very high, then

that if the phosphate level is very high, then adding calcium will lead to

level is very high, then adding calcium will lead to calcium deposition and tissue damage. Thus
level is very high, then adding calcium will lead to calcium deposition and tissue damage. Thus

calcium deposition and tissue damage. Thus attempts should be made to

reduce the phosphate (so as to keep the calcium and the phosphate product

(so as to keep the calcium and the phosphate product less than 55) 1 0 .

less than 55) 10 . These neonates need supplementation with calcium (50

0 . These neonates need supplementation with calcium (50 mg/kg/day in 3 divided doses) and 1,25(OH)

mg/kg/day in 3 divided doses) and 1,25(OH) 2 Vitamin D 3 (0.5-1 g/day). Syrups

with 125 mg and 250 mg per 5ml of calcium are available.1,25(OH) 2 vitamin D 3

per 5ml of calcium are available.1,25(OH) 2 vitamin D 3 g capsules. Therapy may be stopped

g capsules.

Therapy may be stopped in

2 vitamin D 3 g capsules. Therapy may be stopped in (calcitriol) is available as 0.25

(calcitriol) is available as 0.25

Therapy may be stopped in (calcitriol) is available as 0.25 hypocalcemia secondary to maternal hyperparathyroidism after

hypocalcemia secondary to maternal hyperparathyroidism after 6 weeks.

4.

Vitamin D deficiency states: These babies have hypocalcemia associated

with hypophosphatemia due to an intact parathormone response on the

kidneys. They benefit from Vitamin D 3 supplementation in a dose of 30-60

ng/kg/day

Monitoring

13

14

The baby is monitored for the SCa, and phosphate, 24 hour urinary calcium,

and calcium creatinine ratio. Try to keep the calcium in the lower range as

defective

distal

tubular

nephrocalcinosis. 11

absorption

leads

to

hypercalciuria

and

Prognosis and outcome

absorption leads to hypercalciuria and Prognosis and outcome Most cases of early neonatal hypocalcemia resolve within
absorption leads to hypercalciuria and Prognosis and outcome Most cases of early neonatal hypocalcemia resolve within

Most cases of early neonatal hypocalcemia resolve within 48-72 hours without

any clinically significant sequelae.

Late neonatal hypocalcemia secondary to exogenous phosphate load and

magnesium

deficiency

also

responds

well

to

and

load and magnesium deficiency also responds well to and phosphate restriction magnesium repletion. When caused by
load and magnesium deficiency also responds well to and phosphate restriction magnesium repletion. When caused by

phosphate

and magnesium deficiency also responds well to and phosphate restriction magnesium repletion. When caused by
and magnesium deficiency also responds well to and phosphate restriction magnesium repletion. When caused by

restriction

magnesium repletion. When caused by hypoparathyroidism, hypocalcemia

repletion. When caused by hypoparathyroidism, hypocalcemia requires continued therapy with vitamin D metabolites and

requires continued therapy with vitamin D metabolites and calcium salts. The

therapy with vitamin D metabolites and calcium salts. The period of therapy depends on the nature
therapy with vitamin D metabolites and calcium salts. The period of therapy depends on the nature

period of therapy depends on the nature of the hypoparathyroidism which can

be transient, last several weeks to months, or be permanent.

be transient, last several weeks to months, or be permanent. References: 2. Linarelli 1. Schauberger CW,
be transient, last several weeks to months, or be permanent. References: 2. Linarelli 1. Schauberger CW,
be transient, last several weeks to months, or be permanent. References: 2. Linarelli 1. Schauberger CW,
be transient, last several weeks to months, or be permanent. References: 2. Linarelli 1. Schauberger CW,

References:

last several weeks to months, or be permanent. References: 2. Linarelli 1. Schauberger CW, Pitkin RM,

2. Linarelli

1. Schauberger CW, Pitkin RM, Maternal-perinatal calcium relationships.

Obstet Gynecol 1979;53:74-6

LG,

Bobik

J,

Bobik

C.

Newborn

urinary

cyclic

AMP

and

developmental

responsiveness

to

parathyroid

harmone.

Pediatrics

1972;50:14-23

14

15

3. Hillman, Rajanasathit S, slatopolsky E, haddad JG. Serial measurements

of serum calcium, magnesium, parathyroid hormone, calcitonin, and 25-

hydroxy-vitamin D in premature and term infants during the first week

of life. Pediatr Res 1977;11:789-44

4. Salle BL, Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH. Perinatal

Delvin EE, Lapillonne A, Bishop NJ, Glorieux FH. Perinatal of metabolism of vitamin D. Am J

of

metabolism of vitamin D. Am J Clin Nutr 2000;71(5 suppl):1317S-24S.

N, Pearce

SH, Cheetham

T.

The

2000;71(5 suppl):1317S-24S. N, Pearce SH, Cheetham T. The investigation J 5. Singh J, Moghal hypocalcaemia and
2000;71(5 suppl):1317S-24S. N, Pearce SH, Cheetham T. The investigation J 5. Singh J, Moghal hypocalcaemia and

investigation

J

5. Singh J, Moghal

hypocalcaemia and rickets. Arch Dis Child. May 2003;88(5): 403-7.

J,

Bourgeois

M.

Neonatal

Dis Child. May 2003;88(5): 403-7. J, Bourgeois M. Neonatal Indian 6. Oden endocrinology. Pediatr 2000;67:217-23 7.

Indian

6. Oden

2003;88(5): 403-7. J, Bourgeois M. Neonatal Indian 6. Oden endocrinology. Pediatr 2000;67:217-23 7. Schwartz R, Teramo

endocrinology.

Pediatr

2000;67:217-23

Indian 6. Oden endocrinology. Pediatr 2000;67:217-23 7. Schwartz R, Teramo KA. Effects of diabetic pregnancy on
Indian 6. Oden endocrinology. Pediatr 2000;67:217-23 7. Schwartz R, Teramo KA. Effects of diabetic pregnancy on

7. Schwartz R, Teramo KA. Effects of diabetic pregnancy on the fetus and

R, Teramo KA. Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol 2000;24:120-35 8.
R, Teramo KA. Effects of diabetic pregnancy on the fetus and newborn. Semin Perinatol 2000;24:120-35 8.

newborn. Semin Perinatol 2000;24:120-35

8.

Nekvasil R, Stejskal J, Tuma A. Detection of early onset neonatal

R, Stejskal J, Tuma A. Detection of early onset neonatal hypocalcemia in low birth weight infants

hypocalcemia in low birth weight infants by Q-Tc and Q-oTc interval

in low birth weight infants by Q-Tc and Q-oTc interval measurement. Acta Paediatr Acad Sci Hung.

measurement. Acta Paediatr Acad Sci Hung. 1980;21(4):203-10.

9.

Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med

Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863-75 10. Sharma J, Bajpai A, Kabra M,
Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863-75 10. Sharma J, Bajpai A, Kabra M,

2000;343:1863-75

10.
10.

Sharma J, Bajpai A, Kabra M, Menon PSN. Hypocalcemia – Clinical,

biochemical, radiological Profile and follow-up in a Tertiary hospital in

India. Indian Pediatrics 2002; 39: 276-282.

11. Rigo J, Curtis MD. Disorders of Calcium, Phosphorus and Magnesium

Metabolism.In Richard J Martin, Avory A Fanaroff, Michele C Walsh (eds) .

15

16

Neonatal Perinatal Medicine- Diseases of the fetus and infant. 8 th edition;

Elsevier, Pihladelphia, 2006: p1508-14

Perinatal Medicine- Diseases of the fetus and infant. 8 t h edition; Elsevier, Pihladelphia, 2006: p1508-14

16

17

Table 1 Causes of early onset hypocalcaemia ∑ Prematurity ∑ Preeclampsia ∑ Infant of Diabetic
Table 1 Causes of early onset hypocalcaemia
∑ Prematurity
∑ Preeclampsia
∑ Infant of Diabetic mother
∑ Perinatal stress/ asphyxia
∑ Maternal intake of anticonvulsants (phenobarbitone, phenytoin sodium)
∑ Maternal hyperparathyroidism
∑ Iatrogenic (alkalosis, use of blood products, diuretics, phototherapy, lipid
infusions etc)

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18

Table 2 Causes of late onset hypocalcemia

Increased phosphate load Cow milk, renal insufficiency

Hypomagnesemia

Vitamin D deficiency Maternal vitamin D deficiency Malabsorption Renal insufficiency Hepatobiliary disease

PTH resistence Transient neonatal pseudohypoparathyroidism

Hypoparathyroidism Primary Hypoplasia, aplasia of parathyroid glands - (Di George’s syndrome), CATCH 22 syndrome (cardiac anomaly, abnormal facies, thymic aplasia, cleft palate, hypocalcaemia with deletion on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism

on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism
on chromosome 22) Activating mutations of the calcium sensing receptor (CSR) Secondary Maternal hyperparathyroidism

Metabolic Syndromes Kenny-caffey syndrome Long-chain fatty acyl CoA dehydrogenase deficiency Kearns-sayre syndrome
Iatrogenic Citrated blood products Lipid infusions Bicrbonate therepy Diueretics (loop diuretics) Glucocorticosteriods Phosphate therepy Use of Aminoglycosides (mainly gentamicin) as single dose Alkalosis Phototherapy

Glucocorticosteriods Phosphate therepy Use of Aminoglycosides (mainly gentamicin) as single dose Alkalosis Phototherapy 18
Glucocorticosteriods Phosphate therepy Use of Aminoglycosides (mainly gentamicin) as single dose Alkalosis Phototherapy 18

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Table 3 Investigations required in infants with persistent / late onset hypocalcaemia

Investigations required First line Serum phosphate Serum alkaline phosphatase (SAP) Liver function tests Renal
Investigations required
First line
Serum phosphate
Serum alkaline
phosphatase (SAP)
Liver function tests
Renal function tests
X ray chest/ wrist
Arterial pH
Second line
Serum magnesium
Serum parathormone
levels (PTH)
Urine calcium creatinine
ratio
Maternal calcium,
phosphate, and alkaline
phosphatase
Others
CT brain for calcification
Echocardiography
Vitamin D levels (1,25
D3)
Hearing evaluation
Serum cortisol
Thyroid function tests
S
Disorder causing
Findings
N
hypocalcaemia
o
1
Hypoparathyroidism
High : Phosphate
Low : SAP, PTH, 1,25 D3
2
Pseudo
Hypoparathyroidim
High : SAP, PTH, Phosphate
Low : 1,25 D3
3
Chronic renal failure
High : phosphate, SAP, PTH, pH (acidotic), deranged
RFT
Low : 1,25 D3
4
Hypomagnesemia
High : PTH
Low : Phosphate, Mg,1,25 D3
5
VDDR1
High : SAP, PTH
Low : Phosphate, 1,25 D3
6
VDDR II
High : SAP, 1, 25 D3, PTH
Low : Phosphate
(VDDR, vitamin D dependent rickets)

19