Transcript Calcium Emergencies - London Health Sciences Centre

Calcium
Emergencies
EMILY BRENNAN
WEDNESDAY OCTOBER 1, 2014
Objectives

To understand calcium regulation

To be able to calculate the corrected calcium

Outline the most common etiologies of hypocalcemia and
hypercalcemia

Outline the clinical manifestations of hypocalcemia and
hypercalcemia

To be able to manage hypocalcemia and hypercalcemia
Calcium Actions:
Extracellular Functions

bone mineral

blood coagulation

membrane excitability
Intracellular Functions:

neuron activation

hormone secretion

muscle contraction
Tightly regulated by PTH and Vitamin D
Calcium Regulation
PTH

Bones


Mobilize Ca and PO4
Kidneys

Resorb Ca

Excrete PO4

Synthesis of calcitriol
Calcium Regulation
Vitamin D

Bones



Kidneys

Resorb Ca

Resorb PO4
GI


Mobilize Ca and PO4
Increased Ca Intestinal
absorption
Parathyroid

Decrease PTH
Calcium Homeostasis
Lange Endocrine
Physiology
Corrected Calcium
•
The ionized (free) fraction is the biologically active and tightly
controlled
•
The measured serum calcium is the total calcium (bound +
unbound), and therefore, influenced by the albumin level
•
Normal range 2.15-2.55 mmol/L
corrected Ca = measured Ca + 0.02 x (40 – albumin)
Case 1

38 year old female with Graves
disease. She was started on
methimazole 10 mg daily for
treatment.

However, she developed
neutropenia as a side effect to
the methimazole along with an
infection


She stopped the medication,
and unfortunately developed
severe thyrotoxicosis resulting in
admission to the ICU.
She underwent emergent
thyroidectomy, and her postoperative laboratory studies
were:
Na
145 mmol/L
K
3.4 mmol/L
Ca
1.25 mmol/L
Cr
256 umol/L
Corrected Calcium
corrected Ca = measured Ca + 0.02 x (40 – albumin)
corrected Ca = 1.25 + 0.02 x (40-20)
corrected Ca = 1.65 mmol/L
Ca
1.25 mmol/L
Albumin
20 g/L
Definition

Mild: 2 - 2.15 mmol/L (asymptomatic)

Severe: under 1.9 mmol/L
Clinical Manifestations
Acute



neuromuscular irritability

perioral paresthesia, cramps, tingling, spontaneous or
latent tetany (Chvostek’s, Trosseau’s), laryngospasm

seizures (profound, acute fall)
conduction changes

Prolonged QT (risk of torsades, heart block)

Marked QRS and ST-segment changes

VT is rare
neurologic

Depression/mood/psychosis
Chvostek’s and Trousseau’s
Signs

http://www.nejm.org/doi/full/10.1056/NEJMicm1110569
Sign
Method
Manifestation
Chvostek
Tap facial nerve
1-2 cm anterior
to earlobe with
fingertip
Twitching of upper
lip at the corner only
 can include
orbicularis oculi
Trousseau
Inflate BP cuff
on upper arm
above systolic
pressures for 3
minutes
Carpal spasm: wrist
and
metacarpophageal
joint extension, and
digit adduction
Clinical Manifestations
Chronic

Milder neuromuscular
irritability/asymptomatic

Bone mineralization disorders
(renal osteodystrophy, Rickets,
osteomalacia)

Ectopic calcium deposition
(basal ganglia calcification,
blood vessels, posterior lens of
the eyes)

long standing, associated with high
PO4
DDx Acute Hypocalcemia

Post-surgical

Parathyroidectomy

Thyroidectomy

Radical neck surgery

Hungry bone syndrome

Critically ill (pancreatitis, rhabdo, tumour lysis syndrome)

Severe magnesium deficiency

Blood transfusion related

Drugs

High dose bisphosphonate

Denosumab

Calcium chelators
Etiology of Hypocalcemia
Low PTH
Absence/destruction of
Parathyroid Glands of
PTH
Decreased PTH
secretion (low Mg,CaSR
mutations)
High PTH
Vitamin D
deficiency/resistance
PTH resistance
Hypomag
Chelation (drugs)
Critical Illness
Alterations in Bound
Calcium
High phosphate
(tumour lysis, rhabdo,
enemas in CRF)
High citrate (complexes
calcium, transfusions,
PLEX)
Etiology of Hypocalcemia
Parathyroid-Related
Absence/destruction of
Parathyroid Glands of
PTH
(congenital, post-surgical,
infiltrative, autoimmune)
•
Impaired Secretion of
PTH
(hypomag, resp alkalosis,
Activating mutation of the
CaSR)
•
• Target Organ Resistance
(hypoMag,
pseudohypoparathyroidism
Vitamin D Related
•
Vitamin D deficiency
•
Accelerated loss
•
Impaired synthesis
•
Target organ resistance
Other
•
Excessive calcium
deposition in skeleton
(hungry bone,
malignancy)
•
Chelation
•
HIV infection
•
Critical illness
Evaluation


Confirm hypocalcemia

Ionized calcium

Total calcium (+ albumin)
Clinical Evaluation


History, physical
Labs:

PTH

Ca, PO4, Mag, albumin

Vitamin D
Hypocalcemia - Management

Increase calcium supplementation/replacement

Increase GI absorption

Reduce renal excretion
Calcium Replacement
IV


Calcium gluconate (preferred)

IV bolus: 1-2 grams over 20 minutes

IV: 2-5 grams over 2-5 hours

Infusion: 11 grams in 1L NS or D5W (990mg elemental), start about 0.51.5mg/kg/hr (~25-75ml/hr)
Calcium chloride

Should be given by central vein

Extravasation into tissue can cause inflammation and local calcium deposition
Oral

elemental calcium 400-800 mg q6h
Vitamin D

Vitamin D requirements vary considerably between
patients

Need to consider the presence/absence of PTH
Vitamin D
Calcitriol
1a,25-(OH)2D3
Active Metabolite
0.25-0.5 mcg
bid
Alfacalcidol
1a-(OH)D3
Activated by the
liver by 25hydroxylase
0.25-0.5 mcg
bid
tabs and
drops
Cholecalciferol
Unhydroxlyated
form
“D3”
Requires liver and
50,000IU
kidney hydroxylation
(PTH required)
Ergocalciferol
Unhydroxlyated
form
“D2”
Activated by the
kidneys by 1ahydroxylase
(PTH required)
Increased Resorption

Decrease renal excretion

Vitamin D

Thiazide diuretic
Other considerations:

Magnesium depletion is common

Results in PTH resistance and diminished secretion

Measure and replace as needed
Specific Clinical Scenarios:

Hypoparathryoidism risk post-surgery

Hungry Bone Syndrome

Hypocalcemia in the Critical Ill
Hypoparathyroidism Risk
Page et al. (2007):

hypoparathyroidism risk in total thyroidectomy for
bilateral, benign, multinodular goiter

351 surgical cases.
Hypoparathyroidism Risk
Page et al . 2007
351
1.4%
ATA Guidelines on Outpatient
Thyroidectomy 2013

Significant temporary hypocalcemia in 25% of postoperative patients

Usually manifests within 48-72 hours

Recommend:

CaCO3 1000 mg q6h-q8h +/- calcitriol 0.5-1 mcg daily

checking PTH in the recovery room (1-2hr post surgery)
Hungry Bone Syndrome

Rapid, profound and prolonged hypocalcemia associated
with low PO4 and low Mag worsened by suppressed PTH

Occurs post parathyroidectomy in patients with severe primary
hyperparathyroidism and pre-operative high bone turnover

Witteveen et al (2013):

Systematic review

No clear guidelines for management  treat the severe
calcium deficit and restore normal bone turnover

Risk Factors:: older age, higher pre-op Ca, PTH, and alk phos
levels (increased turnover), radiological evidence of bone
disease before surgery, volume/weight of resected parathyroid
gland

Prevention: pre-op vitamin D replacement,
bisphosphonate(two case reports)
Hypocalcemia and the
Critically Ill

Ranges from 15-50% and correlates with illness
severity

Mechanism: impaired PTH, vitamin D
deficiency/resistance, calcium sequestration,
impaired mobilization of calcium from bone
Hypocalcemia and the
Critically Ill

Cochrane Review 2008. Parental calcium for
intensive care unit patients

Impact of calcium replacement on: mortality, multiple
organ dysfunction, ICU and hospital length of stay,
costs, and complications of calcium administration.

No formal studies looking at association of calcium
supplementation of critical ill

Significant heterogeneity in the studies; no clear
evidence that parental calcium supplementation
impacts outcomes of critical ill patients
Back to the Case …
*
Back to the case…

Patient required IV calcium infusion for approximately 12 hours along with IV
calcium boluses

Alfacalcidol 2.5 mcg/day + Ca EFF 1000 TID

PTH – 0.8
POD #29

Calcium 2.00 mmol/L and albumin 35 g/L
Current regimen:

Alfacalcidol 1.5 mcg daily

Cholecalciferol (D3) 2000 units

Ca EFF 1000 mg PO TID

Doing well, on the floor ….
Case 2



91 year-old woman from a nursing
home presenting with progressive
confusion and generally being
unwell.
The nursing home staff report a 2month history of fatigue, anorexia,
thirst, polydipsia, and polyuria.
On physical exam, temperature is
37.2, blood pressure 96/60 mm Hg,
pulse rate is 107, and respiratory
rate is 20/min. The patient is
cachectic and confused.
Na
145 mmol/L
K
3.4 mmol/L
Ca
3.38 mmol/L
Albumin
30 g/L
Cr
256 umol/L
Corrected Calcium
corrected Ca = measured Ca + 0.02 x (40 – albumin)
corrected Ca = 3.38 + 0.02 x (40-30)
corrected Ca = 3.58 mmol/L
Na
145 mmol/L
K
3.4 mmol/L
Ca
3.38 mmol/L
Albumin
30 g/L
Cr
256 umol/L
Clinical Manifestations
“moans, stones, groans, and bones”
Neurological/Psychiatric
•
anxiety, depression, cognitive dysfunction
GI
•
constipation, anorexia, nausea
Renal
•
stones, nephrogenic DI, renal insufficiency
CVS
•
Short QTc
MSK
•
Muscle weakness, bony pain (if malignancy)
Top DDx?

Hypercalcemia of malignancy

Hypercalcemia of malignancy

If no malignancy:

vitamin D or vitamin A toxicity

granulomatous diseases

rarely acute hypercalcemia in hyperparathyroidism
Etiology of Hypercalcemia
Low PTH
High PTH
Neoplasms
• PTHrP dependent/Humoral
• Osteolytic disease
• Excess Vitamin D
Primary Hyperparathyroidism
PTHrP excess (non-neoplastic)
Tertiary Hyperparathyroidism
Excess Vitamin D
• Excess ingestion
• Granulomatous disease
• Williams’ syndrome
Familial Hypocalciuric
Hypercalcemia
Thyrotoxicosis
Li-associated Hypercalcemia
Adrenal Insufficiency
Pheo
Acromegaly
Antagonistic autoantibodies to
CaSR
Renal failure
Immobilization
Drugs (Vitamin A, milk-alkali,
thiazides, theophylline)
Evaluation


Confirm hypercalcemia

Ionized calcium

Total calcium (+ albumin)
Clinical Evaluation


History, physical
Labs:

PTH, PTHrP

PO4

Vitamin D
Hypercalcemia of Malignancy
Stewart NEJM 2005
Prognosis
Stewart (2005):

Hypercalcemia affects 20-30% of patients with
malignancies

Confers a worse prognosis with almost 50% of
patients dying within 30 days
Principles of Management

Fluid hydration

Profoundly volume depleted related to
nausea/vomiting, decreased oral intake, nephrogenic
DI

Typically: 1-2L NS bolus, then 200-250ml/hr with frequent
reassessment of serum calcium and volume status
Bone Resorption Inhibitors

Bisphosphonates

Highly effective in malignancy-associated
hypercalcemia

Inhibit the activity of osteoclasts

Expect to see decrease in calcium within 12 hours,
nadir in 4-7 days
Bisphosphonates
Major et al. 2001: (J Clin Oncol)

Two identical concurrent, parallel, multi-center RCT
(double-blind), compare zoledronic acid and
pamidronate in hypercalcemia of malignancy


275 patients with mod-severe HCM (CSC > 3 mmol/L) were
treated with a single dose of:

zolendronic acid 4 mg IV (n=86)

zolendronic acid 8 mg IV (n=98)

pamidronate 90 mv IV (n =103)
Followed for 56 days or until relapse (CSC > 2.9 mmol)

Zolendronic acid more effective than pamidronate(in two
RCTs, both 4mg and 8mg were superior to 90mg
pamidronate)
Bone Resorption Inhibitors

RANK Ligand Inhibitor

Only been studied in metastatic carcinoma and
multiple myeloma

Hu et al JCEM 2014:

33 patients with advanced cancer (solid tumours or heme),
refractory SCS > 3.1mmol/L despite bisphosphonates given
at 7 days and 30 days before screening

120mg SC day 1, 8, 15, 29 then q4 weeks
In patients with
hypercalcemia of
malignancy with
recent IV
bisphosphonate use:
denosumab lowered
serum calcium in 64%
of patients within 10
days, inducing
durable responses.
Calcitonin

Transiently lowers calcium levels; helpful as
adjunctive treatment when used with
bisphosphonates

Effect limited due to tachyphylaxis, which typically
occurs in 48 hours

Dose: 4 units/kg q12h SC
Glucocorticoids

Role in patients with vitamin D mediated
hypercalcemia (i.e. lymphoma)

Decreased calcitriol production by the activated
mononuculear cells in the lung/lymph nodes in 2-5
days

Dose: prednisone 20-40 mg/day
Other options:


Gallium nitrate

?unsure mechanism, but likely inhibits bone resorption

200mg/m3 x 5 days; but high risk of anemia and AKI
(not used)
Mithramycin (used before bisphosphonates)

Remains effective, but limited by adverse effects
(thrombocytopenia, platelet-aggregation defect,
anemia, leukopenia, hepatitis, renal failure)

Not recommended
Enhanced calcium excretion


Furosemide

Only case reports/case series advocating role of
furosemide

Should limit use to those who demonstrate signs of
volume overload
Hemodialysis


Highly effective in selected patients (low GFR, presence
of CHF)
Remove calcium from feeds/TPN as required
Back to the case…

The patient was treated with NS 250ml/hr and given
pamidronate 90 mg IV

Repeat calcium was 2.98 mmol/L

Malignancy-focused physical exam found palpable
breast mass

The patient’s family decided to not proceed with
investigations, and changed goals of care to comfort
only
Take-Home Messages:
Hypocalcemia

Severe symptomatic hypocalcemia is usually in a
post-operative setting

IV calcium bolus only lasts 30 minutes

Need adequate calcium and vitamin D replacement
(consider if PTH is present or absent)

Need to correct low magnesium
Take-Home Messages:
Hypercalcemia

Most common cause of severe hypercalcemia in
hospitalized patients is malignancy

Confers a worse prognosis because the underlying
cancer usually is advanced

Treat with aggressive fluids along with IV
bisphosphonates

? role for denosumab
References

Reagan P. et al. Approach to diagnosis and treatment of hypercalcemia in a patient
with malignancy. Am J Kidney Dis. 2014;63(1):141-147.

Stewart. Hypercalcemia associated with cancer. NEJM. 2005;352373-9.

Kelly, A. et al. Hypocalcemia in the critically ill patient. J Intensive Care Med. 2013
28:166.

Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia
of malignancy. J Clin Endocrinol Metab 2014; 99:3144.

Page C, and V. Strunsky. Parathyroid risk in total thyroidectomy for bilateral, benign,
multinodualr goitre: report of 315 surgical cases. JLO 2007. 121.237-241

Major, P. et al. Zoledronic acid is superior to pamidroante in the treatment of
hypercalcemia of malignancy. A pooled analysis of two randomized, controlled
clinical trials.

Pocket Medicine Handbook

Williams’ Textbook of Endocrinology

Lange Endocrine Physiology

DynaMed

Uptodate
Questions?
Thanks!