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Hypocalcemia

ISSN 2398-2950

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Synonym(s): Hypocalcaemia

Introduction

  • Definition:
    • Low total serum calcium concentration< 7mg/dl.
    • Low ionized serum calcium concentration < 1.1 mmol/L.
  • Calcium is important for many intra and extracellular functions. Required for bone formation, muscle contraction, nerve conduction, neuromuscular transmission, enzymatic reactions, blood coagulation, maintenance of vascular tone, regulation of hormones (PTH, calcitonin, vitamin D), cell growth and division.
  • Total calcium is composed of 50% ionized calcium (iCa), 40% protein bound calcium (pCa) and 10% complexed calcium. iCa is the biologically active fraction.
  • Calcium regulation is a complex process involving parathyroid hormone ( PTH), vitamin D metabolites and calcitonin.
  • Clinical signs are usually present when serum tCa is less than 6 mg/dL or iCa is less than 0.8 mmol/L.

Presenting signs

  • The duration, magnitude of ionized hypocalcemia and the rate of decline contribute to the severity of clinical signs.
  • The lower the blood pH, the lower the iCa can be without clinical signs, with higher pH signs might be seen at a higher iCa. Signs may be intermittent.
  • Common:
    • Muscle trembling or twitching or fasciculation.
    • Facial rubbing.
    • Ataxia or stiff gait.
    • Muscle cramping.
    • Behavioral changes: 
      • Restlessness or excitation.
      • Aggression.
      • Hypersensitivity to stimuli.
      • Disorientation.
  • Occasional:
    • Diarrhea.
    • Seizures.
    • Panting.
    • Pyrexia.
    • Vomiting.
    • Anorexia. 
    • Prolapse of the third eyelid (cats).
    • Posterior lenticular cataract in patients with primary hypoparathyroidism Hypoparathyroidism.
    • Tachycardia or ECG alteration (ie prolonged qt interval).
  • Uncommon:
    • Polyuria or polydipsia.
    • Hypotension.
    • Respiratory arrest and death.

Acute presentation

  • Depend on the severity and rate of decline of iCa concentration.
  • Severe acute presentation:
    • Cardiac arrest secondary to hypotension and decreased myocardial contractility.
    • Respiratory arrest from paralysis of respiratory muscles.
  • Acute presentation:
    • Focal twitching.
    • Behavioral changes (restlessness, aggression, disorientation).
    • Rubbing face.
    • Tetany.
    • Seizures.

Geographic incidence

  • None.

Age predisposition

  • None.

Breed/Species predisposition

  • None.

Public health considerations

  • None.

Cost considerations

  • None.

Special risks

  • General anesthesia.
  • Animals with severe hypocalcemia (serum calcium concentration < 0.8 mmol/l) are at increased risk of bradycardia and ECG abnormalities ECG: principles of interpretation, that may include prolonged QT intervals, deep wide T wave, atrioventricular block, hypotension and anesthetic-related death.
  • Cardio-respiratory arrest.

Pathogenesis

Pathophysiology

  • Most of the clinical signs are associated with increased neuromuscular tissue excitability.
  • Different causes for hypocalcemia:
  • Common cause:
    • Low concentrations of binding proteins:
      • Hypoalbuminemia Hypoproteinemia. (Usually not clinical relevant as affect the protein bound fraction and ionized calcium unaffected. Correction formulas only appropriate for animals with low total protein or albumin and no longer commonly used. Should be confirmed with ionized calcium.)
    • Chronic renal failure Kidney: chronic kidney disease:
      • Decrease calcitriol synthesis (reduced calcium intestinal absorption and increased skeletal resistance to PTH) and increase phosphorus serum concentration.
    • Puerperal tetany:
      • Loss of calcium into the milk during lactation, fetal skeletal ossification, and parathyroid dysfunction.
    • Acute pancreatitis Pancreatitis:
      • Sequestration or saponification of calcium in the peri-pancreatic fat, increased calcitonin and hypomagnesemia Hypomagnesemia. Possible glucagon-stimulated release of calcitonin as well as decrease in PTH and hypomagnesemia.
    • Acute renal failure Kidney: acute renal failure.
  • Occasional cause:
    • Hypoparathyroidism Hypoparathyroidism (decreased or absent PTH secretion)
      • Primary:
        • Idiopathic or spontaneous.
        • Post-operative bilateral thyroidectomy.
      • After sudden reversal of chronic hypercalcemia Hypercalcemia: overview (as result of parathyroid gland atrophy).
      • Secondary to magnesium depletion or excess (inhibition of PTH).
    • Ethylene glycol intoxication Ethylene glycol poisoning (chelation of iCa with oxalic acid).
    • Phosphate enema.
    • After sodium bicarbonate administration Sodium bicarbonate.
  • Uncommon cause:
    • Laboratory error.
    • Improper sample anticoagulant handling (contamination with EDTA).
    • Rapid intravenous infusion of phosphate.
    • Rapid infusion of calcium-free fluid (rare).
    • Intestinal malabsorption.
    • Severe starvation.
    • Hypovitaminosis D (secondary to malabsorption).
    • Nutritional secondary hyperparathyroidism Nutritional secondary hyperparathyroidism.
    • Tumor lysis syndrome (from rapid increase in phosphate and deposition of calcium /phosphate complexes).
    • Blood transfusion (citrate anticoagulant) Blood transfusion.

Timecourse

  • None.

Epidemiology

  • None.

Diagnosis

Client history

  • Depends on underlying cause
    • Seizure and neurological abnormalities:
      • Hypoparathyroidism:
        • Clinical signs associated with hypocalcemia, hungry bone syndrome.
      • Lethargy, depression anorexia polyuria/polidipsia and weight loss:
        • Chronic renal failure.
      • Vomiting and diarrhea:
        • Associated with acute pancreatitis.
        • Malabsorption.
        • Ethylene glycol intoxication ( associated with neurological signs and oliguric kidney failure).
      • Recent blood transfusion.
      • Recent treatment of lymphoma Lymphoma with chemotherapy +/- radiation therapy in the presence of a large tumor burden.

Clinical signs

  • See client history.

Diagnostic investigation

  • Blood work:
  • Urinalysis.
  • Other laboratory tests:
    • Ethylene glycol test.
    • PTH assay ( to diagnose primary hypoparathyroidism) PTH assay.
  • Imaging:
    • Abdominal ultrasound.
    • Thoracic and abdominal radiographs.
  • ECG:
    • Prolongation of the ST and Q-T segments.
    • Sinus bradycardia.
    • Wide T waves or T wave alternant. Tall R-waves and T-wave abnormalities.

Confirmation of diagnosis

Discriminatory diagnostic features

  • Blood work.
  • ECG:
    • Prolongation of the ST and Q-T segments.
    • Sinus bradycardia.
    • Wide T waves or T wave alternant.

Definitive diagnostic features

  • Depends on the underlying causes.

Gross autopsy findings

  • Depends on the underlying cause:
    • Bi-refringent crystals, renal tubular necrosis and tubular obstruction with calcium oxalate crystalluria in cases of ethylene glycol intoxication.
    • Inflammatory or neoplastic destruction of the parathyroid glands.
    • Atrophy of the parathyroid glands.

Histopathology findings

  • Depends on the underlying causes.

Differential diagnosis

  • Primary hypoparathyroidism.
  • Secondary hypoparathyroidism.
    • Secondary to thyroidectomy and parathyroid damage.
  • Puerperal tetany (eclampsia).
  • Renal failure.
  • Ethylene glycol toxicity Ethylene glycol poisoning.
  • Acute pancreatitis.
  • Intestinal malabsorption.
  • Nutritional secondary hyperparathyroidism.

Treatment

Initial symptomatic treatment

  • Acute therapy indicated if clinical signs present (if hyperthermia (>41°C) cool):
    • Calcium gluconate Calcium gluconate 10% solution:
      • 5-15 mg/kg (0.5-1.5 ml/kg) slowly to effect over a 10 minute period.
    • Calcium chloride Calcium chloride 10% solution: 
      • Extremely caustic if administered extravascularly.
      • More potent than calcium gluconate. The dose is 0.15-0.5 ml/kg.
        Note there are two different concentrations of Cagluc and both Cagluc and CaCl should be given over 10-30 mins and monitored with an ECG during infusion. Can take several hours after normalization of Ca for all clincial signs to resolve.

Standard treatment

  • In asymptomatic patient swith a mild decrease in iCa that is not decreasing calcium supplementation may not be necessary and the underlying cause should be addressed. 
  • Therapy is recommended in asymptomatic patients in which the iCa is decreasing or expected to decrease treament may be indicated.
  • Subacute therapy:
    • Oral calcium 25 mg/kg q8-12 h.
    • Calcium gluconate bolus (see acute treatment)
    • Continuous rate infusion (CRI) of calcium. A CRI of elemental calcium can  be delivered at 1-5+ mg/kg/h  in 0.9% NaCl. Do not administer in fluids containing acetate, lactate or bicarbonate as precipitation can occur. Diluted 1:1 Cagluc can be given SC but occasional severe cutaneous reactions have been reported.
    • Vitamin D metabolite (usually only necessary in cases of hypoparathyroidism (primary or secondary):
      • Calcitriol:
        • Induction 20-30 ng/kg Q24 h for 3-4 days.
        • 5-15 ng/kg q 24h for maintenance therapy.

Monitoring

  • Monitor iCa q 6-12 h during supplementation.
  • During intravenous calcium gluconate administration monitor for:
    • Cardiac toxicity:
      • Bradycardia.
      • ECG:
        • Prolonged PR interval.
        • Widen QRS complex.
        • Shorten QT interval.
        • Elevated or shorten or absent ST segment.
        • Widened T wave.
  • Serum electrolytes serum concentration.

Subsequent management

Treatment

  • Sub acute and long-term therapy is usually needed in case of primary and secondary hypoparathyroidism and puerperal tetany. 
  •  Long term therapy:
    • Oral calcium (calcium carbonate, calcium lactate, calcium chloride, calcium gluconate):
      • Dose 25-50 mg/kg q 24h (or more frequently).
    • Calcitriol (see sub acute management)
    • Adequate and balanced diet  recommended in patients with nutritional secondary hyperparathyroidism and renal failure.

Monitoring

  • Serum electrolyte (iCa) concentration.
  • Depends on underlying disease.

Prevention

Outcomes

Expected response to treatment

  • After administration of the calcium bolus it may take up to 30-60 minutes for the clinical signs to resolve especially panting, behavioral changes and restlessness.

Further Reading

Publications

Refereed papers

Other sources of information

  • Small Animals Critical Care Medicine (2008) Eds D C Silverstein and K Hopper. Saunders Elsevier, S Louis Missouri.
  • Fluid, Electrolytes and acid-base Disorders in Small Animal Practice (2006) Eds S P DiBartola, Saunders Elsevier , St Louis Missouri.
  • The Veterinary ICU Book (2002) Eds W E Wingfield and M R Raffee. Teton New Media, Jackson Hole, WY.