Puerperal Hypocalcemia in Small Animals

(Postpartum hypocalcemia, Periparturient hypocalcemia, Puerperal tetany, Eclampsia)     Puerperal hypocalcemia is an acute, life-threatening condition usually seen at peak lactation, 2-3 wk after whelping. Small-breed bitches with large litters are most often affected. Hypocalcemia may also occur during parturition and may precipitate dystocia.

Etiology and Pathogenesis:

Hypocalcemia most likely results from the loss of calcium into the milk and from inadequate dietary calcium intake. This imbalance in calcium metabolism occurs because calcium mobilization from bone into the serum pool is insufficient to maintain the efflux of calcium leaving through the mammary glands. Heavy lactational demands from large neonates or a large litter are often noted. The incidence is increased in small breeds of dogs, although puerperal hypocalcemia can occur in any breed of dog, with any size litter, and at any time during lactation. Rarely, it occurs during late gestation in bitches. Although uncommon in queens, it may occur during early lactation. Inadequate production of parathyroid hormone (PTH) during the hypocalcemic crisis is not responsible for eclampsia. In dairy cows with a similar condition.  production of PTH is adequate, but the pool of osteoclasts for PTH to stimulate is not. The small osteoclast pool results from feeding a high level of dietary calcium during the nonlactating period, which suppresses parathyroid gland secretion of PTH and stimulates C-cell secretion of calcitonin. In dogs, supplementation with oral calcium during pregnancy may predispose to eclampsia during peak lactation, because excessive calcium intake during pregnancy causes downregulation of the calcium regulatory system and subsequent clinical hypocalcemia when calcium demand is high. The paresis seen in cattle, rather than the tetany seen in dogs, is probably the result of a combination of factors. Cows often have concurrent mild hypermagnesemia and fail to release acetylcholine at neuromuscular junctions, have increased volatile fatty acids (which are inhibitory at neuromuscular synapses), and have a higher threshold for firing of neuromuscular junctions than do dogs. In dogs, hypocalcemia has an excitatory effect on nerve and muscle cells. Excitation-secretion coupling is maintained at the neuromuscular junction in dogs with hypocalcemia. Tetany occurs as a result of spontaneous repetitive firing of motor nerve fibers. As a result of the loss of stabilizing membrane-bound calcium, nerve membranes become more permeable to ions and require a stimulus of lesser magnitude to depolarize. Hypoglycemia can occur concurrently.

Clinical Findings:

Panting and restlessness are early clinical signs. Mild tremors, twitching, muscle spasms, and gait changes (stiffness and ataxia) result from increased neuromuscular excitability. Behavioral changes such as aggression, whining, salivation, pacing, hypersensitivity to stimuli, and disorientation are frequent. Severe tremors, tetany, generalized seizure activity, and finally coma and death may be seen. Hyperthermia may occur in severe cases. Prolonged seizure activity may cause cerebral edema. Tachycardia, hyperthermia, polyuria, polydipsia, and vomiting are sometimes seen. Historically, the bitch has been otherwise healthy and the neonates have been thriving. Although hypocalcemia usually occurs postpartum, clinical signs can appear prepartum or at parturition. Hypocalcemia, with a serum calcium concentration >7 mg/dL but below the low normal level, may contribute to ineffective myometrial contractions and slow the progression of labor without causing any other clinical signs. Heavy panting may produce a respiratory alkalosis. Ionized calcium concentration is affected by protein concentration, acid-base status (alkalosis favors protein binding of serum calcium and exacerbates hypocalcemia), and other electrolyte imbalances. Thus, the severity of clinical signs may not correlate with the total calcium concentration.

Diagnosis:

Diagnosis is often made from the signalment, history, clinical signs, and response to treatment. A pretreatment serum calcium concentration <7 mg/dL (<6 mg/dL in cats) confirms the diagnosis. (IV therapy with calcium is often started, however, before serum calcium concentration is determined.) A serum chemistry profile is useful to rule out concurrent hypoglycemia and other electrolyte imbalances. Prolongation of the QT interval and ventricular premature contractions may be seen on the ECG. Differential diagnoses include other causes of seizures such as hypoglycemia, toxicoses, and primary neurologic disorders such as idiopathic epilepsy or meningoencephalitis. Other causes of irritability and hyperthermia such as metritis and mastitis should also be ruled out.

Treatment and Prevention:

Slow IV administration of 10% calcium gluconate is given to effect (0.5-1.5 mL/kg over 10-30 min; 5-20 mL is the usual dose). This usually results in rapid clinical improvement within 15 min. Muscle relaxation should be immediate. During administration of calcium, heart rate should be carefully monitored for bradycardia or arrhythmia by auscultation or by ECG. Signs of toxicity from too rapid administration of calcium include bradycardia, shortening of the QT interval, and premature ventricular complexes. If an arrhythmia develops, calcium administration should be discontinued until the heart rate and rhythm are normal; then administration is resumed at half the original infusion rate. It is important to calculate the dosage of calcium based on elemental (available) calcium, because different products vary in the amount of calcium available. The dosage of elemental calcium for hypocalcemia is 5-15 mg/kg/hr. Calcium gluconate, 10%, contains 9.3 mg of elemental calcium/mL. Calcium chloride, 27%, contains 27.2 mg of elemental calcium/mL. Thus, for 10% calcium gluconate, the dosage is 0.5-1.5 mL/kg/hr, IV, and for 27% calcium chloride the dosage is 0.22-0.66 mL/kg/hr, IV. Calcium gluconate, as a 10% solution, is recommended because unlike calcium chloride, calcium gluconate extravasation is not caustic. Once the animal is stable, the dose of calcium gluconate needed for initial control of tetany may be diluted in an equal volume of normal (0.9%) saline and given SC, tid, to control clinical signs. (Calcium chloride cannot be given SC.) Alternatively, 5-15 mg of elemental calcium/kg/hr can be continued IV. This protocol effectively supports serum calcium concentrations while waiting for oral vitamin D and calcium therapy to have effect. Ideally, serum calcium concentration should be maintained >8 mg/dL. Serum calcium concentrations at <8 mg/dL indicate the need to increase the dose of parenteral calcium, whereas concentrations >9 mg/dL suggest that it be reduced. The aim of longterm therapy is to maintain the serum calcium concentration at mildly low to low-normal concentrations (8-9.5 mg/dL). The bitch may remain nonresponsive after correction of hypocalcemia if cerebral edema has developed. Cerebral edema, hyperthermia, and hypoglycemia should be treated if present. Fever usually resolves rapidly with control of tetany, and specific treatment for fever may result in hypothermia. It is best not to let the puppies or kittens nurse for 12-24 hr. During this period, they should be fed a milk substitute or other appropriate diet; if mature enough, they should be weaned. If tetany recurs in the same lactation, the litter should be removed from the bitch and either hand raised (<4 wk of age) or weaned (>4 wk of age). After the acute crisis, 25-50 mg of elemental calcium/kg/day in 3 or 4 divided doses is given PO for the remainder of the lactation. Again, the dose of calcium is based on the amount of elemental calcium in the product (ie, calcium carbonate tablets contain 295 mg elemental calcium/1 g tablet). In dogs, the dosage is usually 1-4 g/day, in divided doses. In cats, the dosage of calcium is approximately 0.5-1 g/day, in divided doses. Longterm maintenance therapy with oral vitamin D and oral calcium supplementation usually requires a minimum of 24-96 hr before an effect is achieved. Hypocalcemic animals should, therefore, receive parenteral calcium support during the initial post-tetany period. Calcium carbonate is a good choice because of its high percentage of elemental calcium, ready availability in drugstores in the form of antacids, low cost, and lack of gastric irritation. The dose of calcium can be gradually tapered to avoid unnecessary therapy; there is usually sufficient calcium in commercial pet food to meet the needs of dogs and cats. However, to avoid acute problems of hypocalcemic tetany, oral calcium supplementation should continue throughout lactation. Vitamin D supplementation is used to increase calcium absorption from the intestines. The concentration of serum calcium should be monitored weekly. The dosage of 1,25-dihydroxyvitamin D3 (calcitriol) is 0.03-0.06 µg/kg/day. Calcitriol has a rapid onset of action (1-4 days) and short half-life (<1 day). Iatrogenic hypercalcemia is a common complication of this therapy. If hypercalcemia results from overdosage, it can be rapidly corrected by discontinuing calcitriol. The toxic effects resolve in 1-14 days. This is a much briefer period than that seen with dihydrotachysterol (1-3 wk) or ergocalciferol (vitamin D2 ; 1-18 wk). Corticosteroids lower serum calcium and, therefore, are contraindicated. They may interfere with intestinal calcium transport and increase urinary loss of calcium. Owners should be warned that this condition is likely to recur with future pregnancies. Steps to consider to prevent puerperal hypocalcemia in the bitch include feeding a high-quality, nutritionally balanced, and appropriate diet during pregnancy and lactation, providing food and water ad lib during lactation, and supplemental feeding of the puppies with milk replacer early in lactation and with solid food after 3-4 wk of age. Oral calcium supplementation during gestation is not indicated and may cause rather than prevent postpartum hypocalcemia. Calcium administration during peak milk production may be helpful in bitches with a history of puerperal hypocalcemia.