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.
Hypocalcemia most likely results from 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 puppies or a large litter are often noted. The incidence is increased in small breeds of dogs, although puerperal hypocalcemia can occur in any breed, 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. 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.
Inadequate production of parathyroid hormone (PTH) during the hypocalcemic crisis is not responsible for eclampsia in dogs. In dairy cows with a similar condition (see Parturient Paresis in Cows), 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 parafollicular C-cell secretion of calcitonin. Hypocalcemia at parturition interferes with the release of acetylcholine at the neuromuscular junction, which is normally mediated by extracellular calcium entering presynaptic nerve terminals through voltage-gated calcium channels and triggering the fusion of acetylcholine-filled synaptic vesicles with the presynaptic nerve terminus. 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. Magnesium is a calcium-channel antagonist and plays a key role in modulating any activity governed by intracellular calcium fluxes. Cows also have increased volatile fatty acids (which are inhibitory at neuromuscular synapses), and cows have a higher threshold potential at neuromuscular junctions than do dogs.
In dogs with hypocalcemia, unlike cows, excitation-secretion coupling is maintained at the neuromuscular junction. The low concentration of calcium in the extracellular fluid has an excitatory effect on nerve and muscle cells, because it lowers the threshold potential (voltage level at which sodium channels become activated) so it is closer to the resting membrane potential. With hypocalcemia, sodium channels become activated (opened) by very little increase in membrane potential from their normal, negative level. Therefore, the nerve fiber becomes highly excitable, sometimes discharging repetitively without provocation rather than remaining in the resting state. The probable way that calcium ions affect the sodium channels are that calcium ions bind to the exterior surfaces of sodium channels. The positive charge of these calcium ions alters the electrical state of the sodium channel protein, thus altering the voltage level required to open the sodium channel. Because of the loss of stabilizing membrane-bound calcium ions, nerve membranes become more permeable to sodium ions and require a stimulus of lesser magnitude to depolarize. Tetany occurs as a result of spontaneous repetitive firing of motor nerve fibers. Hypoglycemia can occur concurrently.
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. Mild hypocalcemia (serum calcium concentration >7 mg/dL but below the normal reference range) 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 is the physiologically available fraction; it is affected by protein concentration, acid-base status (alkalosis favors protein binding of serum calcium and will decrease blood levels of the biologically important ionized calcium, thus exacerbating hypocalcemia), and other electrolyte imbalances. Thus, the severity of clinical signs may not correlate with total calcium concentration.
Diagnosis is often made from the signalment, history, clinical signs, and response to treatment. A pretreatment total 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 exclude 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 excluded. If the parathyroid glands are functioning normally, serum PTH will be increased in the face of hypocalcemia. Low or undetectable serum PTH in a hypocalcemic animal is strongly suggestive of primary hypoparathyroidism (see Hypoparathyroidism). A commercially available human intact-PTH assay has been validated in both cats and dogs; PTH-calcium curves are also similar in cats and dogs.
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 by auscultation or by ECG for bradycardia or arrhythmias. 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 <8 mg/dL indicate the need to increase the dosage 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 old) or weaned (>4 wk old).
After the acute crisis, elemental calcium at 25–50 mg/kg/day in three or four 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 ~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 posttetany period. Calcium carbonate is a good choice because of its high percentage of elemental calcium, general availability in drugstores in the form of antacids, low cost, and lack of gastric irritation. The dosage 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 D (calcitriol) is 0.03–0.06 mcg/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) therapy.
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 puerperal hypocalcemia is likely to recur with future pregnancies. Preventive steps to consider 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.