Metabolic disorders of small ruminants (Proceedings)

Hypocalcemia

Multiple physiologic mechanisms act in concert to maintain the concentration of ionized calcium in the extracellular fluid (ECF) within a very tightly-regulated range. Hypocalcemia most commonly occurs when the physiologic demand for calcium for fetal bone growth or milk production exceeds the dietary supply of calcium and overwhelms the homeostatic systems aimed at maintaining adequate ionized calcium in the ECF. While diets limited in calcium are often ingested by ruminants on range pastures during gestation, dams in such populations can often maintain normocalcemia by mobilization of bone mineral. Bone mineral mobilization occurs under conditions of bone exposure to parathyroid hormone (PTH) in conjunction with the active form of vitamin D. Adequate magnesium concentration in the ECF is necessary to enable optimal release of parathyroid hormone from the parathyroid gland.1 Adequate dietary levels of vitamin D are necessary for optimal calcium absorption from the gut and maximal calcium mobilization from bone, in conjunction with PTH. Given that the efficiency of bone mineral mobilization appears to decrease with age in other species, older sheep and goats may be more prone to clinical disease. Hypocalcemia may contribute to the development of severe pregnancy toxemia through impairment of endogenous glucose production.2

Pregnant ewes, particularly those with multiple fetuses, have a relatively large fetoplacental mass and smaller udder than do dairy cattle. This phenomenon is the logical basis for the contention that hypocalcemia tends to occur more often in late gestation than at the onset of lactation in sheep.3 The author has intervened in three flock-wide outbreaks of hypocalcemia that occurred during shearing of late-pregnant range ewes. It was hypothesized that the cessation of feeding for several hours, in addition to the stress imparted by the sorting and shearing process, caused an acute decline in serum calcium or magnesium concentration, or both. An abrupt decline in serum magnesium concentration may occur subsequent to catecholamine release, and if this perturbation is maintained for sufficient time, calcium homeostasis may fail as a sequel to impairment of magnesium-mediated PTH release. The close temporal association between hypomagnesemia and hypocalcemia may explain why ewes with hypocalcemia can demonstrate transient, intermittent, or persistent muscular rigidity. Flaccid paresis and an obtunded demeanor of variable severity can also occur; many of the ewes in the aforementioned outbreak were found to be in a dog-sitting posture and unable to rise to a full standing position. Others were found in sternal recumbency and unable to raise their heads. Other signs of ovine hypocalcemia include ataxia, loss of the anal reflex, constipation, tachycardia, ruminal stasis or tympany, salivation, and tachypnea.4

Hypocalcemia in goats can occur prepartum as is the trend in sheep; however, given the greater propensity for milk production in dairy breeds, hypocalcemia tends to occur during the lactation period as well. Range goats may develop hypocalcemia when oxalate-containing forbs are ingested while other forages are sparse; renal failure typically accompanies these rare cases of oxalate intoxication. Pet small ruminants may develop hypocalcemia and severe metabolic acidosis subsequent to ethylene glycol intoxication.

Differential diagnoses for hypocalcemia in small ruminants include pregnancy toxemia (which can coexist with hypocalcemia), hypoglycemia, hypomagnesemia, rumen acidosis, nutritional myodegeneration, exertional myopathy, ionophore intoxication, ethylene glycol intoxication, polioencephalomalacia, botulism, and enterotoxemia. Whenever possible, a urine sample should be obtained from affected animals and evaluated by dipstick. Ketonuria and aciduria are findings compatible with pregnancy toxemia. Glucosuria may occur with enterotoxemia and severe hypoglycemia. Pigmenturia and proteinuria are compatible with myopathies and ionophore intoxication. Botulism is characterized by flaccid generalized weakness and hyporeflexia that involves muscles innervated by the cranial nerves (e.g. reduced jaw and tongue tone). Cortical blindness is characteristic of polioencephalomalacia; in severe cases, affected animals show opisthotonus and increased limb tone, which must be carefully differentiated from the tetany characteristic of hypocalcemia with concurrent hypomagnesemia. A history of potential exposure is key to establishing a diagnosis of ethylene glycol intoxication. It is important to note that combinations of these differential diagnoses may be present in a single animal.

Prior to treatment, a serum sample and a whole blood sample should be obtained, should treatment prove unsuccessful or further investigation of metabolic diseases be subsequently requested. These samples can always be discarded if treatment proves successful. Calcium salts (0.5 – 1.0 ml of 23% calcium borogluconate / kg) can be infused slowly IV or administered subcutaneously. The author prefers to administer half of the calculated dosage slowly IV through a large syringe attached by an extension tubing set to a needle well-seated in the jugular vein; the remaining half of the dosage can be administered subcutaneously. Administration of calcium salts into the peritoneal cavity does not have any documented advantage over the subcutaneous route; creation of intra-abdominal adhesions or infections is an additional risk of intraperitoneal administration. Calcium salts that contain magnesium should be used for animals showing tetany. These magnesium-containing calcium solutions may contain glucose as well; these solutions appear to be more irritating when administered subcutaneously. The author typically dilutes these solutions 1:1 with saline and administers them in multiple subcutaneous depots (neck, axillae) to limit the chances of abscess formation. Oral administration of calcium salts at the same dosage rate, along with oral electrolytes and propylene glycol (1 ounce / 50 kg PO q 12 h) can be administered to prevent relapse. Oral drenches should not be administered to obtunded animals with a potentially impaired swallow reflex; rather, orogastric intubation should be performed. Affected ewes should be propped in sternal recumbency to limit the chances of bloat or aspiration of rumen contents. Physical therapy may be needed for older dams or those recumbent for prolonged periods of time.

Prevention requires supplementation of calcium and magnesium to animals at highest risk, particularly older dams in late pregnancy or those producing large volumes of milk. These can be in block or lick form. Legume hay is also a source of calcium and magnesium that can be fed to animals at highest risk. Provision of calcium / magnesium supplements or legume hay prior to scheduled, stressful events (e.g. shearing, transport) might also reduce risk.

Pregnancy Toxemia

Pregnancy toxemia occurs under conditions of chronic negative energy balance in late gestation. The heavy fetal demands for glucose exceed the capacity for the ewe or doe to maintain normoglycemia through gluconeogenesis. Mobilization of fat reserves and the resultant flood of fatty acids entering the hepatocytes can exceed the liver's ability to completely metabolize the fatty acids, triggering ketogenesis and hepatic fat deposition. Unchecked, these processes can proceed to ketosis, ketoacidosis, and hepatic lipidosis.

Initial signs are vague, possibly reflecting the effects of hypoglycemia and / or ketosis on the CNS. Common signs include separation from the flock and a lethargic, glassy-eyed, mentation; affected ewes may lose their normal apprehension of being approached. Weakness and anorexia are common owner complaints. Affected ewes are often slow to rise, may stagger when they initially stand up, and then lag behind others as the flock moves. Nebulous signs of illness in a ewe or doe of any age in late gestation may be indicative of pregnancy toxemia. As the degree of hepatic lipidosis, ketoacidosis, and hypoglycemia progresses, ataxia, and profound lethargy occur. Recumbency and an inability to stand without assistance is a frequent finding in advanced cases; such animals frequently develop secondary dehydration caused by an inability to find water or an inability / unwillingness to drink when water is provided. Affected ewes may appear to be blind, although when severe depression is present, it may be difficult to interpret a menace response. A ketone odor to may be detected on the breath. Ballottement of the abdomen or abdominal ultrasonographic examination reveals the presence of one or more fetuses. Usually, the urine is strongly positive for ketones on dipstick urinalysis. Aciduria can reflect the presence of high levels of ketones (ketoacids) in the bloodstream or aciduria secondary to potassium depletion. The author routinely uses a battery-operated glucometer, designed for diabetes monitoring in people, to measure blood glucose in affected animals. Hypoglycemia is a very frequent finding. No fever is present, unless pregnancy toxemia occurs secondary to an inflammatory disease such as pneumonia or footrot. If treatment is not provided, affected ewes progress to coma and death. The list of differential diagnoses is similar to that of hypocalcemia.

The course of medical management of pregnancy toxemia is dictated in large degree by the owner's priorities. Is the primary goal of case management to save the dam's life or to deliver live offspring, or both? If the primary goal is saving the dam, termination of pregnancy by cesarean section is the most expedient means of removing the primary metabolic drain. In many cases, however, saving the offspring or the offspring and the dam is the primary goal. In such instances, unless meticulous breeding records are kept, the veterinarian is often challenged by not knowing the dam's expected due date. Typically, these cases are managed medically until parturition begins or is judged to be near. At that time, the dam's status can be assessed to determine if vaginal delivery can occur, or if cesarean delivery is warranted. However, such courses of action are often difficult to deploy in ambulatory practice. More importantly, the clinical course of prolonged medical management of pregnancy toxemia is often difficult to predict – something the owner must clearly understand before medical treatment is enacted. Hospitalization or referral is a consideration for valuable cases wherein the owner requests long-term medical management for salvage of the offspring.

Affected ewes and does can be offered small amounts of novel, palatable feeds, such as corn, alfalfa hay, or grass. Propylene glycol (30 ml PO q 12 h) can be administered orally, either as a drench or by orogastric tube as a glucose precursor; in the latter case, it can be mixed in 60 ml/kg warm water to help meet the animal's fluid needs. Animals with significant impairment of hepatic function, such as those with advanced hepatic lipidosis, may not efficiently convert propylene glycol into glucose. Owners should take caution to not overdose propylene glycol, owing to the potential for CNS depression caused by this alcohol compound. Supplemental calcium should be initially administered parenterally because impaired rumen motility may reduce the rate of passage of orally-administered calcium supplements. Supplemental B vitamins can be administered parenterally.

Fluid and glucose therapy can be provided by administration of an oral drench consisting of dextrose- and bicarbonate - containing electrolyte replacer solutions for calves at a dosage of approximately 2 ml/kg every 4-8 hours until normal appetite resumes.5 It has been hypothesized that the salinity of this solution induces closure of the esophageal groove, thereby directing the dextrose-rich solution into the abomasum. In the duodenum, the dextrose is digested and absorbed as glucose. A British study showed increases in blood glucose in minutes following this treatment, and the rise in blood glucose was far more rapid and greater in magnitude than what was achieved with oral propylene glycol solution.5 One must drench the solution to allow contact with the oropharynx in order to trigger the esophageal groove reflex; administration of such solutions via stomach tube will result in passage of the dextrose into the rumen, and the increase in blood glucose will likely be far more gradual. The author typically adds 100-150 ml of 50% dextrose to 1 liter of conventional calf electrolyte solutions that contain dextrose and bicarbonate in order to obtain a dextrose concentration that is closer to what was used in the electrolytes administered in the study5 by Bushwell and colleagues. The author also administers oral propylene glycol at the previously listed dosage in addition to oral electrolyte drenches.

To induce parturition in an average-sizes adult ewe, a dose of 126 and 167 mg of dexamethasone IM have been used with success. Dexamethasone has been used to successfully induce ovine parturition at 141 days of gestation and later; in healthy ewes, lamb viability is not affected.6,7 Lambing usually occurs 36-48 hours later, although this may be more reliable in ewes beyond 143 days of gestation.6-8 In late-term goats, parturition can be induced with a single intramuscular dose of 5.0-7.5 mg of dinoprost tromethamine or 125 µg cloprostenol, with parturition typically occurring 28-40 hours later. To aid in promotion of fetal pulmonary maturity, Rowe8 recommends that dexamethasone (15-20 mg, IM) be administered either at the time of, or 12 hours prior to, prostaglandin injection. The onset of milk production may be slow in dams for which parturition was induced, so alternate sources of colostrum and supplemental feeding may be necessary. It is important to note that these guidelines were established in studies of healthy animals; therefore, close monitoring of the pregnancy toxemia patient is warranted, as uterine inertia and maternal hypoglycemia may manifest to complicate normal delivery. Careful observation may aid in determining when parturition is beginning in the compromised dam, and early intervention can be sought if parturition does not progress normally.

References

1. Anast CS, Winnaker JL, Forte LR, et al. Impaired release of parathyroid hormone in magnesium deficiency. J Clin Endocrinol Metab 42:707-717, 1976.

2. Schlumbohm C, Harmeyer J. Hypocalcemia reduces endogenous glucose production in hyperketonemic sheep. J Dairy Sci 86:1953-62, 2003.

3. Oetzel GR. Parturient paresis and hypocalcemia in ruminant livestock. Vet Clin N Amer: Food An Pract 4: 351-364, 1988.

4. Hypocalcemia in 23 ataxic / recumbent ewes: Clinical signs and likelihood ratios. Vet Rec 144: 529-532, 1999.

5. Buswell JF, Haddy JP, Bywater RJ (1986). Treatment of pregnancy toxaemia in sheep using a concentrated oral rehydration solution. Vet Rec 118: 208-209.

6. Peters AR, Dent CN (1992). Induction of parturition in sheep using dexamethasone. Vet Rec 131:129-129.

7. Kastelic JP, Cook RB, McMahon LR, et al (1996). Induction of parturition in ewes with dexamethasone or dexamethasone and cloprostenol. Can Vet J 37:101-102.

8. Rowe JD. Reproductive management – Part II. Proceedings, Small ruminants for the mixed animal practitioner, Western Veterinary Conference, Las Vegas, NV, 1998, 142-146.