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Forty-eight Holstein cows with two or more previous lactations and no history of parturient paresis were randomly assigned to one of four prepartum diets in a 2 x 2 factorial design to determine the effect of dietary supplementation with ammonium salts and Ca intake on serum Ca concentrations at calving. Four diets provided either 53 g total dietary Ca/d or 105 g Ca/d and were either supplemented with ammonium salts [100 g/d each of NH4Cl and (NH4)2SO4] or unsupplemented. Anion-cation balance of the diets, calculated as milliequivalents (Na + K)--(Cl + S), was -75 meq/kg DM with ammonium salts and +189 meq/kg DM without ammonium salts. Experimental diets were fed from 21 d prior to expected parturition until calving. Calcium intake during the feeding period did not affect the incidence of parturient paresis or serum concentrations of ionized Ca at calving. The incidence of parturient paresis was 4% with and 17% without the ammonium salts. Cows fed diets containing ammonium salts had higher serum ionized and total Ca concentrations at parturition. Serum concentrations of Mg, P, Na, K, and Cl on the day of parturition were unaffected by dietary treatment.

During 1967, 1968 and 1969, blood samples were taken from 83 cows affected by parturient paresis. Whole blood glucose estimations were made on these samples. The range was 1.33 to 10.22 mmol/1 with an average of 3.94 mmol/1. Eighteen cows known to have been affected less than 4 hours had average levels of 3.06 +/- 1.11 mmol/1. All (except one) "previously untreated" cows with levels less than 3.33 mmol/1 were on their feet within 10 minutes whereas cows with higher levels than this had a 28.6% delayed recovery rate. The evidence suggests that low levels have no clinical significance but that higher levels are significant in that they occur as a result of prolongation of attacks of parturient paresis.

A comparative assessment was made of the hormonal control of calcium homeostasis in eight dairy cows which developed parturient paresis and in seven normal animals from the same herd. Plasma levels of calcium, phosphorus, magnesium, free hydroxyproline, 25-hydroxycholecalciferol (25-OHD), 1,25-dihydroxycholecalciferol (1,25-(OH)2D), parathyroid hormone, calcitonin, prolactin and oestrogen were monitored from 30 days prepartum to 15 days post partum. Prepartum levels of plasma calcium, hydroxyproline and calcitonin were depressed in the paretic animals, and plasma levels of phosphorus and oestrogen were elevated. Plasma levels of 25-OHD remained stable in both groups, whereas levels of 1,25-(OH)2D, parathyroid hormone and prolactin rose sharply at parturition. Plasma hydroxyproline, an index of bone resorption, began to rise 2 days prepartum in the control cows but not until 2 days post partum in the paretic cows. The data indicate that bone resorption was inhibited in the paretic group at the onset of lactation, and that a decreased capacity for bone resorption is a major factor in the susceptibility of some cows to this disease. The failure of the paretic animals to resorb bone was not associated with an inability to synthesize the calcium-mobilizing hormones parathyroid hormone or 1,25-(OH)2D, or to regulate the production of calcitonin. However, hypocalcaemia in the affected animals was associated with a significantly higher plasma level of oestrogen (a known inhibitor of bone resorption) in the immediate prepartum period. Following parturition, plasma levels of oestrogen fell rapidly and active bone resorption ensued in the paretic animals.

In one study, a comparison was made of the concentrations and ratios of certain blood cations in 2 groups of cows with milk fever, one showing normal consciousness (n = 8) and the other depressed consciousness (n = 24). There were no significant differences in the mean concentrations of serum total calcium, plasma inorganic phosphorus and potassium, erythrocyte sodium and potassium, the serum calcium/serum magnesium ratio or the plasma sodium/erythrocyte sodium ratio. There were significant differences (all P less than 0.05) in the mean (+/- SD) concentrations of serum magnesium and plasma sodium concentrations, and the plasma sodium/serum magnesium ratio of 0.8 +/- 0.28 vs 1.2 +/- 0.37 mmol/l, 155 +/- 3.0 vs 147 +/- 6.4 mmol/l and 180 +/- 40.1 vs 116 +/- 34.1 for normal vs depressed cows, respectively. In a second study, a comparison was made of the concentrations and ratios of the same blood cations in 3 groups of cows in different positions when attended for milk fever, namely standing (n = 6), sternal recumbency (n = 24) and lateral recumbency (n = 31). There were no significant differences between the mean concentrations or ratios of any of the cations.

The efficacy of 1alpha-OH cholecalciferol for the prevention of milk fever has been tested in a controlled field trial using 597 cows on 19 farms all of which had previously had a high incidence of milk fever. Of 293 cows receiving 1alpha-OH cholecalciferol 34 had milk fever and of 304 control cows 51 had milk fever. Although there was an apparent efficacy of 31 per cent the difference in incidence was not statistically significant. There was no effect if 1alpha-OH cholecalciferol was administered less than 24 hours before the cows succumbed to milk fever. However, if 1alpha-OH cholecalciferol was administered more than 24 hours and less than one week before the occurrence of milk fever the efficacy increased to 61 per cent and the effect was highly significant.

The degree of hypocalcaemia was determined from serum total, and serum ionized calcium concentrations in 27 cows with parturient paresis. Electrocardiographic recordings were made just before the start of the intravenous calcium treatment. The T-oTc interval was determined, but could only be adequately measured in 16 cases because of inherent difficulties in recording from paretic animals. No significant correlation was found between the degree of hypocalcaemia and Q-oTc interval, whether the hypocalcemia was determined from serum total or serum ionized calcium concentrations. This study indicated that measurement of the Q-oTc interval was of very little value as a clinical test for detection of hypocalcaemia and indication of the degree of hypocalcaemia in parturient paresis.

Concentrations of calcium, phosphorus, and 1,25-dihydroxyvitamin D in plasma of four young, four nonparetic aged, and four paretic aged cows were measured during the lactation cycle. Concentration of 1,25-dihydroxyvitamin D in plasma was elevated significantly in paretic aged cows as compared to nonparetic aged and young cows from the day of calving to 3 days postcalving. In paretic aged cows, severe hypocalcemia and hypophosphatemia developed on the day of calving, whereas hypocalcemia and hypophosphatemia were only transient in nonparetic aged and young cows at this time. Changes were only minor in concentration of 1,25-dihydroxyvitamin D in plasma from 7 days postcalving to 7 days precalving in all cows.

A synthetic biologically active derivative of vitamin D (350 microgram of 1alpha-hydroxycholecalciferol [1alpha(OH)CC]) was injected into 2 nonlactating 7-year-old Israeli-Friesian cows. Plasma calcium values increased after 24 hours, peaked at 48 hours, and returned to base-line values 120 hours after injection. An injection of 350 microgram of 1alpha(OH)CC was given to 23 parturient-paresis-prone Israeli-Friesian cows from 7 days to 6 hours prepartum; 13 cows were injected once, 6 were injected twice, and 4 were injected 3 times, all at 48-hour intervals. Parturient-paresis-prone cows (n = 23) of the same breed were used as controls. Within 0 to 36 hours postpartum, plasma calcium concentrations were found to be higher in cows injected with 1alpha(OH)CC than in the control cows. The increase was highly significant (P less than 0.01) in cows injected at least twice. None of the cows injected with 1alpha(OH)CC, within 72 to 24 hours prior to calving developed parturient paresis; but 9 of 23 control cows developed parturient paresis. Prior to calving, none of the injected cows developed hypercalcemia and there was no local or systemic clinically detectable signs of toxiosis. When given at the right time prepartum, 1alpha(OH)CC is considered to be an improvement over previous methods of preventing bovine parturient paresis.

Forty-one aged Jersey cows were fed a high Ca diet prior to parturition to predispose them to parturient paresis. Twenty-one of the cows were treated with 24-F-1,25-dihydroxyvitamin D3, a synthetic analogue of 1,25-dihydroxyvitamin D3, 7 d before the expected parturition. Treated cows received either 100 micrograms (n = 7) or 150 micrograms (n = 14) of 24-F-1,25-dihydroxyvitamin D3, intramuscularly at 7-d intervals until the cow calved. Incidence of parturient paresis among untreated animals was 85% (17/20). Injections of 100 micrograms of 24-F-1,25-dihydroxyvitamin D3 reduced the incidence of parturient paresis to 43% (3/7), whereas 150 micrograms injections of 24-F-1,25-dihydroxyvitamin D3 reduced the incidence of parturient paresis to 29% (4/14). Plasma concentrations of hydroxyproline were not elevated prior to parturition in 24-F-1,25-dihydroxyvitamin D3-treated cows, indicating that treatment did not stimulate bone resorption and that the ability of 24-F-1,25-dihydroxyvitamin D3 to prevent parturient paresis likely resides in its ability to stimulate intestinal Ca absorption prior to parturition. Further, cows treated with 24-F-1,25-dihydroxyvitamin D3 that developed parturient paresis had lower than normal plasma concentrations of 1,25-dihydroxyvitamin D, indicating that 24-F-1,25-dihydroxyvitamin D3 treatment impairs the metabolism of 25-hydroxyvitamin D in response to hypocalcemia. These data suggest that injection of 24-F-1,25-dihydroxyvitamin D3, delivered at 7-d intervals prior to parturition, can effectively reduce incidence of parturient paresis in dairy cows.

The concentration of 1,25-dihydroxyvitamin D was measured by means of a radioactive receptor assay in the plasma of cows during the period immediately prior to, during, and following parturition. Nonparetic cows showed initially a slight decrease in plasma 1,25-dihydroxyvitamin D which was followed by a significant increase during parturition and 2 days postpartum. The highest concentration achieved in the control or nonparetic cows was 100 picograms per milliliter. In the paretic animals the plasma 1,25-dihydroxyvitamin D concentration increased sharply during the day preceding calving and reached a maximum of 200 picograms per milliliter at parturition. This level was maintained during the ensuing 2.5 days. These results demonstrate that parturient paresis cannot be the result of insufficient synthesis or secretion of 1,25-dihydroxyvitamin D.

The efficacies of vitamin D3 and its 1-alpha hydroxyl derivative (1-alpha) in controlling clinical milk fever, hypocalcaemia and hypophosphataemia in parturient cows have been compared. A corticosteroid was used in some cases to optimise and control the interval between prophylactic treatment and parturition. Our observations suggest that the combination of 1-alpha and corticosteroid was particularly valuable and could be used in the development of a successful prophylactic regime. This conclusion is supported by both clinical and biochemical measurements.

In the late summer and early autumn of 1977, seven cases of milk fever were observed on a dairy farm. It was believed that condition was most likely to be due to preparturient hypomagnesaemia. Therefore the magnesium levels in the blood and urine of both lactating and non-lactating cows were determined in this herd during several months.

We studied the relationship of serum prolactin, estradiol-17 beta, and progesterone concentrations to plasma calcium, phosphorus, and free hydroxyproline concentrations, as well as to dry matter intake, in 14 aged dairy cows (mean of 4.5 parities), 7 of which became paretic, from 28 days before to 4 days after calving. Plasma calcium and phosphorus concentrations and dry matter intake decreased more at parturition in paretic cows than in nonparetic cows. Prolactin concentrations were not different between paretic and nonparetic cows, but were variable. Concentrations of estradiol were higher in paretic cows from 15 to 5 days before parturition, whereas hydroxyproline concentration was lower in paretic cows on days 10 through 3 before parturition. Progesterone concentration was lower in paretic cows and decreased earlier at parturition, compared with that in nonparetic cows. The findings suggested that high estradiol concentrations in late pregnancy inhibit bone resorption and predispose aged cows to parturient paresis. The earlier decrease in progesterone concentration at parturition and lower concentrations throughout late pregnancy might have contributed to the greater inappetence in paretic cows at parturition. The importance of prolactin in the pathogenesis of parturient paresis is not clear.

Parturient paresis (milk fever) is a hypocalcemic disorder caused by the onset of lactation in the dairy cow. In most cows a complete recovery follows a single iv calcium treatment to correct the acute hypocalcemia. However, about 20% of cows treated for parturient paresis experience recurring episodes of hypocalcemia (relapses) requiring further treatment. Analysis of plasma from 8 nonrelapsing parturient paretic and 11 relapsing parturient paretic cows revealed differences in plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations before and during the development of hypocalcemia. In nonrelapsing cows, plasma 1,25-(OH)2D increased to 4- to 5-fold as plasma calcium concentrations declined during the first stage of parturient paresis. In relapsing cows, decreases in plasma calcium concentrations during the first stage of parturient paresis were accompanied by just a 2- to 2.5-fold increase in plasma 1,25-(OH)2D. Plasma 1,25-(OH)2D eventually increased 4- to 5-fold in the relapsing cows, but this response was delayed 24-48 h compared with the response in the nonrelapsing cows. Plasma PTH concentration profiles were similar in relapsing and nonrelapsing cows, suggesting that renal 25-hydroxyvitamin D 1 alpha-hydroxylase was temporarily refractory to stimulation by PTH in the relapsing cows. In both groups of cows recovery from parturient paresis began about 12-24 h after plasma 1,25-(OH)2D concentrations had increased 4- to 5-fold. These data imply that lack of production of 1,25-(OH)2D is an important factor in predisposing the cow to relapses of parturient paresis and is critical for recovery from the hypocalcemia associated with the onset of lactation.