Milk fever: new approaches to treatment and control (Proceedings)

Periparturient hypocalcemia (milk fever) is a common condition of dairy cows with an annual incidence of 5 to 8%. Effective treatment and control programs for milk fever are therefore required for dairy cattle. When used for treatment, calcium should be administered by the intravenous, subcutaneous, or oral route, depending on the severity of the clinical signs.

Oral CaCl2 (calcium gels) have been used in Europe since 1962. These are commercially available and are preferred to calcium drenches, which are more likely to be aspirated. Most formulations contain 50-70 g calcium per dose. Retreat at 12-24 hours, and don't exceed 120 g in a 24-hour period. Oral calcium salts are effective at increasing plasma calcium concentration; orally administered calcium is absorbed by a dose-dependent passive diffusion process across ruminal epithelium and a dose-independent calcium-binding protein mechanism in the small intestine that is modulated by Vitamin D. Passive diffusion across the ruminal epithelium occurs when the ruminal calcium concentration >1.5 mmol/L but is substantial when the calcium concentration in rumen fluid is greater than 6 mmol/L, which is approximately 2-3 times the normal value in plasma (normal range 2.2-2.6 mmol/l). Rapid correction of hypocalcemia by oral calcium administration must utilize passive ruminal diffusion, as small intestinal absorption is too slow to be of clinical value.

Two calcium formulations are currently recommended for oral administration to ruminants; CaCl2 and calcium propionate, but most commercially available products contain 50 g of CaCl2. Calcium chloride has the advantage of low cost and low volume (because of its high solubility), but CaCl2 can severely damage the pharynx and esophagus in ruminants with reduced swallowing ability, can lead to necrosis of the forestomach and abomasum when administered in high doses, and can lead to aspiration pneumonia when administered as a drench. Calcium propionate has the advantages that it is less irritating while providing a gluconeogenic substrate (propionate), but the disadvantages of higher volumes and cost. The effectiveness of ororuminal administration of higher volume calcium propionate solutions has been evaluated. Oral calcium solutions should only be administered to cattle that have normal swallowing ability, precluding their administration to animals with advanced clinical signs of hypocalcemia. Higher plasma calcium concentrations are obtained more quickly when calcium solutions are drenched after administration of vasopressin to induce esophageal groove closure, or when the calcium solution is administered as a drench instead of ororuminal intubation.

Intravenous calcium is an effective treatment at an approximate dose of 2.2 g calcium / 100 kg body weight, with cardiac monitoring during administration. Calcium gluconate and calcium borogluconate are the preferred forms for intravenous and subcutaneous administration because CaCl2 causes extensive necrosis and sloughs of tissue when administered perivascularly. Compared to calcium gluconate, calcium borogluconate has improved solubility and shelf life. Plasma ionized calcium concentrations are increased to a greater extent following CaCl2 treatment when high equimolar solutions of CaCl2 and calcium gluconate are administered, leading to more cardiac arrhythmias during CaCl2 administration. A typical treatment to an adult lactating dairy cow with periparturient hypocalcemia is 500 ml of 23% calcium borogluconate by slow intravenous injection with cardiac auscultation, this provides 10.7 g of calcium. Although the calculated calcium deficit in a recumbent periparturient dairy cow is 4 g calcium, we should provide additional calcium to overcome the continued loss of calcium in milk. A field study comparing the effectiveness of different doses of calcium for treating periparturient milk fever determined that 9 g of calcium was superior to 6 g. A good rule of thumb for administering 23% calcium borogluconate solutions (2.14 g calcium/100 ml) to cows with periparturent hypocalcemia is therefore to administer 1 ml/kg body weight.

Subcutaneous administration of calcium solutions has been practiced for many years. To facilitate absorption, it is preferable to administer no more than 125 ml at a site, although this supposition (and volume) do not appear to have been verified. A 14-gauge needle is placed subcutaneously over the lateral thorax, 125 ml is administered, the needle is redirected and another 125 ml administered. The process is then repeated on the other side of the cow. Calcium chloride is not recommended for subcutaneous administration because of extensive tissue damage; the addition of dextrose to the administered calcium is also not recommended because it increases the tonicity of the solution and propensity for bacterial infection and abscessation. Rectal calcium administration is not recommended because it causes severe mucosal injury and tenesmus but does not increase plasma concentrations of calcium.

Feeding rations with low dietary cation-anion difference (DCAD) to dairy cows for at least 2 weeks before calving decreases the incidence of periparturient hypocalcemia. The most likely reason for this effect is that ingestion of a low DCAD diet increases calcium (Ca) flux, which is non-lactating cows is most readily detected as an increase in urinary calcium excretion. An increase in calcium flux allows the periparturient dairy cow to more readily cope with the abrupt and marked increase in calcium demand that occurs at the onset of lactation by shifting calcium from urine to milk. The result is a smaller decrease in serum [Ca2+] on the first day after calving when compared to cows fed a high DCAD diet during the last weeks of gestation.

Ingestion of an acidogenic ration increases calcium exit from the exchangeable calcium pool by decreasing renal tubular calcium reabsorption of filtered calcium, manifest as hypercalciuria. Low luminal pH in the second half of the distal convoluted tubule and connecting tubule decreases the number of epithelial Ca channels termed TRPV5 (transient receptor potential vanilloid member 5); the TRPV5 channel was previously termed EcaC, ECaC1, and CaT2 and is considered to be the primary gatekeeper of active calcium reabsorption in the distal region of the urinary tract. Low luminal pH also decreases the pore size of the TRPV5 channel, resulting in decreased calcium uptake from the tubular lumen into the epithelial cell. The low luminal pH-induced decrease in TRPV5 number and activity result in decreased calcium absorption in the distal convoluted tubule and connecting tubule, thereby directly resulting in hypercalciuria. If this mechanism is active in cattle similar to rabbits, then low luminal pH (due to a decreased urinary strong ion difference and manifest as low urine pH) and not decreased blood pH is the major drive for hypercalciuria in cattle ingesting a low DCAD ration. If this assumption is true, then the logical goal of milk fever prevention programs should be to decrease urine pH (and urine strong ion difference) without changing blood pH.

Concerns have been raised about the safety of feeding low DCAD diets in that acidogenic rations can decrease dry matter intake in late gestation and lactation thereby exacerbating the metabolic effects of negative energy balance in early lactation. The reduction in dry matter intake only occurs when blood pH is decreased below the reference range; once again this emphasizes the goal of feeding low DCAD diets is to decrease urine pH and urine strong ion difference without changing blood pH. Assuming that increased calcium flux is the most important method for decreasing the incidence and severity of hypocalcemia at calving, and assuming that urine [Ca2+] provides a clinically useful insight into calcium flux in the periparturient cow, it appears that measurement of urine [Ca2+] may provide the best method for evaluating the risk of periparturient hypocalcemia and the effectiveness of feeding a DCAD ration. However, more research is needed to clarify the role that calcium intake has on urine [Ca2+], and the optimal calcium intake for cattle being fed low DCAD diets. The linear negative association between urine [Ca2+] and urine pH suggests that measurement of urine pH may provide a practical on farm method for evaluating calcium flux in cows before parturition.

The most accurate insight into acid-base homeostasis in healthy cattle is obtained by measuring urine net acid excretion (NAE) or net base excretion (NBE). However, when urine pH is between 6.3 and 7.6, urine pH provides an inexpensive and clinically useful insight into acid-base homeostasis in cattle. This is because the change in urine pH over this pH range accurately reflects the change in NAE or NBE. Optimum target values for urine pH to decrease the incidence of milk fever in dairy herds have not been identified and recommendations for optimal urine pH values vary widely. We have recently developed a general electroneutrality equation for bovine urine, such that urine pH = 6.12 + log10(NBE + [NH4 +]) = 6.12 + log10([K+] + [Na+] + [Mg2+] + [Ca2+] + [NH4 +] – [Cl-] – [SO4 2-]). This equation indicates that an increase in urine [Ca2+] without a change in urine strong anion concentration will alkalinize urine; the observation that urine [Ca2+] increases as urine pH decreases in all species studied to date is consistent with our working hypothesis that a low luminal pH in the distal urinary tract drives the increase in urine [Ca2+] and therefore the increase in the rate of calcium loss from the exchangeable calcium pool. A recent meta-analysis suggested that decreasing urine pH from 7.0 to 6.0 or lower led to a modest decrease in the incidence of milk fever but markedly increased the risk of decreased dry matter intake in the prepartum period. The goal of milk-fever prevention strategies should therefore be to increase calcium flux by challenging but not overwhelming acid-base and calcium homeostasis. The influence of calcium intake on flux needs to be clarified; it is currently believed that an acute increase in calcium intake increases calcium flux by increasing the moles of calcium absorbed but a sustained increase in calcium intake decreases calcium flux and absorption via changes in Vitamin D activity and other homeostatic systems.

Urine appears to be the optimal fluid to monitor calcium and acid-base status in dairy cattle; however, it remains to be determined whether laboratory measurement of urinary calcium concentration is more accurate and cost-effective than cow-side measurement of urine pH or laboratory determination of urinary strong ion difference and NBE when evaluating the effectiveness of milk-fever control programs. Measurement of urinary strong ion difference, NAE or NBE is more time consuming and expensive than measurement of urinary pH and has been difficult to perform on the farm. However, the general electroneutrality equation for urine indicates that in alkaline urine (particularly when pH > 8.0), urine strong ion difference ≈ urine [HCO3 -] because [NH4 +] ≈ 0 mEq/L, and therefore NBE ≈ [HCO3 -]. Accordingly, measurement of total CO2 by use of an automatic analyzer in an anaerobically collected and stored urine sample (no loss of Pco2 from urine) may provide a simple but clinically useful method for determining NBE in alkaline urine samples from cattle. This supposition needs to be verified.

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