The ketotic cow (Proceedings)

The periparturient period is a very stressful time of transition for the dairy cow and as a result many diseases, such as milk fever, ketosis, metritis, and fatty liver to name a few are contracted through this period. Some studies have suggested that as many as 30-50% of all cows that go through early lactation are affected by some metabolic disease.  Periparturient disease reduces animal welfare on farms and results in decreased production and decreased reproductive performance.

The development of sub-clinical (SCK) or clinical ketosis (CK) is often a result of insufficient response to negative energy balance and excess mobilization of fat from peripheral tissues.  Depending on the source, SCK is defined as having a beta-hydroxybutyrate (BHBA) level greater than 10.0 – 14.4 mg/dL and CK is defined as a BHBA level greater than 23.5 – 30 mg/dL.  Ketosis can be a primary condition or can occur secondarily to many concurrent diseases.  In addition, secondary ketosis can also develop from the consumption of silages that are high in butyrate due to improper ensiling resulting in improper fermentation.

Ketosis has been categorized as type I and type II based on blood glucose and insulin levels.  Type I ketosis has been described as classical or primary ketosis as it results from negative energy balance during early lactation resulting in low blood glucose levels and fat mobilization with the eventual development of elevated ketone bodies. Type II ketosis involves high blood insulin and potentially transient high blood glucose levels as a result of fatty infiltration of the liver. 

There are often disproportionate levels of circulating fat present as non-esterified fatty acids (NEFA).  Cows with Type II ketosis may have some of insulin resistantance.  Type II ketosis typically occurs between 5-21 days in milk and results from decreased dry matter intake during the dry period or immediate post-partum period.  Type I ketosis is often seen between 20-50 days in milk and is often seen in herds that feed a component ration.  Differentiating between Type I and Type II ketosis will result in slightly different approaches in treatment and will also have different techniques applied for monitoring and prevention.

Epidemiology

According to Large Animal Internal Medicine (Smith, 4th ed.), incidence rates for clinical ketosis have been shown to range from 1.8-13% while incidence rates for subclinical ketosis range from 7.3-12.1%.  However, a recent study which compared incidence rates across five US states and one Canadian province indicated the incidence was 32% (range 3-80%) (Duffield, 2010).  The presence of clinical ketosis has been referred to the “tip of the iceberg” when considering the overall problem at the herd level, including SCK.

Sub-clinical ketosis has been shown to reduce milk production by 4.4-6% over an entire lactation while CK has been associated with a 2.5% increase in production when compared to cows that did not develop CK.  There is also an inverse relationship between cows in the development of ketosis and being culled from the herd.  This is likely due to the fact that higher producing cows are more prone to the development of ketosis.  Both SCK and CK will result in decreased reproductive performance. 

Various estimates have been placed on the cost of clinical and sub-clinical ketosis per case, with these estimates ranging from less than $100 to more than $500 depending on what variables are included in the evaluation.  Duffield (2006) argued that regardless of the cost per case, SCK is more costly than CK as it has a much higher incidence and therefore, routine monitoring for SCK at the herd level will be beneficial to most dairies.  

Another often unaccounted cost that occurs with ketosis is the negative effect on the immune system.  CK and SCK have been demonstrated to weaken the immune system.  For example, Kremer et al (1993) undertook a study looking at the relationship between in vitro neutrophil chemotaxis and the severity of induced E coli mastitis between ketotic and non-ketotic cows.  In non-ketotic cows, mastitis cases ranged from mild to severe with the severity of the infection negatively correlated with the degree of pre-calving neutrophil chemotaxis.  The challenge infection in the ketotic group resulted in all cows developing severe mastitis regardless of the state of pre-calving neutrophil chemotaxis. 

Treatment

Traditional treatment for primary ketosis should be centered on improving glucose availability to the tissues and reducing fat mobilization.  Treatment of secondary ketosis should center on treatment of the primary disease along with appropriate supportive therapy. 

Primary ketosis has traditionally been treated with intravenous therapy with 500 mLs of 50% dextrose.  This produces a transient hyperglycemia that has been shown to be clinically effective in immediately dropping ketone levels and increasing milk production by 5-10 lbs, at least for one milking.  Interestingly, the amount of energy supplied from 500 mLs of 50% dextrose is only sufficient to support approximately three pounds of milk.  The transient hyperglycemia returns to pre-treatment levels in approximately two hours.  BHBA and NEFA levels return to pre-treatment levels in approximately twelve hours (Wagner, 2010). 

Many individuals have adopted a philosophy that if one bottle of 50% dextrose is good then two bottles must be better.  Wagner (2010) compared several serum parameters following the administration of 500 or 1000 mLs of 50% dextrose versus control cows that received no glucose.  All cows were clinically normal at the initiation of the trial.  Their data demonstrated that both dextrose treatments initially increased blood glucose levels, both of which returned to normal values within two hours.  The average peak blood glucose concentration was 50.4 mg/dL in the control group compared to 180 and 310 mg/dL in the 500 mL and 1000 mL dextrose groups, respectively.  

Likewise, insulin concentrations increased significantly in the dextrose treated groups over the control group but, the peak insulin concentrations between the two dextrose treated groups was not significantly different.  Insulin concentrations in both groups returned to pre-treatment levels in two hours.  As stated earlier, administration of dextrose reduced both NEFA and BHBA levels compared to control cows but, the reduction was not significantly different between the two treatment groups.  Based on this data, the administration of 1000 mLs versus 500 mLs of 50% dextrose may have merit if the primary benefit from dextrose therapy is caused solely by increasing blood glucose concentrations. 

However, if the beneficial effects are mitigated by increasing insulin concentrations, then administration of 1000 mLs of 50% dextrose potentially has no additional benefit over the administration of 500 mLs.  The authors suggested that the beneficial effects of glucose therapy was most likely due to increased insulin concentrations, as insulin as beneficial antiketogenic and antilipolytic effects.

Recently there has been much debate in the veterinary community about the appropriateness of ketosis therapies that result in hyperglycemia.  Therapies that lead to hyperglycemia include routine and indiscriminate use of dextrose containing fluids (50% dextrose or cal-dex solutions), concurrent use of corticosteroids along with 50% dextrose, and repeated administration of corticosteroids.  This has recently lead to the debate about the appropriateness of even using one bottle of 50% dextrose versus using only 250 mLs or no dextrose at all in the therapy for ketosis.  The evidence for this suggestion comes from a trial that demonstrated that induced hyperglycemia (equivalent to approximately 120 mg/dL) slowed abomasal emptying time. 

As a result of this finding, the authors of this manuscript suggested that hyperglycemia may be predisposing dairy cattle to the development of left displaced abomasum (Holtenius, 2000).  At this point, more work needs to be done to support this conclusion.  In any case, almost every cow that I have treated for ketosis in the last two years has had a low or low normal blood glucose level prior to administering any therapy and most animals showed a clinical improvement (increased alertness, increased appetite) after treatment with glucose.

The use of glucose precursors, such as propylene glycol, as an aid to IV therapy or as a sole treatment for cows with SCK is appropriate provided the product is not overdosed.  A suggested regimen (Smith, 4th ed.) is to administer 8 ou of propylene glycol orally BID for 2 days and the decrease the dose to 4 ou BID for an additional two days.  Excess amounts of propylene glycol can result in death of rumen microflora, decreased rumen motility and the development of diarrhea.  Transfaunation of the rumen may be necessary if this condition develops.

Glucocorticoids have long been touted as an ancillary aid in the treatment of CK.  The two glucocorticoids that are labeled for cattle include dexamethasone and isoflupredone acetate.  Glucocorticoids have been shown to improve blood glucose levels by increasing gluconeogenesis for 6-9 days and temporarily reducing milk production (1 to 7 days).  However, the uniform administration of glucocorticoids to all cattle with CK is not currently supported with clinical evidence. 

Characterization of ketosis into Type I and Type II ketosis along with improved feeding practices has shifted the types of ketosis that many practitioners currently see from Type I to Type II.  Type I ketosis is characterized by high milk production prior to the onset of CK.  In these situations, improving glucose status through the use of a corticosteroid is appropriate. 

In contrast, Type II ketosis typically occurs in the first fourteen to twenty-one days in milk and typically is associated with some degree of hepatic lipidosis.  Milk production in these animals is typically not high and the level of endogenous steroids is already elevated.  The administration of additional glucocorticoids is not warranted in these animals and may contribute to hyperglycemia.    

There have been reports that the use of one or more doses of isoflupredone acetate being involved with the development of non-responsive down cows with a profound hypokalemia (Sielman, 1997; Peek, 2002).  Isoflupredone acetate has mineralcorticoid activity in addition to its glucocorticoid activity and this results in increased secretion of potassium through the kidneys. 

In a separate report, Coffer (2006) demonstrated a single injection of 20 mg of isoflupredone acetate induced severe hypokalemia (serum potassium <2.3 mEq/L) in 1 of 6 cows while they induced severe hypokalemia in 5 of 7 animals that received 2 doses at 48 hour intervals.  In contrast, Seifi (2006) injected one 20 mg dose of isoflupredone acetate with and without concurrent insulin administration to cows between day 1 and 8 in milk. 

None of the cows in this trial were detected to develop hypokalemia nor did the cows exhibit signs of weakness or recumbency.  They did show that cows treated with isoflupredone acetate, with or without insulin, had higher BHBA and NEFA levels than control cows one week after isoflupredone acetate injection.  In addition, cows that started the trial without SCK were more 1.72 and 1.52 times more likely, with isoflupredone acetate and insulin or isoflupredone acetate alone respectively, to develop SCK as compared to controls.  Based on these data, it seems prudent to use isoflupredone acetate very cautiously in lactating dairy cattle. 

Cows with chronic fat mobilization and hepatic lipidosis are challenging to treat.  Administration of large volumes of 2.5 to 5% dextrose solutions with or without concurrent insulin therapy has shown the most promise but, is difficult to complete in the field.  Good supportive care is necessary with these cows.  Supplying feedstuffs to the rumen bacteria is essential.  Twice daily oral therapies with alfalfa meal, 4 ou of KCl and rumen contents from a healthy animal have been shown to be effective but it will take several days before an improvement may be apparent (Peek and Divers, 2008).  In addition, if blood analysis is available, correction of electrolyte abnormalities will speed the animal's recovery.

Incorporation of six ounces of niacin per day in the lactating diet has been shown to increase milk production and decrease ketone levels.  Niacin is often utilized in cattle with chronic ketosis.  Numerous other compounds have been added to treatments or diets of cattle in attempts to minimize the effects of ketosis.  Lipotropic agents such as choline or methionine have been utilized but data is lacking on their effectiveness.  Cobalt and vitamin B12 deficiencies have also been implicated in the development of ketosis.  Support for supplementation of these products in diets to reduce ketosis incidence is lacking (Smith, 4th ed.).    

Inclusion of monensin in the diets of dry and lactating cows has proven to be effective in reducing the incidence of ketosis in lactating cows.  Ionophores like monensin exert their effects by increasing the proportion of propionate produced in the rumen at the expense of acetate and butyrate.  Acetate and butyrate are typically ketogenic VFA's while propionate is glycogenic.  During normal rumen fermentation in animals that are not fed ionophores, there are four ketogenic VFA''s produced for every glycogenic VFA.  Improving propionate availability should reduce the risk for cows developing SCK and CK.

Monitoring and prevention

Like almost all diseases in dairy cattle, dollars spent preventing the disease are much more effective than treating diseases.  Ketosis is no exception.  Making sure that cows are fed a properly formulated ration in the pre and post-partum period, providing adequate bunk space per cow (>30”/cow for Holsteins), limiting pen moves during the transition period and providing excellent cow comfort are all strategies that will result in adequate dry matter intake.  None the less, cows will experience a decrease in dry matter intake around the time of calving.  High fiber (straw based) diets have shown to decrease the degree of dry matter depression as compared to more traditional close-up diets.  Despite our best efforts at preventing dry matter intake depression, a certain amount of SCK and CK are going to develop in dairy herds.  

For several years, veterinarians have utilized various blood parameters to create a metabolic profile to monitor cow health during the periparturient period.  Over time, the use of NEFA analysis in pre-fresh cows and BHBA and NEFA analysis in post-fresh cows has proven to be the best predictor of levels of ketosis in a herd.  In herds where I monitor metabolic health, I use blood or milk BHBA monitoring in cows 5-20 days in milk. Peak BHBA levels are found 4-5 hours after the start of feeding. 

It has been suggested that the minimum sample size should be at least twelve cows in order to establish significance.  If more than 10% of cows have a blood BHBA value >14.4 mg/dL indicates that a problem is present with 75% confidence.  Similar results can be obtained using the Keto-Test milk strip using a 100 micromols/L as a cut-off.

In situations where I have an excessive number of animals with elevated BHBA's, I look for risk factors associated with the development of ketosis.  Pre-fresh animals (both close-up and far-off) are evaluated for excessive fat mobilization by drawing blood and having NEFA analysis performed.  Pre-fresh animals should stay in positive energy balance until approximately 2 days before calving.  Animals should be sampled just prior to feeding in order to capture peak values. 

A cutoff of 0.4 mEq/L in animals from 2-14 days prior to calving and 0.325 mEq/L should be used to establish alarm levels.  Like BHBA's, having more than 10% of any particular group above the cut-off should cause concern.  Modification of management practices should be implemented to reduce fat mobilization and reduce the incidence of ketosis in the herd.

Summary

Ketosis is a very subtle disease in cattle and difficult to properly assess without the use of ancillary tests.  Studies have shown that SCK is more costly to dairies than CK due to the number of animals affected.  In addition, ketosis suppresses the immune system making the cow more susceptible to disease and to exhibit clinical signs more severely than non-ketotic cows.

The underlying pathophysiology has changed over time in most herds.  Currently, most cows developing ketosis have some degree of hepatic lipidosis (Type II ketosis).  Therapy for ketosis should be aimed at improving energy availability and reducing fat mobilization.  Ketosis therapy is somewhat controversial at this time due to limited research about the benefits and complications of therapeutic agents.  Judicious use of 50% dextrose and glycogenic agents is beneficial to cows experiencing Type II ketosis while the indiscriminate use of glucocorticoids should not be undertaken.   

Regular monitoring of cows for SCK helps management assess cow health and determine whether management changes should be implemented.