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«A variety of non-antibiotic measures are frequently used in cows with clinical mastitis in conjunction with or in place of antibiotic therapy. Fluids ...»

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Dawn E. Morin

University of Illinois

Urbana, Illinois

A variety of non-antibiotic measures are frequently used in cows with clinical mastitis in

conjunction with or in place of antibiotic therapy. Fluids and electrolytes are administered to combat

circulatory changes and electrolyte disturbances. Steroidal and non-steroidal anti-inflammatory

agents are used to reduce pain, inflammation, and fever. Oxytocin administration and frequent milkout are used to promote milk ejection and removal of secretions. Concern about antibiotic residues in milk and frustration over poor cure rates associated with traditional mastitis treatments have prompted dairy producers and veterinarians to try many other systemic and local measures, most of which have not been scientifically evaluated. This paper will review published data for the bestdocumented non-antibiotic treatment practices and discuss potential uses and limitations.

Fluid and Electrolyte Therapy Cows with clinical mastitis can develop fluid and electrolyte disturbances as a result of decreased feed and water intake, rumen stasis, ileus, or diarrhea. Severely affected cows, particularly those with coliform mastitis, may develop septic or endotoxic shock; in these cows death or organ damage can occur as a result of decreased effective circulating volume.

Hydration status has been associated with the outcome of clinical mastitis in several studies. In a field trial of 54 cows with clinical mastitis (Green et al, 1998), non-survivors (n=25) were compared with survivors (n=29). Non-surviving cows had a higher hematocrit (mean 46.4%) and eyelid skin tent duration (mean 6.7 seconds) than did surviving cows (39.5% and 3.6 seconds, respectively), indicating poorer hydration status. Similarly, in a study of 44 cows admitted to a teaching hospital with severe coliform mastitis (Cebra et al, 1996), non-surviving cows (n=12) had a higher serum creatinine concentration (median 2.5 mg/dl) than did surviving cows (n=32;

1.6 mg/dl). Hydration status appears to be important even in milder cases of mastitis. For example, in a field trial of 84 cows with mild to moderate clinical mastitis (Sischo et al, 1997), hematocrit on day 5 after mastitis onset was correlated with subsequent lactational milk yield;

cows with a hematocrit 32% had below median 305-day mature equivalent milk yield. Because of its perceived clinical importance, assessment of hydration status is often incorporated into mastitis severity scoring systems (Morin et al, 1998a; Wenz et al, 2001, Roberson, 2003).

Assessment of hydration status: The hydration status of an adult cow is usually assessed subjectively, by observing skin tent duration on the neck or eyelid and position of the globe in the orbit. Unfortunately, findings can be influenced by the body condition of the cow. Objective criteria for estimating the extent of dehydration have been reported for dairy calves (Constable et al, 1998a), but have not been established for adult cows. Extrapolating from calves, a healthy cow would be expected to have a cervical skin tent duration of 2 seconds and no recession of the eyeball. Skin tent durations of 4, 6, or 8 seconds, and eyeball recession of 2, 4, or 7 mm would correlate with 4, 8, and 12% dehydration, respectively. Other indicators of reduced NMC Annual Meeting Proceedings (2004) 13 peripheral perfusion are cold extremities (ears, tail, fetlocks [only reliable at moderate ambient temperatures]) and a dry muzzle or mouth (Constable et al, 1998b). Hematocrit and serum or plasma protein concentration are not reliable indicators of hydration status in an individual cow due to the wide range of normal values and the effects of inflammation and stage of lactation on total protein concentration.

Acid-base balance: Most cows with clinical mastitis, even severe mastitis, have normal acid-base balance or metabolic alkalosis; metabolic acidosis is uncommon and is associated with a poor prognosis. For example, 18 of 37 cows admitted to a teaching hospital with severe coliform mastitis had a blood pH between 7.35 and 7.45 (Cebra et al, 1996). Fourteen of the 37 cows had a pH 7.45 and only 5 had a pH 7.35; non-surviving cows had a lower blood pH (median 7.35) than did surviving cows (median 7.45). In one field trial (Katholm and Andersen, 1992), blood pH values were similar for 12 cows with acute coliform mastitis and their control herdmates. Such findings suggest that there is no need for routine IV administration of alkalizing agents, such as bicarbonate or lactate, to cows with clinical mastitis. Nor should oral products containing magnesium hydroxide be administered to mastitic cows, as these products can exacerbate metabolic alkalosis (Kasari et al, 1990).

Oral fluid therapy: Fluids can be administered by the oral (intraruminal) or IV route. The oral route is least expensive and is often adequate for cows with mild to moderate dehydration. Oral fluids should be hypotonic and contain sodium in order to create an osmotic gradient between ruminal fluid and blood and enable sustained absorption of fluid and electrolytes; hypertonic oral fluids must be avoided (Constable, 2003). A 600 kg (1,320 lb) cow that is 6% dehydrated needs to absorb 36 liters (approximately 9 gallons) of fluid to replace her deficit. This volume can be administered safely, but oral ingestion of larger volumes of hypotonic fluid might lead to hypothermia and intravascular hemolysis (Bianca, 1970). Oral fluids are not sufficient for cows with severe dehydration, as they do not allow rapid resuscitation.

Intravenous fluid therapy: Ringer’s solution, which is iso-osmotic, mildly acidifying, and contains physiologic concentrations of sodium, chloride, potassium, and calcium is the fluid of choice for rapid IV resuscitation of adult ruminants (Constable, 2003). However, administration of Ringer’s solution (or other iso-osmotic crystalloid solutions) can be difficult due to the large volume of fluid required and the need for IV catheterization. A 600 kg (1,320 lb) cow that is 8% dehydrated requires 48 L (approximately 12 gallons) of fluid just to replace her deficit. Ringer’s solution can be made by mixing NaCl (8.6 g/L), KCl (0.3 g/L), and CaCl2-dihydrate (0.3 g/L) with water. Although some practitioners mix the salts with tap water, this carries a risk of endotoxin administration; mixing with sterile distilled water is safer.

A practical (although inferior) alternative to iso-osmotic IV fluid therapy is IV administration of hypertonic (7.2%, 2,460 mosm/L) saline solution. This is administered through a large bore needle at a dose of 4-5 ml/kg body weight over 4-5 minutes and MUST be accompanied by oral administration of water (5 gallons). Rapid administration is required in order to rapidly increase blood osmolality and create an osmotic gradient to draw fluid from the intercellular spaces and gastrointestinal tract (mainly rumen) into the blood stream. Although hypertonic saline does not have a sustained effect and will not completely correct a large fluid deficit, it rapidly increases plasma volume and improves cardiac output and tissue perfusion. This may allow the cow to be 14 NMC Annual Meeting Proceedings (2004) maintained by oral fluid therapy. Hypertonic saline administration was shown to be safe in cows with experimental endotoxic mastitis (Tyler et al, 1993a, Tyler et al, 1993b, Tyler et al, 1994).

Electrolyte disturbances: Clinical mastitis is often accompanied by mild to moderate hypocalcemia. Hypocalcemia has been documented for cows with coliform mastitis (Katholm and Andersen, 1992; Wenz et al, 2001) and the odds of hypocalcemia increase as the severity of clinical signs increases (Wenz et al, 2001). Less is known about the calcium status of cows with Gram-positive mastitis, but a retrospective study of cows admitted to a teaching hospital showed no difference in serum calcium concentration between cows with Gram-negative mastitis and those with Gram-positive mastitis (mean values below the reference range in both cases [Smith et al, 2001]). Therefore, calcium supplementation is logical. Supplementation can be by the oral, subcutaneous, or slow intravenous route depending on the severity of clinical signs, form of calcium used, and route of concurrent fluid administration. To my knowledge, no studies have scientifically evaluated the effects of calcium supplementation on the outcome of clinical mastitis.

Other serum electrolytes are variable in cows with clinical mastitis (Cebra et al, 1996; Katholm and Andersen, 1992; Smith et al, 2001). It is logical to assume that inappetent cows are hypokalemic. Hypertonic saline administration also causes a transient reduction in serum potassium concentration. Potassium chloride can be supplemented orally at a rate of up to 240 grams divided 2-3 times/day, with lesser amounts (30 to 120 grams) being satisfactory for mild to moderate hypokalemia (Sweeney, 1999). Sodium or chloride deficits are typically mild and can be addressed by balanced oral or IV fluids or hypertonic saline administration. Cows with clinical mastitis are not typically hypoglycemic and do not routinely require dextrose administration. However, IV dextrose may be warranted in cows with concurrent ketosis.

Anti-inflammatory Therapy

Anti-inflammatory agents are frequently used in cows with clinical mastitis. Anti-inflammatory therapy seems logical since many of the physiological and pathological changes associated with clinical mastitis are a result of the inflammatory response to infection. We must strive to control pain and suffering in mastitic cows, so anti-inflammatory agents (which also have analgesic effects) may be indicated for welfare reasons. However, the inflammatory response has beneficial as well as harmful consequences for the cow and anti-inflammatory agents can produce detrimental side-effects in some cases. The benefits and risks of anti-inflammatory therapy must be weighed. Some anti-inflammatory agents are quite expensive, making repeated doses potentially cost-prohibitive. Also, some of the anti-inflammatory agents used in the United States are not labeled for use in lactating dairy cows, which raises concern about extra-label drug use and milk and meat drug residues.

Pharmacokinetic parameters have been determined for many anti-inflammatory agents (eg, flunixin meglumine, phenylbutazone, ibuprofen, carprofen, ketoprofen, isoflupredone acetate) in cattle. Studies are often done in healthy cows and do not account for potential effects of clinical mastitis on drug distribution and clearance. Most efficacy trials have used cows with experimentally-induced coliform or endotoxic mastitis, with treatment administered before or soon after mastitis induction; results of these trials may or may not be applicable to cows with NMC Annual Meeting Proceedings (2004) 15 naturally-occurring mastitis that are clinically ill at the time of first treatment. Only a small number of controlled field trials have investigated the efficacy of anti-inflammatory agents for naturally-occurring clinical mastitis, and the best drug and optimum duration of treatment have not been established. Cost-benefit analyses for different anti-inflammatory agents and dosing regimens have not been reported.

Anti-inflammatory agents used to treat bovine mastitis include glucocorticoids (GC) and nonsteroidal anti-inflammatory drugs (NSAIDs). These agents reduce eicosanoid production by inhibiting arachidonic acid release (GC) or metabolism (NSAIDs), but a variety of other mechanisms contribute to their anti-inflammatory effects.

Glucocorticoids: Two GC used to treat clinical mastitis in the United States are dexamethasone and isoflupredone acetate (Predef2X). Both are labeled for use in lactating dairy cows, are inexpensive ($5/day), and have no milk-withholding requirement. Dexamethasone is labeled for IV or IM use for treatment of ketosis and a variety of inflammatory conditions, including mastitis. The labeled dose is 5-20 mg, repeated as needed, “provided infection is controlled by appropriate chemotherapeutic agents”. Isoflupredone acetate is labeled for IM use for treatment of ketosis or conditions requiring anti-inflammatory or supportive effect, including mastitis. The labeled dose is 10-20 mg, repeated in 12-24 hours if needed, and treated animals must be withheld from slaughter for 7 days. Each of these agents has potential adverse effects.

Dexamethasone is immunosuppressive and can cause abortion in pregnant cows, especially after 5 months of gestation. Isoflupredone acetate is a less potent GC than dexamethasone, does not cause abortion, and presumably has less risk of immunosuppression. However, isoflupredone acetate has more mineralocorticoid activity, which can lead to hypokalemia and recumbency when repeated doses are used in sick cows (Sielman et al, 1997; Sattler et al, 1998).

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