Vet Clin Food Anim 21 (2005) 595–614

Supportive Therapy of the Toxic Cow

Geof W. Smith, DVM, MS, PhD
Department of Population Health and Pathobiology, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC, 27606, USA

Endotoxin is a component of the outer cell wall of gram-negative

bacteria. The endotoxin structure is composed of an innermost portion,
termed ‘‘lipid A,’’ an outer series of polysaccharides, and a core oligosac-
charide that links lipid A with the outer polysaccharides. Collectively, the
endotoxin structure is often referred to as lipopolysaccharides that are
released from gram-negative bacteria following cell death or during periods
of rapid bacterial growth. The interaction between the host immune system
and endotoxin triggers a complex cascade of events that often leads to severe
pathophysiologic consequences for the animal (Fig. 1). A complete review of
the inflammatory mediators and cytokines involved in the endotoxin
cascade is beyond the scope of this article, and the reader is referred to
recent review articles on the subject [1,2]; however, a brief discussion of the
physiologic consequences of endotoxemia is warranted to gain a better
understanding of and appreciation for the importance of aggressive therapy
when treating the ‘‘toxic’’ cow.

Physiologic consequences of endotoxemia

Fever
One of the most fundamental events that occurs during endotoxemia is
the production of inflammatory mediators including interleukin (IL)-1, IL-
6, and tumor necrosis factor (TNF)a by the host immune system. These
cytokines circulate in the blood and, once in the brain, can act directly on
the hypothalamus to induce fever. Classically, IL-1 was thought to be the
primary mediator of the febrile response to endotoxin in animals; however,
more recent data indicate that IL-6 is the major endogenous pyrogen [3].
Elevated body temperature is commonly seen in the toxic cow, and can be

E-mail address: Geoffrey_Smith@ncsu.edu

0749-0720/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.cvfa.2005.07.005 vetfood.theclinics.com
596 SMITH

Dehydration

Forestomach hypo-
motility or atony Fever (pyrexia)
Tachycardia

↓ in systemic O2
Hypoxemia Endotoxin delivery

Weakness

↓ cardiac output
& hypotension Leukopenia
(neutropenia)

Diarrhea

Fig. 1. The pathophysiologic consequences of endotoxemia in cattle.

effectively treated with anti-inflammatory drugs that inhibit production of

the cytokines responsible for inducing fever.
Forestomach hypomotility or atony
It has long been known that endotoxemia in cattle is accompanied by
rumen hypomotility [4]. Rumenoreticular stasis associated with endotox-
emia appears to be the combined result of two different pathways:
a prostaglandin-dependent mechanism, and a mechanism involving a2-
adrenergic receptors. In one study [5], yohimbine blocked the inhibitory
effects of endotoxin on forestomach motility, suggesting that either increased
concentrations of circulating catecholamines or increased sympathetic tone
causes excessive stimulation of inhibitory a2-adrenergic receptors. In
addition to rumen hypomotility, endotoxin exposure increases abomasal
emptying time in cattle [6]. The inhibition of forestomach motility associated
with endotoxemia in cattle can be attenuated by the administration of
nonsteroidal anti-inflammatory drugs (NSAIDs) [7].
Dehydration
Endotoxic shock is characterized by a reduction in the effective circulating
blood volume resulting from pooling of blood in venous capacitance beds,
and by a decrease in plasma volume [8]. Plasma is lost into the interstitial
space as a consequence of increased vascular permeability [8,9]. Endotoxemia
in cattle has been shown to induce a marked hypovolemia [10], necessitating
aggressive fluid therapy in these animals.
Leukopenia
Studies in both experimentally induced and naturally occurring models of
endotoxemia in cattle demonstrate significant decreases in white blood cell
 SUPPORTIVE THERAPY OF THE TOXIC COW 597

counts [11–13]. Both neutropenia and lymphopenia have been observed,

with neutropenia being the more severe. Leukopenia appears to be a
response to endotoxin administration that causes an immediate accumula-
tion, margination, and activation of leukocytes in the microcirculation,
particularly in the alveolar capillaries [9,14]. Lymphopenia has been attrib-
uted to the release of endogenous corticosteroids [14], whereas neutropenia
is thought to result primarily from pulmonary sequestration of neutrophils
[15]. Thrombocytopenia can also be observed in endotoxic shock, and is
thought to result from sequestration of platelets in lung, liver, and splenic
capillary beds [16].

Diarrhea
Toxic cattle often have diarrhea as a direct result of endotoxemia.
Although the mechanism of endotoxin-induced diarrhea is not completely
understood, it appears to involve both prostaglandins and nitric oxide. The
administration of endotoxin produces a prostaglandin-mediated accumula-
tion of fluid within the small intestines of animals [17]. There is also an
increase in nitric oxide synthase (NOS) activity in intestinal smooth muscle
that changes the propagation of jejunal contractions, resulting in rapid
intestinal transit [18]. The diarrhea observed during endotoxemia in cattle is
generally described as ‘‘low-volume.’’

Decreased cardiac output and systemic hypotension

There is significant circulatory dysfunction during endotoxemia, charac-
terized by a decrease in cardiac output and systemic hypotension [10,19,20].
This decrease in cardiac output and arterial pressure has been shown to
occur within 30 minutes of endotoxin exposure in cattle, and can result in
circulatory shock and collapse [10]. Increased TNFa causes myocardial
depression and decreased myocardial contractility that begins within 3 to
4 hours of endotoxin exposure [19]. In addition, changes in vascular tone
dramatically alter both cardiac preload and afterload, contributing signif-
icantly to the hemodynamic disturbances seen in toxic animals.

Tachycardia
Toxic cattle typically have elevated heart rates caused by pain, relative
hypovolemia, and systemic hypotension, all of which increase sympathetic
tone.

Hypoxemia
Endotoxin produces a complex pulmonary response in cattle that
includes abnormalities in both airway and vascular function. These
abnormalities include pulmonary hypertension, changes in lung mechanics,
increased microvascular permeability, pulmonary edema, bronchoconstriction,
598 SMITH

ventilation perfusion mismatch, and severe hypoxemia [20–22]. Compared

with other species, ruminants are very sensitive to the effects of endotoxin,
and even small concentrations can cause profound lung injury [21]. Severe
endotoxemia is often clinically associated with diffuse lung injury and death
from respiratory failure in cattle. The cyclooxygenase products of
arachidonic acid metabolism, such as thromboxane A2, are believed to
mediate the abnormalities of respiratory function [23]. Therefore, anti-
inflammatory drugs that block cyclooxygenase enzymes and reduce the
formation of reactive metabolites such as thromboxanes are crucial in
restoring lung function in the toxic cow.

Decreased systemic oxygen delivery

Oxygen is in limited supply during endotoxemia, and its delivery to
tissues in septic cattle is dramatically reduced [22]. Additionally, endotoxin
has been demonstrated to impair the efficiency of oxygen extraction by some
tissues [24]. This is a complex process that involves disturbances in the
microcirculation and changes in cellular metabolism [25]. Together these
alterations lead to a significant reduction in systemic oxygen consumption in
toxic animals that can further contribute to organ damage [22].

Weakness
Toxic cattle are often weak or lethargic as a result of many factors,
including dehydration, electrolyte abnormalities, and severe systemic illness.
Certainly the release of endotoxin by gram-negative bacteria results in
a complex cascade of inflammation that can have profound physiological
consequences for the cattle. Gram-positive bacteria such as Staphylococcus
aureus, Arcanobacterium pyogenes, or Clostridium species are also capable of
toxin production. These toxins include kinases, hyaluronidase, leukotoxins,
and hemolysins that are capable of initiating the inflammatory cascade and
producing clinical signs similar to those seen in endotoxemia. For example,
in many cows that have toxic mastitis, severe systemic signs of illness are
due to gram-positive bacterial infections. Any cow that has severe mastitis,
metritis, peritonitis, or acute enteritis may become toxic and require the
aggressive treatment discussed in this article.

Fluid therapy
Fluid therapy in adult ruminants is often difficult to accomplish because
of the large volume of fluids that are required, and because animals must be
restrained, proper therapy can be very time-consuming, and monitoring is
often impossible. For these reasons, fluid therapy is often avoided in adult
ruminants, despite the fact that intravascular volume expansion is a
fundamental goal in the clinical management of endotoxic shock.
 SUPPORTIVE THERAPY OF THE TOXIC COW 599

The most common indication for fluid therapy in adult ruminants is to

correct dehydration from any number of primary conditions, including toxic
mastitis, metritis, or peritonitis. Estimating the degree of dehydration in
adult ruminants is often difficult. In neonatal calves, eyeball recession and
skin-tent duration are the most accurate indicators of dehydration [26].
Although there is no similar study in adult ruminants, eyeball recession and
duration of skin tent are also used to estimate the extent of dehydration, as
shown in Box 1.
In treating dehydrated cattle, the focus is on correcting the degree of
dehydration, also giving consideration to the animal’s maintenance fluid
requirements. Nonlactating cattle require at least 50 mL/kg of water per day
for maintenance, and lactation adds to the requirement, depending on the
cow’s production level [27]. Adult ruminants rarely develop metabolic
acidosis, as shown in a study of over 500 cattle older than 1 month of age
[28]. In this study, blood gas and serum electrolyte analyses determined that
60% of dehydrated animals had a normal blood pH, with most of the
remaining cattle exhibiting a metabolic alkalosis. Therefore, intravenous or
oral alkalinizing fluids (such as lactated Ringer’s, sodium bicarbonate
solution or others) are rarely indicated in adult ruminants except in cases
of grain overload, chronic ketosis, hepatic lipidosis, kidney disease, or
occasional cases of choke, in which excessive salivation leads to bicarbonate
loss and metabolic acidosis.

Oral fluids
Oral electrolyte solutions have classically been used to replace fluid losses
and correct electrolyte abnormalities in adult ruminants, because they are
affordable and easy to administer on-farm. Because most dehydrated cattle
have either a normal blood pH or a metabolic alkalosis, it is important to
choose an oral electrolyte solution that does not contain bicarbonate,
acetate, or propionate, and therefore is not alkalinizing. Metabolic alkalosis
of cattle is corrected not by administering acid, but instead by providing
extracellular anions in relative excess to cations [27]. In practice, this is

Box 1. Assessment of dehydration in adult cattle

Mild dehydration (6%–8%): slight eyeball recession, skin tent
slightly prolonged (2–3 seconds), mucous membranes moist
Moderate dehydration (8%–10%): eyes obviously sunken, skin
tent obviously prolonged (3–6 seconds), mucous membranes
tacky
Severe dehydration (10%–12%): eyes severely sunken into orbits,
skin remains tented indefinitely, mucous membranes dry
600 SMITH

accomplished with chloride-rich, high potassium solutions. By simply

adding NaCl (7 g/L), KCl (1.25 g/L) and CaCl2 (0.5 g/L) to a liter of
water (or 140 g NaCl, 25 g KCl, and 10 g CaCl2 in 20 L or roughly 5 gallons
of water), a homemade nonalkalinizing oral electrolyte solution for adult
ruminants can be created that will effectively rehydrate animals without
alkalinizing blood pH [27]. Feed-grade salts are weighed out on a small
laboratory scale and combined into individual plastic bags. Once prepared,
these bags can be carried on a truck and have a long shelf life.
Most of the commercial oral electrolyte solutions are formulated for
dehydrated calves that have metabolic acidosis. Therefore, most products
contain metabolizable bases such as bicarbonate that are not indicated for
use in adult ruminants. Some products such as Bovine Bluelite (Techmix
Inc., Stewart, Minnesota) or Magna-Lyte (First Priority Inc., Elgin, Illinois)
contain only very low concentrations of bicarbonate and could be used to
rehydrate adult cattle. Whether the intervention is intravenous (IV) or oral,
and whether commercial or homemade solutions are used, the focus should
be on administering the appropriate volume to correct dehydration. The
renal function that is restored with rehydration is usually effective in
normalizing subtle electrolyte disturbances. Oral fluids typically can be used
successfully in cows that have mild to moderate dehydration; however, in
cows that have severe dehydration or in those that are truly toxic,
intravenous fluids are generally preferred (Fig. 2).

Intravenous fluid therapy

Over the past 10 years, the role that hypertonic saline (2400 mOsm/L)
solution can play in rapidly expanding plasma volume in severely

Sick or Toxic Cow

Clinical Severity–Mild Clinical Severity–Moderate Clinical Severity–Severe

Cow standing & alert Cow standing but depressed Cow very weak or
unable to stand

Mild dehydration Moderate dehydration Severe dehydration

Heart rate < 90 bpm Elevated heart rate Heart rate > 120 bpm
Rumen motility still strong Weak rumen motility Absent rumen motility

Hypertonic Saline IV

Non-alkalinizing oral electrolyte solution or water PO Non-alkalinizing isotonic fluids IV

Fig. 2. Algorithm for the initial fluid therapy of ‘‘toxic’’ or ‘‘sick’’ cattle. Bpm, beats per
minute; PO, orally.
 SUPPORTIVE THERAPY OF THE TOXIC COW 601

dehydrated animals has been appreciated. When combined with adminis-

tration of oral electrolyte solutions or water (without added electrolytes),
intravenous hypertonic saline solution can be extremely effective in
rehydrating sick cattle, and is much easier to administer than large volumes
of isotonic fluids. Adult ruminants have a large water reservoir (rumen) that
enables them to go without water for days and then rapidly rehydrate
without negative effects [29]. The main force for water movement across the
rumen wall is the gradient of osmolality between ruminal fluid (which is
normally isotonic to plasma) and blood perfusing ruminal epithelium [30].
With the IV administration of hypertonic saline solution, plasma osmolality
in adult ruminants is increased at the same time that rumen osmolality is
decreased through oral administration of water or a hypotonic oral
electrolyte solution. The increase in osmolar gradient across the rumen
wall following this combined treatment is in part responsible for the
movement of water from the rumen into the extracellular space, thereby
expanding the plasma volume and correcting dehydration.
Hypertonic saline solutions can be purchased in 1000 mL containers and
should be dosed at the rate of 4 to 5 mL/kg administered over a 4-minute
period (approximately 2 L for an average adult cow). Immediately after,
cattle should be given access to fresh water and most will drink 5 to 10
gallons over the next 10 minutes. Cattle that do not drink at least 5 gallons
of water should have it delivered by orogastric administration into their
rumen. Administration of hypertonic saline alone without providing the cow
fresh water to drink or administration of ororuminal water is ineffective.
This protocol has been shown to be safe and effective for the correction of
dehydration in adult cattle [31,32], and can be repeated once in a 24-hour
period. Combined use of hypertonic saline solution with oral fluids should
be considered to produce far superior resuscitation in the toxic cow than
oral fluids alone.
Administration of isotonic fluids is much more difficult and expensive to
accomplish in the field, requiring intravenous catheterization, appropriate
delivery equipment, and monitoring. For animals in severe shock, however,
large volumes of isotonic fluids are necessary for protracted improvement
in plasma volume, improved blood flow, and electrolytes restoration. For
large-volume replacement in adult ruminants, nonalkalinizing isotonic fluid
types such as saline or Ringer’s are indicated as good base solutions.
Potassium chloride can be added at a rate of 20 to 40 mEq/L during routine
fluid administration (1 g of KCl contains 14 mEq of Kþ). Some dairy cattle
may benefit from the addition of a 500 mL bottle of calcium gluconate to the
first 20 L of fluids intended for intravenous administration, or the
administration of a tube of oral calcium gel. Studies in cattle that have
both experimentally induced and naturally occurring endotoxemia have
shown significant decreases in serum calcium concentrations [13,33,34].
Although the reason for the decrease in calcium concentrations is not fully
understood, toxic cattle that are already at risk for hypocalcemia should be
602 SMITH

supplemented with calcium in addition to what is present in the isotonic

fluids.
The maximal IV flow rate of 40 mL/kg/hr for animals is rarely achieved
with conventional catheters and gravity flow delivery systems. For rapid
administration of large fluid volumes to a toxic cow, a 14-gauge or larger
jugular catheter is required to administer the 40 to 60 L of fluid that is
recommended in the first 12 to 24 hours. When commercially available
products are cost-prohibitive, some practitioners use homemade fluids to
make therapy more economical. By adding reagent-grade salts to filtered
deionized waterdeither Ringer’s, sodium chloride, or a ruminant electrolyte
solution containing additional potassium and calcium [27]dfluids can be
prepared quite economically (Table 1). Although cumbersome or impossible
to use on farm, fluids prepared in autoclavable 20-L containers (Nalgene
Labware, Rochester, New York) are quite practical in clinics that are able
to hospitalize cattle (Fig. 3). Pieces of old simplex tubing can be used to
connect fluid delivery lines to the spigot on the containers. Rapid
administration of large volumes of nonalkalinizing fluids in the severely
toxic cow will produce better clinical results than oral fluids alone, or even
hypertonic saline and oral fluids.
Dextrose is occasionally indicated for treating toxic cattle or those in
early lactation with severe ketosis, hepatic lipidosis, or hypoglycemia.
Glucose as a 5% solution can be administered at a slow rate for several
days; however, this delivers free water and may cause dilution of serum
electrolytes. In general, it is preferable to add 2.5% to 5% glucose to an
isotonic, nonalkalinizing fluid type (Ringer’s), thereby creating a slightly
hypertonic solution, rather than administer isotonic dextrose alone.

Antibiotics
The use of antibiotics in diseases such as mastitis and metritis is
controversial, and a complete discussion of these subjects is beyond the
scope of this article; however, in the toxic cow, most clinicians agree that the
use of systemic antibiotics is an important component of therapy. Recent
studies demonstrate a risk for systemic bacteremia in a substantial
proportion of cows that have moderate to severe coliform mastitis [35,36].

Table 1
Ringer’s, isotonic sodium chloride, and ruminant electrolyte solutions
Ruminant electrolyte
Ringer’s Isotonic saline solution
NaCl 150.5 g 180 g 140 g
KCl 5.25 g 0 g 25 g
CaCl2 5.8 g 0 g 10 g
Water 20 L 20 L 20 L
 SUPPORTIVE THERAPY OF THE TOXIC COW 603

Fig. 3. Homemade isotonic fluids can be economically prepared in autoclavable containers. In

clinics that are able to hospitalize cattle, this can be a practical way to deliver large volumes of
isotonic fluids to ‘‘toxic’’ cows.

It is also likely that some cases of toxic metritis, peritonitis, or acute enteritis
are also associated with a systemic bacteremia, providing an indication for
parenteral administration of antibiotics.
Ideally the choice of antibiotics in the toxic cow would be based on
culture and sensitivity results that are almost never available when treatment
is initiated. The antibiotic choice, therefore, is generally based on clinical
diagnosis and an educated guess as to the most likely pathogen. Because
accurate pathogen prediction is difficult or impossible based on physical
examination findings alone [37], most toxic cows are given broad-spectrum
antibiotic coverage. Antibiotics such as amoxicillin, ampicillin, erythromy-
cin, tylosin, and sulfadimethoxine have been used historically to treat cattle;
however, gram-negative bacterial resistance to these drugs is common, and
the antibiotics are rarely able to achieve plasma concentrations above the
minimum inhibitory concentration (MIC) of many major pathogens. Cur-
rently, the most logical broad spectrum antibiotic choices for the toxic cow
are ceftiofur or oxytetracycline. To the extent that multiple pathogens d
gram-positive, gram-negative, and anaerobic bacteriadare presumed to
play an etiologic role, combination antibiotic therapy may be more effective.
604 SMITH

A limited number of antibiotics are labeled for the treatment of systemic

disease in cows in the United States (erythromycin for mastitis [38], ceftiofur
hydrochloride for metritis), so veterinarians should be guided by prudent
drug use guidelines established by the American Veterinary Medical Asso-
ciation (AVMA) and American Association of Bovine Practitioners
(AABP). With presumably effective antibiotics, consideration must be given
to penetration into the diseased body system. For example, in a cow that has
toxic mastitis, parenterally administered ceftiofur has a good spectrum for
many gram-positive and gram-negative pathogens, but it does not penetrate
the udder well, resulting in extremely low milk concentrations [39,40];
however, when combined with appropriate intramammary therapy, it is
potentially useful. A recent study [41] demonstrated that cows that have
severe coliform mastitis treated with ceftiofur in addition to intramammary
antibiotics were less likely to die or be culled from the herd when compared
with cows that received intramammary antibiotics alone. Therefore ceftiofur
is considered to be a logical choice in cattle that have bacteremia, because
plasma concentrations can be maintained well above the MIC for a wide
range of bacteria, including coliforms.
Aggressive treatment with oxytetracycline at higher than label doses (16.5
mg/kg intravenously, every 24 hours) has also been recommended for the
treatment of clinical mastitis. Cows that received oxytetracycline for
naturally occurring mastitis had higher clinical and bacteriologic cure rates,
fewer subsequent episodes of mastitis in the 60-day period following
treatment, and less severe clinical disease than cattle that got supportive
therapy alone [42]. Although gram-negative bacterial resistance to
oxytetracycline is a concern, approximately 60% to 70% of Escherichia
coli and Klebsilla pneumoniae isolates from bovine mastitis cases over a
7-year period were susceptible to this antibiotic [43]. It should be emphasized
that in cows that have severe systemic signs of infection, intravenous doses of
oxytetracycline (15 to 20 mg/kg IV, every 24 hours) are preferred because
they achieve much higher plasma concentrations than equivalent doses of
other parenterally administered antibiotics [44].
Where they are marketed, potentiated sulfonamides may be useful in the
treatment of the toxic cow. Although few controlled studies exist, the
intravenous administration of trimethoprim and sulfadoxine combination
may be efficacious against most of the major bovine pathogens when used
twice a day [45]; however, rapid rumen metabolism interferes with the
maintenance of effective trimethoprim and sulfonamide concentrations in
adult ruminants, even with susceptible organisms [46]. Ceftiofur is currently
the only antibiotic approved in the United States for the treatment of acute
postpartum metritis in cattle. Following parenteral administration, ceftiofur
achieves concentrations in uterine tissue and lochial fluid that exceed the
MIC for most of the common metritis pathogens [47], and has been shown to
be efficacious in treating acute postpartum metritis in cattle [48]. Combining
local intrauterine antibiotics with intramuscular (IM) ceftiofur appears to be
 SUPPORTIVE THERAPY OF THE TOXIC COW 605

of no additional benefit [49]. Oxytetracycline has also been widely used for
the treatment of metritis; however, a recent study [47] demonstrated
significant evidence of resistance for several of the major pathogens.
In cases of bovine peritonitis, the goal of therapy is to localize the
infection and prevent dissemination. The most common cause of peritonitis
in adult cattle is foreign body penetration of the reticulum. Many cases may
recover spontaneously or remain as chronic localized peritonitis [50].
Although there have been no controlled studies to determine the best
antibiotic for treating peritonitis in cattle, high doses of penicillin (9000 to
15,000 IU/kg IM, q12h) are often recommended because of the large
population of anaerobic bacteria that may be present. In a cow that is toxic
with peritonitis, the addition of ceftiofur or oxytetracycline to penicillin
could improve drug efficacy against aerobic gram-negative bacteria;
however, once the peritonitis disseminates and becomes diffuse, the
prognosis is generally considered extremely poor.
There may be other clinical conditions that make a cow toxic and that
warrant antibiotic therapy. These conditions include acute salmonellosis,
endocarditis, liver abscess syndrome, or pleuropneumonia. Ceftiofur or
oxytetracycline is frequently the initial drug of choice until a definitive
diagnosis, culture, and sensitivity results can be obtained. The author
believes that because a high percentage of toxic cattle have a systemic
bacteremia, aggressive therapy with systemic antibiotics is indicated.

Glucocorticoids
Glucocorticoids are a group of drugs that have historically been used as
anti-inflammatory agents. The mechanism of these drugs involves direct
binding to a specific family of glucocorticoid receptors found on membranes
of various cells. Activated glucocorticoid receptor complexes can bind to
and inhibit production of several inflammatory mediators, including
cytokines, chemokines, arachidonic acid metabolites, and adhesion mole-
cules. It is important to emphasize that activated glucocorticoid receptors
bind what are termed ‘‘glucocorticoid response elements’’ in the promoter
region of genes, and the anti-inflammatory effects of these drugs involve
modifications in protein synthesis. Therefore these drugs are most effective
when administered before the onset of endotoxemia, and their effectiveness
rapidly diminishes as the time from the onset of endotoxemia to the time of
treatment initiation increases [51].
Dexamethasone and isoflupredone acetate are both approved in the
United States as anti-inflammatory drugs to be used in the supportive therapy
of mastitis, metritis, or other severe toxic conditions. These glucocorticoids
have been shown to work quite well in experimental models when given at
the time of initial infection. For example, in one study [52], 30 mg of
dexamethasone was given intramuscularly immediately following the intra-
mammary infusion of E coli in the rear quarters. Dexamethasone-treated
606 SMITH

cows had a significantly lower rectal temperature, increased rumen motility,

less udder inflammation, and an improved 14-day milk yield compared with
controls. When glucocorticoid treatment is administered later in the course of
disease, however, the treatment has often been of no benefit. In one study [53],
isoflupredone acetate failed to lower rectal temperature or heart rate, or to
improve rumen motility in cows that had experimentally induced E coli
mastitis. In another study [54], intravenous prednisolone was not able to
alleviate the clinical signs associated with endotoxemia when given 15
minutes after the start of a 3-hour infusion of E coli lipopolysaccharide in
calves. One of the best illustrations of this concept was a study using a model
of E coli-induced mastitis in adult dairy cows [55]. The intramammary
administration of prednisolone and the intramuscular injections of either
dexamethasone or flumethasone were able to abolish fever and prevent the
leukopenia associated with endotoxemia when given at the time of initial
infection. When given 4 hours post-infection, however, glucocorticoids were
not able to prevent the adverse clinical signs or leukopenia seen in control
cows.
Glucocorticoids are well known for their ability to cause immunosup-
pression, and are often avoided by many clinicians in animals that have
infectious diseases; however, a single dose of dexamethasone (0.02 mg/kg,
IM) administered to postpartum dairy cows had no affect on lymphocyte
function, including subpopulation patterns (CD2, CD4, CD8, and CD18),
or on lymphocyte blastogenesis, when compared with untreated cows [56].
The study authors concluded that a single dose of glucocorticoids should
not induce significant immunosuppression, and was indicated for the
treatment of ketosis in postpartum cattle. Although glucocorticoids in
general have been shown to be less effective in alleviating the clinical signs
associated with endotoxemia in cattle as compared with NSAIDs (see
‘‘Glucorcoticoids versus NSAIDs’’ below), a single dose would not be
contraindicated in a toxic cow that had concurrent metabolic disease.

Nonsteroidal anti-inflammatory drugs

NSAIDs are substances other than steroids that inhibit some component
of the inflammatory cascade. For the purpose of this article, the definition of
NSAIDs is limited to those substances that exert their anti-inflammatory
actions via inhibition of cyclooxygenase enzymes. These drugs typically are
weak organic acids that possess anti-inflammatory, antipyretic, and
analgesic properties. The drugs most commonly used in ruminants include
aspirin, flunixin meglumine, phenylbutazone, ketoprofen, meloxicam,
carprofen, and tolfenamic acid. Etodolac is discussed in the article on
pain management by Anderson and Muir elsewhere in this issue.
Arachidonic acid metabolism is one of the key components of the
inflammatory cascade, and the formation of eicosanoids such as throm-
 SUPPORTIVE THERAPY OF THE TOXIC COW 607

boxane is directly responsible for many of the adverse pathophysiologic

consequences of endotoxemia. Arachidonic acid is obtained from dietary
linoleic acid and esterified into cell membrane phospholipids. Enzymatic
action of phospholipase A2 on cell membrane phospholipids initiates the
arachidonic acid cascade. Metabolism of arachidonic acid by the enzymes
cyclooxygenase and lipoxygenase catalyzes the formation of various
eicosanoids [57]. The NSAIDs exert their actions by specifically inhibiting
the enzyme cyclooxygenase (Fig. 4), and thus suppress the formation of
inflammatory mediators such as thromboxane.
Cyclooxygenase exists as two isoforms designated COX-1 and COX-2.
Classically, COX-1 has been referred to as the ‘‘housekeeping’’ enzyme that
is constitutively expressed and has several functions, including maintaining
gastrointestinal mucosal integrity, platelet aggregation, and renal blood
flow. The COX-2 isoform is considered ‘‘inducible,’’ and is upregulated in
response to inflammatory stimuli including endotoxin [58]. Most traditional
NSAIDs inhibit both COX-1 and COX-2, which produces the desired anti-
inflammatory actions but also leads to the inhibition of prostaglandins that
leaves the gastrointestinal tract more susceptible to injury. Both in human
and veterinary medicine, the use of NSAIDs has been associated with
subsequent gastrointestinal injury and other toxic side effects, including
inhibition of cartilage metabolism and bone healing [57]. Therefore there
has been an emphasis in the pharmaceutical industry on creating new

Cell Membrane phospholipid

phospholipase A2

Arachidonic acid

blocked by Cyclooxygenase
NSAIDs

PGG2

PGH2

PGE2 PGF PGI thromboxane A2

2 2

Fig. 4. The arachidonic acid cascade and its inhibition by NSAIDs.

608 SMITH

NSAIDs that are ‘‘selective’’ or ‘‘specific’’ for the COX-2 isoform, and that
do not affect the homeostatic COX-1 enzyme. These drugs theoretically
would have more potent anti-inflammatory activity, but would not affect
physiologic functions. Although these selective NSAIDs have become
popular in small animal veterinary medicine, their importance in ruminants
is not well-understood.
Aspirin is the classic cyclooxygenase inhibitor that has been used in
ruminants for many years. Most aspirin products are not approved for use
in lactating dairy animals, and therefore extralabel use guidelines must be
followed. One of the drawbacks to oral aspirin therapy is that a functional
rumen is needed for drug absorption. In cattle that have forestomach
hypomotility or atony, the boluses often sit in the rumen for long periods
of time and are not absorbed. Aspirin can be an effective antipyretic drug
in some cases; however, its anti-inflammatory activity should considered
inferior to other NSAIDs when used in the toxic cow.
Flunixin meglumine is the only NSAID currently approved for use in
both beef and dairy cattle in the United States. It is labeled for the control of
inflammation associated with endotoxemia, including bovine respiratory
disease and acute mastitis. Flunixin is a nonselective inhibitor of the
cyclooxygenase enzyme, and blocks both the COX-1 and COX-2 isoforms.
It has been widely used in the supportive treatment of bovine mastitis, and
has been shown to reduce rectal temperature and improve clinical
depression scores in affected cattle [59]. Flunixin meglumine blocks the
expected increase in thromboxane concentration that occurs in cases of toxic
mastitis, and thus is also able to ameliorate the local inflammation and pain
in the mammary gland [60].
Flunixin meglumine is recently shown to be effective in the supportive
therapy of bovine metritis. In a study involving 259 dairy cows that had
postpartum metritis from 21 different dairy farms in Greece [61], cows
receiving flunixin meglumine had lower rectal temperatures, faster uterine
involution, and a significantly shorter calving-to-first estrus interval than
those that did not receive flunixin. In an experimentally induced model of
sepsis in calves [62], flunixin meglumine was able to ameliorate most of
the clinical signs associated with endotoxemia, and treated calves had an
improved clinical attitude when compared with controls. Flunixin
meglumine should be considered the gold standard NSAID in the United
States, and is the most logical choice currently for supportive therapy of the
toxic cow.
Phenylbutazone is another NSAID that has classically been used as an
anti-inflammatory drug in ruminants. It has a much longer half-life than
flunixin meglumine and was preferred by some practitioners because once-
daily or every-other-day oral dosing could achieve and maintain plasma
drug concentrations within the therapeutic range [63]; however, in a model
of naturally occurring mastitis [64], phenylbutazone was not as effective
as flunixin meglumine in mediating the signs of endotoxemia. Because
 SUPPORTIVE THERAPY OF THE TOXIC COW 609

phenylbutazone can cause fatal hypersensitivity reactions and blood

dyscrasias in humans, its use in adult dairy cattle is prohibited [65].
Moreover, its use in beef cattle is strongly discouraged, and if used,
a minimum slaughter withdrawal interval of 60 days following either IV or
IM administration should be imposed.
Ketoprofen is another NSAID that has been used historically in
ruminants, and has been shown to be effective in alleviating some of the
clinical signs associated with endotoxemia; however, the use of ketoprofen
offers no medical [62,66] or economical advantage over flunixin meglumine
and does not have a food animal label.
Carprofen is a newer NSAID commonly used in small animal veterinary
medicine in the United States. This drug has a much longer plasma
elimination half-life (O30 hours) in cattle than flunixin meglumine, and is
poorly excreted in milk [67,68]. Therefore, carprofen could potentially be
used in a once-daily or every-other-day dosing format with little to no milk
discard in dairy cattle. In an experimentally induced model of mastitis [68],
carprofen was able to reduce heart rate, rectal temperature, and quarter
swelling when compared with control cows. A single dose of carprofen was
also shown to be equally effective as three daily doses of flunixin meglumine
in the supportive therapy of acute respiratory disease in calves [69].
Carprofen is currently approved in several European countries for use in
cattle that have acute mastitis and, if ever labeled for bovine use in the
United States, it could potentially offer several advantages to flunixin
meglumine (shorter dosing interval, no milk discard).
Tolfenamic acid is a NSAID in the anthracilic acid (fenamate) class. It
undergoes extensive enterohepatic recirculation in cattle, and a single
injection can maintain therapeutic blood concentrations for at least
48 hours. When combined with oxytetracycline, tolfenamic acid has been
shown to improve clinical signs, increase weight gain, and reduce the
frequency of relapses in cattle that have respiratory disease as compared
with treatment with oxytetracycline alone [70]. The drug penetrates well into
inflamed tissue and has a longer half-life than most other NSAIDs [71].
Tolfenamic acid is approved in several European countries and Canada as
a single intravenous injection for use in cattle that have acute mastitis or
respiratory disease.
Meloxicam is newer NSAID in the oxicam group that has preferential
(but not specific) binding to COX-2 receptors. This drug is approved in
Europe and Canada as for the supportive therapy of acute mastitis and
respiratory disease; however, there are few published studies on its efficacy
as an anti-inflammatory drug in cattle.
The mixed animal practitioner should be reminded that dipyrone has
been associated with serious toxic effects in humans and has been illegal for
use in food animal species since 1997 [72]. In addition, the use of dimethyl
sulfoxide (DMSO) is prohibited by the Grade A Pasteurized Milk
Ordinance and is not appropriate in dairy cattle [72].
610 SMITH

Glucocorticoids versus nonsteroidal anti-inflammatory drugs in cattle

There is disagreement amongst practitioners as to whether glucocorti-
coids or NSAIDs are more effective when used in supportive therapy of the
toxic cow. Although there are few controlled studies that have compared the
two classes of drugs, more recent data have indicated that NSAIDs are
likely to be more effective in alleviating the clinical signs associated with
endotoxemia in cattle than glucocorticoids. In a model of experimentally
induced mastitis [73], cows treated with flunixin meglumine had decreased
rectal temperature and heart rate and increased rumen motility compared
with control cows. Cattle treated with isoflupredone acetate in this study
had a decrease in heart rate; however, their rectal temperatures remained
elevated and rumen motility did not increase. Neither anti-inflammatory
drug was able to improve milk production or alleviate mammary gland
inflammation.
In another study [54], neonatal calves were given a 3-hour infusion of
E coli lipopolysaccharide. Flunixin meglumine was able to decrease plasma
eicosanoid concentrations (including thromboxane and 6-keto-prostaglan-
din F2a) and mitigate clinical signs associated with endotoxemia. In con-
trast, prednisolone was not able to improve clinical parameters in treated
calves, and plasma eicosanoid concentrations increased significantly over
the course of the endotoxin infusion.
A trial conducted in 4- to 5-week old Holstein calves that had an
experimentally induced model of Mannheimia hemolytica pneumonia [74]
also suggested that NSAIDs would be more beneficial than corticosteroids
in the supportive treatment of bovine respiratory disease. Calves treated
with dexamethasone after the initial infection had a decrease in rectal
temperature, but their respiratory rates remained elevated, and they had
a significant decrease in arterial oxygen tension (PaO2) and impaired lung
mechanics. In contrast, calves treated with ketoprofen had improved
respiratory function (mechanics), were less tachypneic, and had significantly
higher arterial oxygen tensions. Interestingly, there was no difference in the
oxidative burst intensity of blood neutrophils or alveolar macrophages
between dexamethasone and ketoprofen treated cattle. So, although
dexamethasone was able to reduce rectal temperature and did not seem to
alter immune function in these calves, it was much less effective in mediating
some of the other clinical features of endotoxemia when compared with
ketoprofen.

Summary
Both gram-positive and gram-negative bacteria produce toxins that trigger
a complex inflammatory cascade in cattle. This has profound pathophysio-
logic consequences that can lead to death. Therapy of the toxic cow typically
involves a combination of fluids (see Fig. 2), systemic antibiotics, and
 SUPPORTIVE THERAPY OF THE TOXIC COW 611

NSAIDs. With prompt and aggressive treatment, many of these cases can be
effectively managed, with animals returning to normal production. It should
be emphasized that approved antibiotics and anti-inflammatory drugs exist
for both beef and dairy cattle, and that every effort should be made to follow
Animal Medicinal Drug Use Clarification Act guidelines.

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