Bovine Applications

Pyrexia in Cattle

Pyrexia, or fever, in cattle is an abnormal elevation of body temperature. The normal temperature, as taken by rectal thermometer, is 101.5+° F (38.5+° C). This can vary to some degree depending on environmental temperature and humidity, exercise or stress, and some physiological conditions such as parturition and estrus. In most instances veterinarians do not consider an animal febrile until the temperature passes 103+° F. Most infectious diseases will induce a febrile state in cattle. Examples include respiratory diseases, severe mastitis, metritis, and other soft tissue infections where there is an accompanying toxemia. Fever can also occur in non-infectious conditions such as exposure to toxic chemicals, absorption of tissue breakdown products following surgery, or necrotic tissue or immune reactions following vaccination or anaphylaxis. Fever is usually accompanied by decreased appetite, lethargy, increased respiratory rate, rapid weak pulse, thirst, and constipation or diarrhea. Whether these signs are totally due to the fever or are a part of the disease condition may be debatable. Regardless, they are most often found in the same individual. There are no clinical pathology tests or necropsy findings that are particularly characteristic of fever.

Fever is an expected part of an infectious disease and is not a cause for alarm unless the pyrexia is excessively high (e.g., 106+°-107+° F or greater) or of excessive duration (usually several days). Effective treatment of the infectious agent removes the source of the fever-causing agent (toxins), and the fever declines rapidly. When anti-infective therapy is not effective, additional treatment for reduction of fever is indicated. Examples include acute or prolonged viral infections, conditions with extensive tissue damage and absorption of toxins, and endotoxic shock.

Treatment of pyrexia involves use of large doses of steroidal anti-inflammatory agents (e.g., dexamethasone) or NSAIDs. The disadvantage of using large doses of steroids is their effect of decreased immune function. Effective anti-infectives must accompany the use of steroids in these situations. In the case of NSAIDs, the decreased immune function is not a major concern. Other treatment includes nursing care such as providing adequate clean drinking water and shade to protect from direct sun.

Inflammatory Diseases of Cattle

It is beyond the scope of this document to cover all inflammatory diseases of cattle. The major conditions where application of NSAIDs is indicated will be addressed. In younger growing animals, most cases of inflammation are associated with infectious processes. In older animals, infections and musculoskeletal conditions prevail.

One of the most common infections involves the respiratory tract. Commonly referred to as bovine respiratory disease, or BRD, it is a combination of gram negative bacteria (Pasteurella and Hemophilus) and viral agents such as IBR, BVD, PI3, and BRSV. The clinical disease may be mild or a severe pneumonia. BRD occurs in dairy and beef calves from birth to weaning and is probably most commonly seen postweaning. Although less frequently, it can be seen in adult animals as well.

BRD is characterized by sudden onset, fever, depression, lethargy, decreased appetite, and a tendency to be away from herdmates. In most cases, some degree of pneumonia is present. Inflammatory conditions of the lung are characterized by decreased oxygenation of blood. If the pleura (covering of the lungs) are inflamed (pleurisy), there will be pain upon every breath. Infections of the lung often result in permanent scarring or damage to tissues, leaving the animal with lung consolidation and decreased lung capacity. If the inflammation or lung damage is extensive, future growth and production will be affected and result in extensive long-term economic loss.

Endotoxemia is a condition caused by the release of endotoxins from gram negative bacteria. Endotoxins are a component of the cell wall of gram negative bacteria and are released upon death of the bacteria. They are extremely potent toxins and can cause severe shock and even death when given in micrograms per kilogram body weight. Infections where large numbers of gram negative bacteria are present, such as in the intestinal tract, the mammary glands (coliform mastitis), the reproductive tract (metritis), the lungs (pneumonia), and other soft tissues, can lead to endotoxemia.

Endotoxins cause a decrease in blood pressure, pooling of blood in certain organs while decreasing blood flow to other organs, acidosis due to build up of lactic acid, intravascular coagulation (blood clots) and shock which can be fatal. Endotoxemia occurs in animals of all ages and all species. Treatment is aimed at reversing the effects of the endotoxin, with elimination of the infection as secondary target. In many instances, the infection is already at a decline when endotoxemia is on the increase. This is explained by the release of endotoxin from dying bacterial cells.

Non-infectious conditions of the musculoskeletal system in cattle are usually due to physical injury (trauma) or degenerative conditions related to the aging process. Injury can be to tendons, ligaments, joint surfaces and surrounding muscles. Since cattle require four sound limbs to get up and move about adequately, injury to any limb causes severe problems of locomotion. Often these animals are unable to get to feed or water, and rapid weight loss and debilitation occurs. Milk production can fall to near zero, and breeding bulls' ability to mount may be severely jeopardized. Animals will attempt to compensate by placing additional weight on unaffected limbs, but this causes additional stress to those limbs, which can lead to injury of apparently normal areas. The key to treatment of musculoskeletal disorders in cattle is rapid return to mobility. If this cannot be done, an alternate use of the animal or disposal are about the only remaining options. Treatment is aimed at relief of pain, reduction of inflammation, some nursing care (soft, dry bedding and ease of access to food and water), and correction of the cause, if possible.

Flunixin Meglumine in Cattle

Dose Titration Studies

One study utilized an E. coli endotoxin-induced fever model to establish the effective dose of flunixin meglumine (FM) for reduction of fever. Yearling Hereford heifers were the test subjects, and E. coli endotoxin was administered by intravenous injection. The model induced a significant temperature rise that peaked in four hours and then began to decline. Temperatures of each calf were recorded prior to injection of endotoxin and at 1, 2, 3, 4, 5 and 6 hours post injection of endotoxin. Immediately following the 1-hour temperature recording, flunixin meglumine or placebo was administered by intravenous injection. Doses of FM were 0.22, 2.2 and 6.6 mg/kg body weight. Results are presented in Table 1.

Table 1
Mean Temperature Response (+°F)

Group	Pre-trt.	1 hr.	2 hr.	3 hr.	4 hr.	5 hr.	6 hr.
Placebo	101.7	102.7	103.5	104.3	104.3	103.3	102.6
.22mg/kg	101.6	103.0	103.1	105.2	105.3	104.2	102.9
2.2mg/kg	101.8	102.9	102.7	102.7	103.0	102.4	102.3
6.6mg/kg	101.9	103.0	102.8	102.4	102.5	101.7	101.7

 

Treatment with 0.22 mg/kg of FM resulted in a lower mean temperature than the negative control at one hour post-treatment, but temperatures were higher than the control group thereafter.

Animals receiving the 2.2 mg/kg dose did not show substantial increases in temperature after treatment. The 2-, 3-, and 4-hour temperatures remained within 0.3+°F of the reading at the time of treatment (1 hour). Temperature differences between the negative control group and the 2.2 mg/kg group were statistically significant at 2, 3, 4 and 5 hours.

Animals in the 6.6 mg/kg group behaved much the same as those in the 2.2 mg/kg group; their temperatures remained near the 1-hour value at 2, 3, and 4 hours. Temperatures in the 6.6 mg/kg group declined to lower than pre-endotoxin levels at 5 and 6 hours. Differences between the 2.2 and 6.6 mg/kg groups were significant at only 5 and 6 hours.

Conclusions reached in this trial were: 1) the antipyretic effect of FM was demonstrated against an E. coli endotoxin model, and 2) the dose of 2.2 mg/kg was effective in preventing the rise in temperature generated by the administration of endotoxin.

A second study involved the dose response relationship for FM in a bovine model of acute non-immune related inflammation. Weaned beef calves weighing 125 to 200 pounds were used in the trial. The model consisted of implantation of 5 irritant (carrageenan) soaked sponges into subcutaneous tissues of the neck. These sponges were removed at 1, 2, 4, 6 and 8 hours post-treatment. Five additional sponges were subsequently inserted in each pouch and harvested at 10, 12, 15, 24 and 36 hours. Doses of FM were 0.081, 0.24, 1.1, 2.2, and 6.6 mg/kg given intramuscularly. Pertinent parameters were analysis of blood and sponges for eicosanoids [thromboxane (TXB) and prostaglandin E (PGE)] and plasma concentrations of FM. Results are presented below.

Table 2
Percent Inhibition of Serum TXB

Dose	1 hr.	2 hr.	4 hr.	6 hr.	8 hr.	10 hr.	12 hr.	15 hr.	24 hr.	36 hr.
0.081	73.7	62.1	42.1	5.8	-18.2	-12.4	-26.2	-2.2	-39.8	-40.2
0.24	97.7	92.2	91.8	68.8	71.3	56.1	51.8	44.9	35.2	17.0
1.10	99.0	95.8	90.8	94.3	96.1	79.1	59.6	44.4	10.7	-43.9
2.20	99.6	98.7	99.2	98.9	99.3	96.7	97.0	92.8	82.6	17.4
6.60	99.8	99.8	99.7	99.7	99.7	99.2	99.0	98.0	94.3	69.5

 

Table 3
Percent Inhibition of Exudate PGE

Dose	1 hr.	2 hr.	4 hr.	6 hr.	8 hr.	10 hr.	12 hr.	15 hr.	24 hr.	36 hr.
0.081	-40	53	49	45	39	25	28	-16	-1	-36
0.24	-8	60	52	45	52	43	21	-47	16	-40
1.10	-5	52	77	95	92	88	89	67	36	-12
2.20	-5	57	89	94	94	92	91	85	56	9
6.60	8	50	86	97	98	95	95	97	86	59

 

Table 4
Percent Inhibition of Exudate TXB

Dose	1 hr.	2 hr.	4 hr.	6 hr.	8 hr.	10 hr.	12 hr.	15 hr.	24 hr.	36 hr.
0.081	-65	-67	6	18	38	30	7	2	-28	-25
0.24	13	45	58	77	86	67	53	57	45	40
1.10	37	35	74	92	95	93	84	76	16	56
2.20	2	10	73	92	96	95	95	96	71	64
6.60	45	64	87	92	96	96	97	96	69	54

 

At early sampling times (1 to 4 hrs), a high level of inhibition of prostaglandin (PGE) and thromboxane (TXB) occurred in the higher dose groups (1.1, 2.2 and 6.6 mg/kg bodyweight). A relationship between the administered dose and percent inhibition of PGE and TXB in exudate and TXB in serum became apparent for the three higher dose rates at sampling times of 10 hours and later. The percent inhibition was generally greater with the 2.2 mg/kg dose than with 1.1 mg/kg, particularly from 12 to 24 hours. The inhibition obtained with the 6.6 mg/kg dose was either similar or slightly greater up to 24 hours post-dosing in comparison to the 2.2 mg/kg dose.

In conclusion, similar efficacy is likely from 0 to 12 hours with the 1.1 and 2.2 mg/kg doses, but a more prolonged action could be expected with the 2.2 mg/kg dose. The dose of 2.2 mg/kg produced greater inhibition of PGE and TXB during the 12 to 24 hour post-dating period. Greater inhibition with the 6.6 mg/kg dose was generally apparent only during the 24 to 36 hour period.

Based on the results of these two trials and an extensive literature review, a dose range of 1.1 to 2.2 mg/kg (0.5 to 1.0 mg/lb) was chosen.