UREA POISONING

UREA POISONING

Etiology

                Plants usually contain little or no urea. NPN is any source of nitrogen not present in a polypeptide (precipitable protein) form. The most common sources of NPN in feeds are urea, urea phosphate, ammonia (anhydrous), and salts such as monoammonium and diammonium phosphate. Urea is used as a source of nitrogen, which can be converted to protein in cattle and sheep, and is usually given in the form of a lick. Urea is also used as a means of ammonization of hay, straw or whole-crop cereals. Excessive addition of urea or failure to convert to ammonia (NH₃) in the treated feed can lead to urea poisoning in animals. Because feed-grade urea is unstable, it is formulated (usually pelleted) to prevent degradation to NH₃. Biuret, a less toxic source of NPN, is being used less frequently than in the past. Natural protein sources such as rice hulls, beet or citrus pulp, cottonseed meal, and straw or other low-quality forages may be treated with anhydrous ammonia to increase available nitrogen in supplemented livestock diets. Fermentation byproducts from alcohol (ethanol) manufacture are a source of NPN that comes from incomplete proteins, and these products are commonly used in liquid or feed supplements.

            The rumen adapts to converting urea to protein, and so sheep, which are accustomed to licks, can consume much more without ill effect than those which are abruptly put on a ration containing a "safe" amount of urea.

            The most common source of poisoning of cattle and sheep is via ingestion of toxic levels in concentrate feed, due to an error in urea addition or due to uneven mixing. A less common source of poisoning is via direct ingestion from liquid preparations of urea, from bags of urea, or of urea granules concentrated on pasture due to spillage or uneven spread of fertilizer.

            Most cases of poisoning are caused by faulty formulation where too much urea is added. Other cases are caused by the lick being too readily edible - soft crumbles and liquids with plenty of molasses are particularly dangerous. It has also occurred when hard licks have been wetted by rain and sheep have subsequently drunk the liquid, which contained large amounts of urea.

                Poisoning by ingestion of excess urea or other sources of nonprotein nitrogen (NPN) is usually acute, rapidly progressive, and highly fatal. Sources of NPN have different toxicities in various species, but mature ruminants are affected most commonly.

            Most sources of NPN are provided to ruminants by direct addition of dry supplement to a complete mixed or blended diet, by free-choice access to NPN-containing range blocks or cubes, or by lick tank systems combined with molasses as a supplement.

            Ammonia or NPN poisoning is a common sequela of abrupt change to urea or other NPN in the diet when only natural protein was previously fed; animals have to be gradually acclimated to NPN so that rumen microflora can increase in numbers to use the NH₃ produced.

            Also, farm animals sometimes drink liquid fertilizers or ingest dry granular fertilizers that contain ammonium salts or urea.

            Ruminants are most sensitive, because urease is normally present in the functional rumen after 50 days of age. Dietary exposure of unacclimated ruminants to 0.3–0.5 g of urea/kg body wt may cause adverse effects; dosages of 1–1.5 g/kg are usually lethal. Urease activity in the equine cecum is ~25% that of the rumen, and horses may receive NPN as a feed additive; however, horses are more sensitive to urea than other monogastrics, and dosages ≥4 g/kg can be lethal.

            Ammonium salts at 0.3–0.5 g/kg may be toxic in all species and ages of farm animals; dosages ≥1.5 g/kg usually are fatal.

            Pigs and neonatal calves are generally unaffected by ingestion of urea except for a transient diuresis.

            Wild birds (silver gulls) reportedly have been poisoned after consuming water contaminated with urea fertilizer spillage.

            Livestock may require days or weeks for total adaptation before rumen microflora can utilize the gradually increasing amounts of urea or other NPN in the diets; however, adaptation is lost relatively quickly (1–3 days) once NPN is removed from the diet.

            Diets low in energy and high in fiber are more commonly associated with NPN toxicosis, even in acclimated animals. Highly palatable supplements (such as liquid molasses or large protein blocks crumbled by precipitation), range cubes, or improperly maintained lick tanks may lead to consumption of lethal amounts of NPN.

Toxicity of urea

            Oral urea poisoning is basically poisoning due to excessive NH₃ production in the rumen. After ingestion, NPN undergoes hydrolysis and releases excess ammonia (NH₃) into the GI tract, which is absorbed and leads to hyperammonemia. Ruminants use NPN by converting it via the ruminal microflora to ammonia, which is then combined with carbohydrate-derived keto acids to form amino acids. Rumen microbes convert urea to microbial protein and NH₃. The microbial protein flows past the rumen, for digestion and absorption mainly in the small intestine. The NH₃ is absorbed in the rumen, reticulum and omasum. It is carried in the portal vein to the liver, where it is detoxified to urea, amino-acids, etc. Some NH₃ escapes from the liver into the general circulation.

            Normal levels of NH₃-N are 60-680 mg/L in rumen fluid and 0.8-2.5 mg/L in blood. When NH₃ levels in rumen fluid exceed 500-800 mg/L, NH₃ levels increase in the peripheral blood. Thus, after ingestion of urea, levels of NH₃ in rumen fluid and NH₃ and urea in blood increase markedly and rapidly. When NH₃-N levels exceed 6 mg/L in peripheral blood, signs of poisoning may occur in cattle.

Tolerable and toxic doses of urea

            It is difficult to define a toxic level of dietary urea for ruminants, as their ability to metabolize large amounts of dietary urea safely depends on many factors.

            These include: adaptation of the ruminal microbes; specific dietary factors and other factors. If the amount of urea entering the rumen is excessive over a short period of time, or if the ruminal environment favours very rapid conversion of urea to NH₃, levels of NH₃ in rumen fluid and NH₃ and urea in blood may reach toxic levels.

            Thus, the toxic dose of urea varies. A single oral dose of 330 mg urea/kg live weight (LW) causes increased NH₃ levels in blood of starved naive cattle. Assuming a dietary total dry matter (DM) intake (TDMI) of 3% LW/d, this is equivalent to about 1.1% urea in DM if the TDMI is eaten in a few hours. An oral dose of 200-500 mg/kg LW (about 0.67-1.67% urea in DM, if eaten quickly) can cause signs of poisoning in naive cattle. Single doses of 1000-1500 mg/kg LW are lethal (about 3.3-5.0% urea in DM, if eaten quickly).

            Assuming that the diet of dairy cows has a total crude protein content of 16% DM (thus a total N content of 2.56% DM), urea-N can be fed safely up to 0.41% dietary DM, or 0.878% urea in dietary DM. This is equivalent to circa 132 g urea/cow/day in 15 kg dietary DM. Assuming that concentrates supply 41% of the total DMI (i.e. 7 kg concentrate (6.16 kg DM) in 15 kg TDMI) and that the urea is mixed in the concentrates (fed frequently during the day), the concentrates safely could contain up to 1.9% urea. If the urea intake is increased to 280 g/day (equivalent to 4% urea in 7 kg concentrate), milk yield may fall but other signs of toxicity may be absent. Under optimal conditions, up to 600 mg urea/kg LW can be fed safely to fattening cattle but up to 1500 mg/kg LW can be eaten safely on well balanced diets, if eaten over the whole day. Assuming a TDMI by fattening cattle of 2.2% LW, urea levels of 600-1500 mg/kg LW are equivalent to 2.7-6.7% in TDMI. Given as a drench, a dose of 8-10 g urea can kill sheep, especially if they are malnourished or have liver damage.

Adaptation of rumen microbes

            If the dietary content of urea is increased gradually, healthy cattle on a good diet can tolerate up to 5% urea in the TDMI.

            Healthy sheep on a good diet can tolerate urea up to 6% in feed DM, provided it is well mixed with forage and is fed over the whole day. If, however, unadapted animals ingest a high level over a short period, the result can be acute or subacute poisoning. Tolerance is lost rapidly; animals which receive no urea for 3 days again become susceptible to poisoning.

Specific dietary factors

            A single dose of 25-45 g urea may kill sheep within 1 hour of ingestion. The presence of adequate amounts of fermentable carbohydrate in the rumen is essential for safe utilization of urea. A urea-molasses mixture can be sprayed on roughage. Sheep given a mixture of urea-molasses can tolerate up to 18 g urea/day. An ad libitum intake of up to 10% urea in molasses in ball-lick feeders is safe for sheep or cattle. In other trials, sheep tolerated up to 100 g urea/day (up to 6.7% feed DM) without clinical signs of toxicity. Feeding of lucerne increases tolerance to urea but fasting for 24 hours, starvation or a low-protein diet reduces tolerance. High-nitrate feeds increase rumen NH₃ levels and increase the risk of urea toxicity.

Other factors: Soya meal contains urease. Urea mixed with soya meal is rapidly converted to NH₃ and can be dangerous.

Individual susceptibility: Intercurrent disease, malnutrition and liver damage can increase susceptibility to urea poisoning.

Clinical Findings

            Clinical signs correlate roughly with blood NH₃-N level: ataxia occurs at levels >20 mg/L and death occurs later at levels >49 mg/L. In sheep, deaths occur at blood NH₃-N levels >32 mg/L. In both species, the pH of rumen fluid (post-mortem) is alkaline (7.1-7.9) and has high NH₃ levels. (The pH is much lower (6.4-7.1) in healthy sheep and cattle).

            The period from urea ingestion to onset of clinical signs is 20–60 min in cattle, 30–90 min in sheep, and longer in horses. Early signs include muscle tremors (especially of face and ears), exophthalmia, abdominal pain, frothy salivation, polyuria, and bruxism. Tremors progress to incoordination and weakness. Pulmonary edema leads to marked salivation, dyspnea, and gasping.

            Horses may exhibit head pressing; cattle are often agitated, hyperirritable, aggressive, and belligerent as toxicosis progresses; sheep usually appear depressed. An early sign in cattle is ruminal atony; as toxicosis progresses, ruminal tympany is usually evident, and violent struggling and bellowing, a marked jugular pulse, severe twitching, tetanic spasms, and convulsions may be seen. A related CNS disorder in cattle fed ammoniated high-quality hay, silage, molasses, and protein blocks is thought to be caused by formation of 4-methylimidazole (4-MI) through the action of NH₃ on soluble carbohydrates (reducing sugars) in these feedstuffs. Cattle fed dietary components containing 4-MI develop a syndrome known as the “bovine bonkers syndrome,” named for the wildly aberrant behavior exhibited. Signs relate to CNS effects, with stampeding, ear twitching, trembling, champing, salivating, and convulsions. Because nursing calves are affected, the toxic principle apparently is excreted in milk. Ammoniated low-quality forages do not have sufficient concentrations of reducing sugars to form 4-MI, and thus serve as a relatively safe nitrogen source for acclimated animals.

            The PCV and serum concentrations of NH₃, glucose, lactate, potassium, phosphorus, AST, ALT, and BUN usually are significantly increased.

            Another related disorder involves accidental excessive exposure of ruminants (cattle and sheep) to raw soybeans. Soybeans have high concentrations of both carbohydrates and proteins, as well as urease. Overconsumption can cause acute carbohydrate fermentation and excessive ammonia release, resulting in ammonia toxicosis and lactic acidosis. Affected animals have engorged rumens with a gray, amorphous mass inside.

            As death nears, animals become cyanotic, dyspneic, anuric, and hyperthermic, and blood pH decreases from 7.4 to 7.0. Regurgitation may occur, especially in sheep. Death related to excess NPN usually occurs within 2 hr in cattle, 4 hr in sheep, and 3–12 hr in horses. Survivors recover in 12–24 hr with no sequelae.

            The main signs of urea poisoning are due to the alkaline-corrosive effects of the high NH₃ levels in the digestive tract and other tissues and the neuro-toxic effect on the brain. Signs of poisoning arise within 10-30 minutes of ingestion of toxic doses. There are three main types of poisoning: acute (severe), subacute (moderate) and chronic (mild).

            Acute (severe) signs include salivation, severe abdominal colic, bloat, forced rapid breathing, muscle tremor, incoordination, bellowing, convulsions, violent struggling, weakness, recumbency, coma and death within 4 h of ingestion.

            Subacute (moderate) signs include abdominal colic and milder nervous and circulatory signs.

            Chronic (mild) signs include poor appetite, listlessness and lethargy.

            Shortly after consumption the urea is converted to ammonia, which gives rise to the typical symptoms seen. Animals shiver, stagger, breathe rapidly and die within a short time after violent convulsions have set in. Sheep which have taken lesser amounts of urea may survive, but sick sheep may still be dying 7 days after consumption of urea.

           

Lesions

            Carcasses of animals dying of NPN poisoning appear to bloat and decompose rapidly, with no specific characteristic lesions.

            Gross brain lesions are not usually reported in NPN-induced ammonia toxicosis, but histopathologic lesions may include neuronal degeneration, spongy degeneration of the neuropil, and congestion and hemorrhage in the pia mater.

            Frequently, pulmonary edema, congestion, and petechial hemorrhages may be seen. Mild bronchitis and catarrhal gastroenteritis are often reported.

            Regurgitated and inhaled rumen contents are commonly found in the trachea and bronchi, especially in sheep.

            The odor of NH₃ may or may not be apparent in ingesta from a freshly opened rumen or cecum.

            A ruminal or cecal pH ≥7.5 from a recently dead animal is highly suggestive of NPN poisoning. The ruminal pH remains stable for several hours after death under most circumstances but continues to rise in NPN toxicosis.

            At post-mortem, haemorrhages and watery swelling of the intestines, and froth and water in the lungs are the main lesions seen, Haemorrhages may occur elsewhere in the carcass.

Diagnosis

            Ammonia or NPN poisoning is suggested by signs, lesions, history of acute illness, and dietary exposure.

            Exposure to excess NPN may be evaluated through laboratory analysis for the ammonia nitrogen (NH₃-N) in both antemortem and postmortem specimens and for urea or other NPN in suspected feeds and other dietary sources.

            Specimens for NH₃-N analysis include ruminal-reticular fluid, serum, whole blood, and urine.

            All specimens should be frozen immediately after collection and thawed only for analysis; alternatively, ruminal-reticular fluid may be preserved with a few drops of saturated mercuric chloride solution added to each 100 mL of specimen.

            Animals dead more than a few hours in hot ambient temperatures or 12 hr in moderate climates probably have undergone too much autolysis to be of diagnostic value.

            The amount of urea or the equivalent NPN in biologic specimens is meaningless; however, urea and NPN should be determined in representative feeds and other dietary sources. Values for urea and NPN in feed permit calculation of the protein equivalent (1 part protein = 0.36 parts urea; 1 part urea = 2.92 parts protein) in feed as well as the total estimated dose of NPN ingested.

NH₃-N concentrations of ≥2 mg/100 mL in blood, serum, or vitreous humor indicate excess NPN exposure. Clinical signs usually appear at ~1 mg/100 mL. The concentration of NH₃-N in ruminal-reticular fluid is >80 mg/100 mL in most cases of NPN poisoning and may be >200 mg/100 mL. Acclimated ruminants fed diets high in legume hay, soybean meal, cottonseed meal, linseed meal, fish meal, or milk byproducts may have NH₃-N concentrations in rumen fluid approaching 60 mg/100 mL with no apparent toxicity. The pH of ruminal-reticular fluid should also be determined; a pH of 7.5–8 (at time of death) is indicative of NPN toxicity.

            Differential diagnoses include poisonings by nitrate/nitrite, cyanide, organophosphate/carbamate pesticides, raw soybean overload, 4-methylimidazole, lead, chlorinated hydrocarbon pesticides, and toxic gases (carbon monoxide, hydrogen sulfide, nitrogen dioxide); acute infectious diseases; and noninfectious diseases such as encephalopathies (eg, leukoencephalomalacia, hepatic encephalopathy, polioencephalomalacia), enterotoxemia or rumen autointoxication, protein engorgement, grain engorgement, ruminal tympany, and pulmonary adenomatosis. Nutritional and metabolic disorders related to hypocalcemia, hypomagnesemia, and other elemental aberrations should also be considered.

Treatment

            Examination and treatment may be difficult because of sudden and violent behavior.           Animals that are recumbent and moribund usually do not respond favorably to treatment.

            Treatment aims to reduce or neutralise ruminal and blood NH₃ level and to treat the irritation in the digestive tract, liver, kidney and other tissues, caused by the alkaline-corrosive effect of NH₃. The only reliable treatment is to empty the rumen (by prompt rumenotomy or by large-bore stomach tube plus weak-acid lavage). Weak acids act as chemical antidotes to alkaline poisons. A weak acid will neutralise the ammonia in the rumen. The most practical antidote for the purpose is ordinary vinegar (acetic acid) and about half a bottle per sheep may be given. If possible, affected animals should be treated by ruminal infusion of 5% acetic acid (vinegar, 0.5–2 L in sheep and goats and 2–8 L in cattle). The dose is 3-5 l of table vinegar or 2% acetic acid by stomach tube to adult cattle; 0.5-1.0 l to sheep. Repeated doses may be needed, as signs may recur after 30 minutes. Ruminal-reticular fluid specimens for analysis should be taken before acetic acid therapy. Acetic acid lowers rumen pH and prevents further absorption of NH₃ by converting uncharged NH₃ to the charged ammonium ion (NH₄⁺); administration may have to be repeated if affected animals again show clinical signs. Acetic acid inactivates existing NH₃ in the GI tract and rapidly forms ammonium acetate, which can be used by rumen microflora but does not release NH₃.

            Concomitant infusion of iced (0–4°C) water (up to 40 L in adult cattle, proportionally less in sheep and goats) is also recommended. Cold water lowers the rumen temperature and dilutes the reacting media, which slows urease activity.

            In severely affected valuable animals, removed rumen contents should be replaced with a hay slurry, and a transfer of some rumen contents from a healthy animal may serve as an inoculum to restore normal function.

            Ruminal tympany should be corrected if indicated, and a trocar may be installed to prevent recurrence.

            Supportive therapy is indicated and includes IV isotonic saline solutions to correct dehydration, and IV calcium gluconate and magnesium solutions IV to relieve tetanic seizures. Convulsions may also be controlled with sodium pentobarbital or other injectable anesthestic agents.

            Demulcents, sedatives and stimulants may be used to control specific clinical signs. Treatment often fails.

Prevention and Control

            Once urea poisoning is suspected, the source should be withdrawn immediately and veterinary help should be sought.  

            To prevent poisoning, great care must be taken in making up the lick. Only hard blocks protected from rain should be available. Sheep should gradually become accustomed to taking the full amount and should not be put onto the lick when salt hungry.

            Because of the inherent dangers, valuable animals should not be given urea, but rather a safer source of protein. One such source is biuret, which is non-poisonous even when eaten far in excess of recommended strength. Alternately these animals must be given vegetable or animal meals, such as peanut oil cake meal or carcass meal, to supply the necessary protein in the ration.

            Urea should not be fed at a rate exceeding 2%–3% of the concentrate or grain portion of ruminant diets and should be limited to ≤1% of the total diet.

            Additionally, NPN should constitute no more than one-third of the total nitrogen in the ruminant diet.

            Once the decision is made to feed NPN, animals must be slowly adapted to, and maintained on, a consistent dietary NPN content with no significant deviation; cows fed range cubes with NPN must receive the cubes daily with no interruptions.

            Temporary absences of NPN from the diet should be avoided at all costs.      Overconsumption of palatable liquid supplements can be controlled by the addition of phosphoric acid; 1% phosphorus from phosphoric acid should restrict consumption of liquid supplement to ~2 lb/animal/day. Although properly adapted adult cattle can tolerate urea at a rate of up to 1 g/kg body wt/day, a safer feeding rate is no more than half that amount.

Urea should not be given to fasting or malnourished animals, or those with damaged livers. If urea is added to ruminant diets, it should be introduced gradually and increased to a safe level. Concentrate feeds with 3% urea or more in the DM should be regarded as high-urea feeds. Such feeds should be fed in restricted amounts, preferably spread over 12 hours or more of each day.

             Mixing urea with molasses, fodder/sugar beet or good quality silage reduces the risk of poisoning. Urea mixing in the feed should be thorough.

            Fertilizers and feeds containing urea should be stored, used and disposed of properly. Spillage should be cleaned up or dispersed as it arises.

            Pasture should be rested for an adequate time before grazing or cutting after N-application.