* This is the Veterinary Version. *
Overview of Nonprotein Nitrogen Poisoning
Poisoning by ingestion of excess urea or other sources of nonprotein nitrogen (NPN) is usually acute, rapidly progressive, and highly fatal. NPN is any source of nitrogen not present in a polypeptide (precipitable protein) form. Sources of NPN have different toxicities in various species, but mature ruminants are affected most commonly. 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. The most common sources of NPN in feeds are urea, urea phosphate, ammonia (anhydrous), and salts such as monoammonium and diammonium phosphate. 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. 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.
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.
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.
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. Affected cattle with belligerent aberrant behavior may have produced some 4-MI in vivo through reaction of excessive NH3, released from NPN, with carbohydrates and reducing sugars in the rumen. The PCV and serum concentrations of NH3, glucose, lactate, potassium, phosphorus, AST, ALT, and BUN usually are significantly increased.
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.
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.
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.
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.
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). Ruminal-reticular fluid specimens for analysis should be taken before acetic acid therapy. Concomitant infusion of iced (0–4°C) water (up to 40 L in adult cattle, proportionally less in sheep and goats) is also recommended. 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. 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 to relieve tetanic seizures. Convulsions may also be controlled with sodium pentobarbital or other injectable anesthestic agents.
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.
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* This is the Veterinary Version. *