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Nonprotein Nitrogen Poisoning in Animals

(Ammonia Toxicosis, Urea Poisoning)

By

Larry J. Thompson

, DVM, PhD, DABVT, American Board of Veterinary Toxicology

Last full review/revision Apr 2021 | Content last modified Jul 2021

Non protein nitrogen (NPN) poisoning (toxicosis) results from excessive consumption of sources of NPN or urea. It is acute and often rapidly fatal, with clinical signs including muscle tremors, abdominal pain, incoordination, respiratory distress, and recumbency, then death. Diagnosis can be made by analysis of postmortem samples for ammonia content and of suspected sources for non protein nitrogen content; ruminal pH > 7.5 is supportive of the diagnosis. Treatment includes removal of suspected source materials, ruminal infusion of acetic acid and cold water, as well as supportive therapy.

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.

Etiology of Nonprotein Nitrogen Poisoning in Animals

Ruminants use nonprotein nitrogen (NPN) by converting it via 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 (NH3), 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 currently 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. Most sources of NPN are provided to ruminants by means of direct addition of dry supplements to a complete mixed or blended diet, via free-choice access to NPN-containing range blocks or cubes, or as supplements in lick tank systems combined with molasses.

Ammonia or NPN poisoning has been a common sequela of an abrupt change to urea or other NPN in the diet when only natural protein was previously fed. As such, animals should be gradually acclimated to NPN so that rumen microflora can adjust. Furthermore, animals on farms may exposed to liquid fertilizers or ingest dry granular fertilizers containing ammonium salts or urea.

Ruminants are most sensitive to developing NPN toxicosis because urease is normally present in the rumen after 50 days of age. Dietary exposure of unacclimated ruminants to 0.3–0.5 g/kg of urea 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 monogastric species and dosages ≥4 g/kg can be lethal. Ammonium salts at dosages of 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 (eg, silver gulls) reportedly have developed toxicosis after consuming water contaminated with urea fertilizers.

Ruminants may require days to weeks for total adaptation before rumen microflora can utilize gradually increasing amounts of dietary urea or other NPN; however, such 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), 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) via the action of NH3 on soluble carbohydrates (reducing sugars) in these feedstuffs. Cattle fed dietary components containing 4-MI develop a syndrome known as “bovine bonkers syndrome,” named for the wildly aberrant behavior exhibited. Clinical signs relate to CNS effects, with stampeding, ear twitching, trembling, champing, salivating, and convulsions. Because nursing calves can be affected, the toxic component is apparently 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.

Clinical Findings for Nonprotein Nitrogen Poisoning in Animals

The period from urea ingestion to onset of clinical signs of NPN poisoning is generally 20–60 minutes in cattle, 30–90 minutes in sheep, and longer in horses. Early clinical signs include muscle tremors (especially of the face and ears), 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 on auscultation, 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, BUN, and activities of AST and ALT are usually considerably increased.

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

Lesions

Carcasses of animals that died due to NPN toxicosis appear to bloat and decompose rapidly, with no specific characteristic lesions. Gross brain lesions are not usually reported in NPN toxicosis; however, 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 present. 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 of a freshly opened rumen or cecum at necropsy. A ruminal or cecal pH ≥7.5 in 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 increase in cases of NPN toxicosis.

Diagnosis of Nonprotein Nitrogen Poisoning in Animals

  • Based on history and clinical signs, with testing of NPN concentration in postmortem samples

  • Ruminal or cecal pH > 7.5 supports a diagnosis of NPN toxicosis

A diagnosis of NPN poisoning (ammonia toxicosis) is suggested by a history of dietary exposure, clinical signs including those of acute illness, and representative gross and histologic lesions. Exposure to excess NPN may be determined via laboratory analysis for ammonia nitrogen (NH3-N) concentration in both antemortem and postmortem specimens and for presence of urea or other types of 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 at the time of analysis; alternatively, ruminal-reticular fluid may be preserved with a few drops of saturated mercuric chloride solution added per 100 mL sample. Animals dead more than a few hours in hot ambient temperatures or 12 or more hours in moderate climates typically undergo too much autolysis to be of diagnostic value for necropsy examination.

The amount of urea or the equivalent NPN concentration in biologic specimens is difficult to interpret; however, urea and NPN concentrations should be determined in representative samples of 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 concentrations of ~1 mg/100 mL. The concentration of NH3-N in ruminal-reticular fluid is >80 mg/100 mL in most cases of NPN toxicosis and levels 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 signs of toxicity. The pH of ruminal-reticular fluid should also be determined; a pH of 7.5–8 (at time of death) is supportive of a diagnosis of NPN toxicosis.

Differential diagnoses include toxicoses due to ingestion of nitrate/nitrite, cyanide, organophosphate/carbamate pesticides, excess raw soybeans, 4-methylimidazole, lead, chlorinated hydrocarbon pesticides and toxic gases (carbon monoxide, hydrogen sulfide, nitrogen dioxide). Other differentials should include acute infectious 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 should also be considered.

Treatment of Nonprotein Nitrogen Poisoning in Animals

  • Removal of the suspected source

  • Ruminal infusion of 5% acetic acid and water after collection of ruminal-reticular fluid specimens

  • Supportive care

Examination and treatment for NPN poisoning 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 means of 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 obtained 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 clinical signs recur. Cold water decreases the rumen temperature and dilutes the reacting rumen 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 help restore normal function. Supportive therapy includes IV fluid therapy (isotonic saline solution) to correct dehydration and IV administration of calcium gluconate and magnesium solutions to relieve tetanic seizures. Convulsions may also be controlled with sodium pentobarbital or other injectable anesthetic agents.

Prevention and Control of Nonprotein Nitrogen Poisoning in Animals

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 notable deviations. For example, cows fed range cubes with NPN must receive the cubes daily with no interruptions. Overconsumption of palatable liquid supplements can be controlled via the addition of phosphoric acid; 1% phosphorus from phosphoric acid should restrict consumption of liquid supplement to ~2 lb/animal per day. Although properly adapted adult cattle can tolerate urea at a rate of up to 1 g/kg body weight per day, a safer feeding rate does not exceed half this amount.

Key Points

  • NPN compounds (eg, feed additives, fertilizers) release ammonia into the gastrointestinal tract, leading to acute toxicosis if the amount consumed is too high.

  • Ruminants are more susceptible than monogastric animals. Clinical signs include muscle tremors, abdominal pain, incoordination, respiratory distress, recumbency, and death.

  • Diagnosis is made on the basis of testing postmortem specimens for ammonia concentration and feed to detect levels of urea or sources of NPN. Rumen pH >7.5 is supportive of a diagnosis of NPN toxicosis.

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