Download 1. Objectives of the Presentation 2. General Key Points: 3. Key

Title: Urea and Nitrate Poisoning of Ruminants
Jeffery O. Hall, D.V.M., Ph.D., Diplomat A.B.V.T.
Utah Veterinary Diagnostic Laboratory, Utah State University.
1. Objectives of the Presentation
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Provide basic knowledge of urea poisoning in ruminants.
Provide basic knowledge of nitrate poisoning in ruminants
Provide clinical points for diagnosis of urea and nitrate poisoning cases.
Provide diagnostic criteria for evaluation of urea and nitrate poisoning cases.
Provide protocols for treatment of urea and nitrate poisoning cases.
2. General Key Points:
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Urea poisoning and nitrate poisoning are mutually exclusive.
Urea poisoning is associated with rumen microbial metabolism of urea to ammonia at rates too
fast for the rumen microbes to incorporate it into microbial proteins. This results in systemic
ammonia intoxication.
Nitrate poisoning is associated with the rumen microbial reduction of nitrate to nitrite. Nitrite that
is absorbed converts hemoglobin to methemoglobin, which cannot transport oxygen. This results
in poisoning due to tissue hypoxia.
3. Key Clinical Diagnostic Points:
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Urea Poisoniong:
 Clinical disease is associated with excessive urea in feed, feed supplements, or ingestion of
urea based fertilizers.
 Clinical course is relatively rapid with onset of clinical signs being 20 minutes to 4 hours post
ingestion of a toxic dose. Death often follows within 1-3 hours of the onset of clinical signs.
 Clinical signs include excitability, muscle tremors, incoordination, vocalization, dyspnea,
tachypnea, frequent urination, frequent defecation, bloat, rumen atony, cyanosis,
recumbency, terminal convulsions, and death.
 The only clinical pathologic abnormalities are of systemic metabolic acidosis, rumen
alkalosis, increased BUN, hemoconcentration, hyperkalemia, hyperphosphatemia, and
increased AST.
 Gross necropsy and histopathology findings are of pulmonary edema, systemic congestion,
petechial hemorrhages, and occasionally a catarrhal gastroenteritis.
 Testing of rumen content, serum, whole blood, vitreous fluid, and CNS fluid for ammonia can
be beneficial, but the samples must be collected and immediately frozen until analyzed.
Post-mortem samples from animals that have been dead more that 4-12 hours (dependent
on the environmental temperature) are of little diagnostic benefit.
 Testing of the diet/diet components for urea or other non-protein nitrogen sources is
recommended, but the urea may not be uniformly mixed in the diet.
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Nitrate Poisoning:
 Clinical disease is associated with ingestion of excessive nitrate in forages or nitrate based
fertilizers.
 Clinical course is relatively rapid with onset of clinical signs being 1 to 4 hours post ingestion
of a toxic dose. Death often follows within 1-3 hours of the onset of clinical signs. With
nitrate fertilizer ingestion, gastrointestinal irritation can also occur and result in diarrhea.
 Clinical signs are of weakness, exercise intolerance, ataxia, tachypnea, dyspnea,
tachycardia, muscle tremors, dark-congested mucous membranes, recumbency, and death.
Abortions can occur in surviving animals several days later.
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The only clinical pathologic abnormalities are of low blood oxygen saturation, chocolate
brown blood, and increased methemoglobin.
Gross necropsy and histopathology findings are of gastrointestional congestion and/or
irritation in some animals, but no abnormalities are often identified. The darkened tissues as
a result of the methemoglobin will only be present for a very short period post-mortem.
Testing for nitrate content in serum, plasma, or blood in live animals, as well as aqueous
humor of dead animals can be used to diagnose nitrate poisoning.
Quantification of nitrate in the plants, hay, diet, or ingested materials is recommended.
4. Key Etiologic and Pathophysiologic Points:
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Urea Poisoning:
 Urea is added to ruminant diets as a non-protein nitrogen source for microbial protein
synthesis.
 Urea is hydrolyzed to ammonia by microbial urease enzymes.
 Ammonia is the actual toxin that affects ruminants systemically.
 Rumen adaptation to increased dietary urea develops when urea is slowly increased in the
diet.
 Higher carbohydrate content of the diet aids in the microbial utilization of the released
ammonia. Thus, poor dietary carbohydrate content increases the potential for urea
poisoning.
 Higher pH (> 7.5) promotes the hydrolysis of urea and ammonia absorption across the rumen
wall. Conversely, acidic pH (< 7) slows the hydrolysis of urea and results in ammonium ions
which do not readily cross the rumen wall.
 The liver converts absorbed ammonia into urea until this detoxification mechanism is
saturated.
 Clinical signs develop when blood or serum ammonia reaches 1 mg/dl.
 Systemic ammonia inhibits the citric acid cycle resulting in increased lactate and decreased
ATP.
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Nitrate Poisoning:
 All plants contain nitrate, but certain plant species accumulate high concentrations.
 Drought stress, high rates of fertilizer application, herbicide application, and environmental
conditions that inhibit photosynthesis predispose to increasing nitrate content of plants.
 Dietary nitrate content of < 0.5% is generally considered safe for ruminants.
 Dietary nitrate content of 0.5 to 1% has risk of intoxication.
 Dietary nitrate content of >1% is frequently associated with nitrate poisoning. But ruminants
can be acclimated to increased dietary nitrate, if it is increased slowly.
 Nitrate is reduced to nitrite in the rumen by microbial conversion.
 Nitrite is the actual toxin that affects the animal systemically.
 Nitrite reacts with hemoglobin causing a conversion to methemoglobin.
 Methemoglobin cannot transport oxygen to the tissues, which results in tissue hypoxia.
 Clinical signs develop when methemoglobin reaches 30-40%.
5: Key Therapeutic Points:
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Urea Poisoning:
 Slowing the urea hydrolysis is key in treatment.
 Rumen infusion of cold water (30-40 L in cattle) slows the hydrolysis of urea.
 Rumen infusion of 5% acetic acid (2-6 L in cattle), vinegar, slows the hydrolysis of urea and
converts ammonia to the ammonium ion which is not readily absorbed across the rumen wall.
 Treatment may be repeated as necessary if clinical signs reoccur.
 Recovery ranges from 8 to 24 hours.
 A post-recovery probiotic rumen inoculation may enhance the gain and productivity of urea
poisoned animals.
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Nitrate Poisoning:
 The stress of handling animals with severe tissue hypoxia can result in death.
 The first specific treatment for nitrate poisoning is removal of the nitrate source.
 Specific treatment is with Methylene blue in physiologic saline at 5 to 15 mg/kg BW
intravenously. Lower doses may be repeated if no clinical improvement is observed.
 Methylene blue has a LONG WITHDRAWL TIME (180 days).
7. Key Prognostic Points:
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Urea Poisoning:
 Once recumbent, prognosis is poor.
 Once clinical signs abate, by 8 to 24 hours, no long term effects are expected.
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Nitrate Poisoning:
 The degree of tissue hypoxia is not directly assessable and the amount of ingestion is
generally not known. So, outcome is often quite uncertain.
 Animals that live beyond 24 hours are likely to fully recover.
 Abortions can occur several days after recovery from the initial acute poisoning. This is likely
due to fetal hypoxia during the maternal hypoxic state.
8. Overview of the Issue
Urea and nitrate poisonings are both toxicoses from nitrogenous compounds, but are completely
unrelated as to mechanism of effects and occurrence. Both materials are generally in the diet, as a feed
additive for urea and as a natural plant component for nitrate. Additionally, both materials can be
components of fertilizers, which are occasionally ingested by ruminants.
Urea poisoning is associated with the hydrolysis of the urea to ammonia, which is the actual mechanistic
toxin. When absorbed at rates that surpass the ability of the liver to remove and detoxify the ammonia,
systemic poisoning occurs. Ammonia inhibits the citric acid cycle, causes hyperkalemia, and metabolic
acidosis as the mechanisms of clinical effect. This results in a common presentation of neurologic clinical
signs.
Urea can be toxic in ruminants at 0.3 to 0.5 gm/kg BW and is often lethal at 1.0 to 1.5 gm/kg BW. But,
ruminants can ingest normally toxic doses without toxic effects when acclimated to increasing dietary
urea content over time. This acclimation process allows the rumen microbes to adapt to increasing
ammonia incorporation. It is necessary that dietary carbohydrates are adequate for optimum microbial
adaptation.
Treatment of urea toxicosis involves limiting further release of ammonia from the rumen. The urease
enzymes have the highest activity when at ph of >7.5 and at physiologic temperatures. Thus,
administration of 2 to 6 liters of 5% acetic acid (vinegar) and 30 to 40 L of cold water will slow the
hydrolysis of the urea. In addition, lower pH results in the formation of an ammonium ion from ammonia
which does not cross the rumen wall efficiently. This treatment may be repeated as necessary.
Dietary concentration of nitrate > 1% is commonly associated with nitrate poisoning. In contrast, dietary
concentrations of less than 0.5% are considered safe for ruminants.
Nitrate poisoning is associated with the ruminal reduction of ingested nitrate to nitrite. Nitrite is absorbed
from the rumen and reacts with hemoglobin to produce methemoglobin. As methemoglobin cannot carry
oxygen, tissue hypoxia develops. As neurologic tissues are sensitive to low oxygen tension, neurologic
clinical signs are commonly encountered.
Treatment of nitrate poisoning involves conversion of methemoglobin back to hemoglobin. This is
accomplished with methylene blue. Methylene blue is administered IV as a 1% solution in physiologic
saline at a rate of 5 to 15 mg/kg BW. With severe cases, repeat treatment with the lower dose may be
requires to produce clinical improvement.
In animals that do not succumb, complete clinical recovery from urea and nitrate poisoning generally
occurs by 24 hours or sooner.
9. Additional Detail
Dose of urea is critical in evaluating potential toxic effects. To calculate the amount of urea in a ration,
divide the percent protein equivalents from urea in the feed by 2.92. This provides the percent of urea in
the feed, which is multiplied by the amount of feed intake per animal to get the total urea per animal.
When this value is divided by the animal weight, one has the exposure rate.
Example: 20 percent crude protein feed with 10% protein equivalent from nonprotein nitrogen
10/2.92 = 3.42%
If a cow were to eat 10 Kg of the diet
3.42% X 10,000 gm = 342 gm
If the cow weighed 450 kg
342 gm/450 kg = 0.76 gm/kg
Thus, this cow would be eating a toxic dose if not acclimated to a urea containing diet. In comparison,
ingestion of only 4 kg of the diet would result in only 0.3 gm/kg BW.
Table 1. Common nitrate accumulating plants.
Amaranthus spp.
Amskinckia spp.
Ambrosia spp.
Avena sativa
Beta vulgaris
Brassica spp.
Chenopodium spp
Cirsium arvense
Conium maculatum
Convolvulus spp.
Cucumis sativus
Cucurbita maxima
Datura spp.
Daucus carota
Eleusine indica
Eupatorium purpureum
Glycine max
Gnaphalium purpureum
Helianthus annuus
Hordeum vulgare
Ipomoea batatas
Kochia spp.
Lactuca sativa
Lactuca serriola
Linum spp.
Malva parviflora
Medicago sativa
Melilotus officinalis
Panicum capillare
Polygonum spp.
Raphanus sativus
Rumex spp.
Salsola iberica
Secale cereale
Solanum spp.
Solidago spp.
Sorghum spp.
Stellaria media
Tribulus terrestris
Triticum sativum
Urtica dioica
Verbesina encelioides
Zea Mays
pigweed
tarweed
ragweed
oats
beets
rutabaga, rape, broccoli, turnip
lamb’s quarters
Canada thistle
poison hemlock
bindweed
cucumber
squash
Jimsonweed
wild carrot, Queen Anne’s lace
goose grass
thoroughwort
soybean
purple cudweed
sunflower
barley
sweet potato
firebush
lettuce
prickly lettuce
flax
small mallow
alfalfa
sweet clover
panic grass
smartweed
radish
dock
Russian thistle
rye
nightshades, potato
goldenrods
Johnson grass, milo, sudan grass
chickweed
puncture vine
wheat
stinging nettle
golden crownbeard
corn
10. Key Drugs, Dosages and Indications
Key Drug
Methylene blue
1%*
Drug Class
Antidote
Dose Range
5 to 15 mg/kg
BW
Frequency
As clinically
indicated
Route
IV
Indications
Methemoglobinemia
From nitrate poisoning
* Withdrawal time of 180 days in food animals.
11. Summary
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Nitrate and urea are both nitrogenous toxicants that are typically ingested in dietary constituents,
but can be ingested as fertilizer components. Both toxicants results in neurologic clinical
manifestations, but by drastically different means. Urea results in ammonia toxicosis and nitrate
results in nitrate induced methemoglobinemia. Urea poisoning is treated by acidification of the
rumen and cold water to slow the breakdown of urea to ammonia and limit the ammonia
absorption. Nitrate poisoning is treated by conversion of the methemoglobin back to hemoglobin
by use of methylene blue. In animals that do not die, full recovery from either poisoning is
generally evident by less than 24 hours post intoxication.
12. References/Suggested Reading
Casteel SW and Evans TJ: Feed-Associated Toxicants: Nitrate. In: Clinical Veterinary Toxicology by
Konnie Plumlee. Mosby. 2004; 127-130.
Lieske C and Volmer PA: Feed-Associated Toxicants: Nonprotein Nitrogen. In: Clinical Veterinary
Toxicology by Konnie Plumlee. Mosby. 2004; 130-132.
Osweiler et al: Nitrates, Nitrites and Related Problems. In: Clinical and Diagnostic Veterinary
Toxicology. 3rd Edition. Kendall/Hunt. 1985; 460-467.
Osweiler et al: Urea and Nonprotein Nitrogen. In: Clinical and Diagnostic Veterinary Toxicology. 3 rd
Edition. Kendall/Hunt. 1985; 160-166.
Nicholson SS. Nitrate and nitrite accumulating plants. In: Veterinary Toxicology Basic and Clinical
principles 2nd ed. by Ramesh Gupta (ed). Elsevier Publishing. 2012: 1117-1120.
Cope R. Nonprotein nitrogen (urea) and hyper ammonemia. . In: Veterinary Toxicology Basic and
Clinical principles, 2nd ed. by Ramesh Gupta (ed). Elsevier Publishing. 20121300-1302.