How to treat nitrate toxicity in Cows

Treatment of Nitrate and Nitrite toxicity

Sources of nitrate (NO3-) and nitrite (NO2-): 

Exogenous sources of NO2- are much less common than those of NO3-. Plants usually contain little or no NO2-. NO3- in green cereal hays (especially oat hay or corn stalks) may be converted to NO2- if the hay is hot and wet and exposed to air, but long exposure converts NO2- to NH3, some of which may evaporate. The most common source of NO2- 
for cattle and sheep is via ingestion of high levels of NO3- in plants. Reduction of NO3- to NO2- occurs in the rumen.

The main sources of NO3- include:
(a) NO3--accumulating plants 
(b) grass (especially ryegrass) grass cubes, silage, cereal crops, hay.

Plant nitrates: NO3- absorbed from the soil by plant roots is converted to NH3-N by the action of plant NO3- reductase enzymes. These enzymes are activated by light and are inhibited in darkness and in cloudy or foggy weather. Plants convert most of their NO3- to amino acids, via NH3-N; plant proteins are formed from the amino acids.

Nitrate and nitrite toxicity

Root uptake of excessive amounts of NO3-, or inhibition of the NO3- reductase system, allows high NO3- levels to accumulate in plants. High NO3- levels can accumulate in young plants after heavy N-fertilisation; during and after periods of drought; in cloudy or humid weather and after use of some herbicides (2-4-D). Young rapidly-growing plants usually contain higher levels than mature plants. Within the plant, root and stem usually have more NO3- than leaves and seeds and older leaves have more than younger leaves.

NO3- accumulation in plants is said to be more likely when plant N exceeds 3% DM. If so, we should expect high NO3- levels in average Irish herbage, as its average N level exceeds 3%. This is uncommon, however.

(a) Nitrate-accumulating plants: Toxic levels of NO3- (0.9-12.0% DM) may occur in Brassicas and Cruciferae (cabbage, sprouts, rape, kale; freshly pulled turnips, swedes) and their tops; lettuce; other root crops (fodder- and sugar- beets, mangels, potatoes) and their tops. NO3- levels in root DM are usually higher than in the tops (stems and leaves). Dozens of weed species, including docks (Rumex), thistles (Carduus, Silybum), red-root (Amaranthus), capeweed (Arctotheca) and chickweed can concentrate NO3-. Beet tops and weeds may accumulate very high NO3- levels after use of the herbicide 2-4-D. Occasionally green soya, flax, alfalfa and millet can contain high levels.

(b) Grass (especially ryegrass), grass cubes, silage, cereal crops, hay: 
High NO3- in herbage can follow heavy application of human sewage sludge, animal slurry, commercial N-fertilisers, or combinations of these. At high levels of N-application (>400 kg N/ha/year), 20% of grass samples in Holland had >0.75% NO3- in DM. After heavy N-usage, herbage may accumulate up to 6% NO3- in the DM, especially in periods of rapid growth following drought. NO3- levels of 6.6-12.5% DM were reported in toxic ryegrass-clover herbage (which also contained some capeweed and red-root plants) in Australia. 
High NO3- levels are more likely to arise in new leys than in old permanent pasture.
Confirmed cases of poisoning in animals whose only NO3- source was grazed herbage are rare, but have occurred .When grazed in situ, fresh grass usually is less dangerous than conserved grass (grass cubes, hay, silage or mown grass fed fresh or wilted indoors). Poisoning is more common after ingestion of heavily fertilised, fresh grass indoors (zero-grazing), or of dried hay, grass-cubes or silage harvested too soon after application of high levels of N-fertilisers. This is because DM intake/hour from conserved grass is more rapid than from fresh grass.

Feeding dried grass cubes containing 2.5-3.1% NO3- in DM produced clinical signs of poisoning and death in cattle in Northern Ireland within days (Purcell et al 1971). Grass cubes with 0.70 % NO3- in the DM produced no clinical signs but other authors suggest that levels >0.7% DM in grass cubes can be toxic.
Ensiling of grass may reduce the NO3- level in silage DM by 40-60%: some NO3- escapes in the effluent and some is destroyed normal fermentation. The intake of silage DM is usually spread over many hours each day and seldom exceeds 1.5-2.0% LW/day. Thus, most grass silage is safe. However, if levels of NO3- are very high in ensiled grass, silage effluent may be toxic and NO3- levels in the silage DM occasionally may be >2% DM and may be toxic.
Cereal crops, cereal stalks and green cereal hays (barley, rye, wheat, oats, maize, sorghum, Sudan grass) and grass hay may contain high NO3- levels and have been toxic to cattle and sheep. NO3- levels up to 10% DM may arise in toxic hay.

NO3- levels in plant samples vary widely (up to 10-fold or more) within and between fields. Uneven N-application (concentrating N application in some areas) and plant regrowth in dung-pad and urine-contaminated patches, explain some of the variation. Harvesting of herbage as large bales of hay or silage can lead to toxic NO3- levels in individual bales, while others can be safe. Thus, the mean NO3- level in a few samples of forage can be misleading. When investigating a suspected outbreak of NO3- poisoning from forage, many samples (representing individual bales or parts of the field) should be analysed individually.

(c) fertilizers containing ammonium salts, urea, NO3- or NO2-

(d) Cattle, sheep and pigs may be poisoned by contaminated deep bore well-water; open water-storage tanks; tanks containing run-off water from roofs or gutters containing rotting organic matter or condensation water. Such water may contain 122-10000 mg NO3-/l. High NO3- levels in swill, brines or preserved whey can be converted to NO2- by gentle cooking, as in preparation of swill for pigs.

(e) Monensin, at recommended levels, may precipitate NO2- poisoning in cattle fed rations high in NO3- (Malone 1978). This may be due to a rapid shift in rumen microbial population, favouring NO2--producing bacteria

(f) high NO3- levels in certain oils

(g) discarded dynamite (containing ammonium nitrate)

Toxicity of nitrates and nitrites: NO3- and NO2- are linked closely as causes of poisoning. Weight for weight, NO2- are about 5-6 times more toxic than NO3- to ruminants. Ruminal microbes can reduce NO3- to NO2-, an intermediate step in the conversion of NO3- to NH3. Toxicity is less likely if rumen NO3- is not reduced to NO2-, or if complete reduction to NH3 is rapid. Sheep are less prone to poisoning than cattle. Restriction of water intake increases the risk of toxicity: the greater the water intake, the faster the elimination of NO3-/NO2- in urine.

High NO3- intake is associated with high levels of NH3 in rumen fluid and blood. NO3- may cause gastroenteritis but their main effect is to act as a source of NO2-, which may be formed before or after ingestion of NO3-.

When NO2- is absorbed from the digestive tract into the blood, it converts the red pigment haemoglobin (Hb) to a dark pigment (met-Hb). Met-Hb can not carry oxygen to the tissues and a syndrome of respiratory distress, due to anaemic anoxia, follows. At a conversion rate of Hb to met-Hb of 20%, the colour of blood may be a light or grey-brown; at 50% it may be brown-black; at 80% it is usually dark brown to black.

At 10-20% conversion to met-Hb, the animals may show no visible signs of poisoning or only mild or chronic signs. Severe signs may occur when met-Hb exceeds 50%. Death due to oxygen-starvation of the brain and other vital tissues can occur when conversion exceeds 80%.
High levels of NO2- in blood also cause vasodilation, drop in blood pressure and circulatory shock.

Tolerable and toxic doses of nitrite and nitrate: These are difficult to define, as there is wide variation in the amount of met-Hb produced by the same dose of NO3-. This variation depends on whether the NO3- dose is ingested in a short time (0-4 hours) or over a long time (12-24 hours); on the degree of adaptation of the rumen microbes (the rate at which they reduce NO3- to NO2- or to NH3) and other factors. High-energy diets (containing rapidly fermentable carbohydrate) decrease rumen reduction of NO3- to NO2-. Cattle on a high-energy diet may be able to tolerate up to 50% conversion of Hb to met-Hb with no ill effect.

Intercurrent disease, poor liver function, cold stress (by increasing the energy requirement), fasting or a low-energy diet, etc increases susceptibility to NO3- and NO2- poisoning, so that at 20-50% conversion of Hb to met-Hb, signs of respiratory and circulatory stress may arise.

The minimum lethal dose of NO2- (in one dose) for cattle and sheep was 67-110 mg/kg LW This translates to 40-66 g NO2- in a single dose for a 600 kg cow.

If the NO3- is eaten in small amounts over a 12-24 hour period, healthy animals adapted to NO3- and on a high-energy diet can ingest large quantities with minimal or no adverse effects. Similar or smaller daily doses, if eaten in a short period, can kill.

As a single dose, the minimum lethal dose (MLD) of NO3- for cattle is 370-550 mg/kg LW. This translates to a single dose of 222-330 g NO3- for a cow of 600 kg. If eaten over 4 hours, 320 mg NO3-/kg LW may poison calves but more than 3 times that amount may be tolerated if fed over 24 hours. NO3- at 610-900 mg/kg LW was lethal in cattle, sheep and also. These data suggest that 122-900 mg NO3-/kg LW may be lethal for cattle. Assuming a TDMI of 3% LW/d, these doses would equate with 0.4-3.0% NO3- (or more) in feed DM. If the daily allowance of these feeds is eaten rapidly (especially in 1-2 feeds per day), or is eaten more slowly by stock unused to high-NO3- feeds, acute poisoning of cattle, sheep and horses could occur on feeds with >1.5% NO3- in DM and subacute or chronic poisoning could occur on feeds with 0.5-1.5% NO3- in DM.

Clinical signs: 

While the main signs are due to met-Hb conversion and tissue anoxia caused by NO2-, other signs are due to the direct caustic irritant effects of NO3- in the digestive tract and arterial hypotension and peripheral circulatory failure due to NO2-.

Signs of poisoning occur very rapidly (within 0.5-5 hours) after ingestion of pre-formed NO2-. While death in NO3- poisoning often occurs within 12-24 hours of exposure, it may occur within 0.5-4 hours of exposure in peracute cases. Signs may be delayed for a few days after access to high-NO3- feed, as rumen microbes need this time to adapt in favour of the NO2--producers.

There are five types of poisoning: peracute (lethal), acute (severe), subacute (moderate), chronic (mild) and sub-clinical.

In peracute poisoning, animals are found dead, without warning. Acute (severe) signs, usually with met-Hb conversion to 80-90% include cyanosis (with mucous membranes brown to black), severe respiratory distress with rapid respiration and rapid weak pulse, weakness, recumbency, coma and death. Some cases may be blind. Acute cardiac and circulatory failure without other signs can occur also. Subacute (moderate) signs, due to the irritant effects of NO3-, include salivation, lacrimation, grinding of the teeth, vomiting, abdominal colic and diarrhoea. Weakness, ataxia, muscle tremor, convulsions, rapid heart rate and breathing difficulty occur also. Chronic (mild) signs include listlessness, lethargy, depressed feed intake, growth rate, fertility and milk yield. 
Some authors claim that prolonged ingestion of sub-lethal doses of NO3-/NO2- has no obvious effect on productivity. Sub-clinical poisoning may show no obvious signs except brownish mucosae, due 10-20% conversion of Hb to met-Hb.

Abortion/stillbirth: Many authors found that pregnant cows aborted between 2-21 days 
after the onset of NO3- poisoning in the herd. Some cows which aborted did not show any other signs of poisoning. Haliburton & Edwards (1978) reported an abortion rate of 12.6% (range 6-71%) in cows exposed to high-NO3- forages (mean 0.8% NO3- in forage DM). Nicholls and Miles (1980) reported an abortion rate of 15-25% of cows which had survived an outbreak of NO3- poisoning about 1 week earlier. Clinical signs of NO3- poisoning in pregnant heifers and cows were not associated with abortion in other studies. Prolonged calving, stillbirth and birth of weak (soft) calves can also occur in cattle with acute, sub-acute or chronic NO3- poisoning.

Treatment

Once NO3-/NO2- poisoning is suspected, the source should be withdrawn and veterinary help should be sought immediately. Methylene blue (5-20 mg/kg LW intravenously, as a 
1-4% aqueous solution in saline or in 5% glucose or 1.8% sodium sulphate solution in ruminants or 1-2 mg/kg LW as a 1% solution in horses and pigs) reduces met-Hb to oxy-Hb within 1 hour. Daily oral doses of tungsten (as sodium tungstate) can prevent reduction of NO3- to NO2- in the rumen but more research is needed on safe dose rates. Vasoconstrictors (adrenalin) and cardiac/respiratory stimulants (etamiphylline camsylate) can save lives in acute cases .Treatment may need to be repeated in severe cases.

Prevention

Ruminant diets should contain low levels of NO3- and NO2-, preferably below 0.6% NO3- 
or 0.12% NO2- in DM. With the exception of grazed herbage (in which up to 2% may be tolerated), feeds with >1.5% NO3- (>0.34% NO2-) are unsafe for ad libitum feeding. All feeds with >0.7% NO3- (>0.14% NO2-) in DM (for instance Brassicas or beet tops) should be regarded as high-NO3- feeds. They should be fed in restricted amounts (a little and often), preferably spread over 12 hours or more of each day. High-NO3- feeds can be diluted with low-NO3- feeds to reduce the NO3- intake and spread it over a long period of each day. Maize yields respond to very heavy applications of slurry. There have been no problems of NO3- poisoning from maize, which is normally fed as silage.

Ruminants likely to be exposed to NO3- should get adequate carbohydrate in the diet. Travelling or hungry animals should not be allowed access to dangerous plants.
Water (from rain-water storage tanks, wells or condensation in animal houses) or whey fed to animals should contain low levels of NO3- or NO2-. Poisonous water can be made safe by prolonged boiling.

Monensin should not be fed with diets high in NO3-

Fertilisers and chemicals containing NO3- or NO2- 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. To minimise plant NO3- levels, forage should be cut for conservation on dry, bright days, if possible. If sewage sludge or animal slurries are applied at high levels, use of inorganic N fertilisers should be reduced or eliminated accordingly.

Prevention using mucous membrane colour as an early-warning sign: Twice daily inspection of the mucosae (for instance in dairy cows at milking time) can be used as an early-warning of NO3-/NO2- toxicity. The mucous membranes of healthy ruminants are salmon-pink. They are inspected easily by everting the conjunctiva or parting the lips of the vagina. Changes in blood colour from light brown to black (corresponding to 20-80% conversion of Hb to met-Hb) are seen easily by inspection of the mucous membranes in cattle. At 20% conversion, the mucosae are a light or grey-brown colour. At this point, signs of poisoning are usually mild or absent.