Sodium Nitrate toxicity
CLINICAL CASE
A phone call is recieved from a high school in the ambulance coordination center, the
caller tels the coordinator that one of the students have eaten a sponfull of salt and has
lost conscience for a short period of time.
When the ambulance arrives to the high schools finds a fifteen year old patient, without
any personal history of illnesses, alergic to acarous and to dogs epitelious without any
pharmacological alergy, with an aproximate weight of 65 Kgs, with correct vaccine
calnedar.
He has accidentally taken sodium nitrate from the laboratory of the school center,
confuing it with salt.
After having ingested the substance, it presents a syncopal episode that recovers
spontaneusly, followed by cyanosis, firstly peripheral and then central, maintaining
oxygen saurations around 85% with suplementary oxygen of 100%. He is transferred to
the nearest hospital (Hospital Comarcal del Vendrell) where a blood test is made,
finding a methemoglobinemia of 57.9%, without gasometric alterations with 100%
suplementary O2: pH 7.42, pCO2 11 pO2 100 HCO3 24 Sat O2 96 %. LDH 390, CPK
248. Rest of biochemistry is normal, so is blood count and coagulation.
The patient maintains correct blood pressures and a normal level of consciousness with
a GCS of 15, with no exploratory findings except cyanosis. He does not present
tachypnea, use of accesory muscles or respiratory work. Hear rate is 110, respiratory
rate 16.
Treatment with blue methylene (70 mg) is initiated, given the lack of resources for the
subsequent follow-up, the patient is transfer is decided to the intermediate care unit of
the referral hospital (Joan XXIII, Tarragona). O2 saturation is around 85% with
suplementary 100% O2.
During the transfer, the patient remains hemodynamically stable. Upon arrival at the
receiving hospital, the methemoglobin level has decreased to 19%, with a HR of 108
(sinus tachycardia) and an O2 saturation of 87% with a inspirated O2 fraction of 100%
SODIUM NITRATE INTOXICATION
Introduction:
Qhemical definition of nitrates
The anion is the conjugate base of nitric acid, consisting of one central nitrogen atom
surrounded by three identically bonded oxygen atoms in a trigonal planar arrangement.
The nitrate ion carries a formal charge of −1. This results from a combination formal
charge in which each of the three oxygens carries a − 2⁄3 charge, whereas the nitrogen
carries a +1 charge, all these adding up to formal charge of the polyatomic nitrate ion.
This arrangement is commonly used as an example of resonance. Like the isoelectronic
carbonate ion, the nitrate ion can be represented by resonance structures:
Almost all inorganic nitrate salts are soluble in water at standard temperature and
pressure. A common example of an inorganic nitrate salt is potassium nitrate (saltpeter).
A rich source of inorganic nitrate in the human body comes from diets rich in leafy
green foods, such as spinach and arugula. NO3- (inorganic nitrate) is the viable active
component within beetroot juice and other vegetables.
Epidemiololgy and toxicity of sodium nitrate
Sodium nitrate is an inorganic product, the salt resulted from nitric acid, used as
microbicide, rodenticide and fertilizer. [1]
Nitrates are mainly produced for use as fertilizers in agriculture because of their high
solubility and biodegradability. The main nitrate fertilizers are ammonium, sodium,
potassium, and calcium salts. Several million kilograms are produced annually for this
purpose.[2]
The second major application of nitrates is as oxidizing agents, most notably in
explosives where the rapid oxidation of carbon compounds liberates large volumes of
gases (see Gunpowder for an example). Sodium nitrate is used to remove air bubbles
from molten glass and some ceramics. Mixtures of the molten salt are used to harden
some metals.
Toxicity
PAN (Pesticide Action Network) clasifies its toxicity as class I. Pesticide Action
Network (PAN) Bad Actor PesticidesIn order to identify a "most toxic" set of
pesticides,Pesticide Action Network (PAN) and Californians for Pesticide Reform
(CPR) created the term PAN Bad Actor pesticides. [2]
Known or probable carcinogens, as designated by the International Agency for Research
on Cancer (IARC), U.S. EPA, U.S. National Toxicology Program, and the state of
California's Proposition 65 list. In the case of the nitrates, carcinogenicity is not proved
but it is proved under laboratory tests that it causes DNA damage.
Reproductive or developmental toxicants, as designated by the state of California's
Proposition 65 list. [3]
Known groundwater contaminants, as designated by the state of California (for actively
registered pesticides) or from historic groundwater monitoring records (for banned
pesticides). [4]
Pesticides with high acute toxicity, as designated by the World Health Organization
(WHO), the U.S. EPA, or the U.S. National Toxicology Program.This acute toxicity is
because of its efect in hemoglobin, it is transformed in methemoglobin.
Hemoglobin can accept and transport oxygen only when the iron atom is in its ferrous
form. When hemoglobin loses an electron and becomes oxidized, the iron atom is
converted to the ferric state (Fe3+), resulting in the formation of methemoglobin.
Methemoglobin lacks the electron that is needed to form a bond with oxygen and thus is
incapable of oxygen transport. [5]
Exposure risks
Under aerobic conditions, nitrate can percolate in relatively large quantities into the
aquifer when there is no growing plant material to take up the nitrate and when the net
movement of soil water is downward to the aquifer. Degradation or denitrification
occurs only to a small extent in the soil and in the rocks forming the aquifer. Under
anaerobic conditions, nitrate may be denitrified or degraded almost completely to
nitrogen. The presence of high or low water tables, the amount of rainwater, the
presence of other organic material and other physicochemical properties are also
important in determining the fate of nitrate in soil (van Duijvenboden & Loch, 1983;
Mesinga, Speijers & Meulenbelt, 2003; Fewtrell, 2004; Dubrovsky & Hamilton, 2010).
In surface water, nitrification and denitrification may also occur, depending on the
temperature and the pH. The uptake of nitrate by plants, however, is responsible for
most of the nitrate reduction in surface water. Nitrogen compounds are formed in the air
by lightning or discharged into it from industrial processes, motor vehicles and intensive
agriculture. Nitrate is present in air primarily as nitric acid and inorganic aerosols, as
well as nitrate radicals and organic gases or aerosols. These are removed by wet and dry
deposition. [6]
Nitrate intoxications are relatively rare among causes of methemoglobinemia.
Methemoglobinemia occurs when red blood cells (RBCs) contain methemoglobin at
levels higher than 1%. This may be from congenital causes, increased synthesis, or
decreased clearance. Increased levels may also result from exposure to toxins that
acutely affect redox reactions, increasing methemoglobin levels. [7]
Clinical presentation
Acute methemoglobinemia can be life-threatening and usually is acquired as a
consequence of exposure to toxins or drugs. Therefore, obtaining a detailed history of
exposure to methemoglobinemia-inducing substances is important. Such history may
not always be forthcoming, but it should always be sought actively since long-term or
repeated exposure may occur. Consultation with a toxicologist may be necessary,
especially with exposure to a new medication, because the list of medications known to
cause methemoglobinemia changes constantly.
Symptoms are proportional to the fraction of methemoglobin. A normal methemoglobin
fraction is about 1% (range, 0-3%).
At methemoglobin levels of 3-15%, a slight discoloration (eg, pale, gray, blue) of the
skin may be present.
Patients with methemoglobin levels of 15-20% may be relatively asymptomatic, apart
from mild cyanosis.
Signs and symptoms at levels of 25-50% include the following:
Headache
Dyspnea
Lightheadedness, even syncope
Weakness
Confusion
Palpitations, chest pain
Methemoglobin levels of 50-70% can cause the following:
Cardiovascular - Abnormal cardiac rhythms
CNS - Altered mental status; delirium, seizures, coma
Metabolic - Profound acidosis
At methemoglobin fractions exceeding 70%, death usually results. [8]
Infants and children can develop methemoglobinemia in association with metabolic
acidosis that is caused by prolonged dehydration and diarrhea. Sources of accidental
toxin exposure that must be considered in infants and children include ingestion of
water from wells contaminated with excess nitrates and exposure to local anesthetics in
teething gels
The clinical effects of methemoglobinemia are exacerbated in the presence of anemia.
Physical Examination
The physical examination of patients with suspected methemoglobinemia should
include examination of the skin and mucous membranes. Vital signs should be
documented, and mental status should be assessed. Careful attention should be paid to
the cardiac, respiratory, and circulatory examinations to assess for evidence of an
underlying disease (either congenital or acquired). [9]
Physical findings may include the following:
Discoloration of the skin, mucous membranes, and blood (the most striking physical
finding)
Cyanosis - This occurs with the presence of greater than 1.5 g/dL of methemoglobin
(compared with 5 g/dL of deoxygenated hemoglobin)
Pallor of the skin or conjunctiva suggests anemia (and possible hemolysis), which can
mask cyanosis if significant.
Seizures
Coma
Cardiac dysrhythmias (eg, bradyarrhythmia or ventricular
dysrhythmia)
Acidosis
Symptoms associated with cardiac and/or neurologic ischemia
Skeletal abnormalities and mental retardation are associated with certain types
of methemoglobin reductase enzyme deficiencies.
Lab test:
MetHb as a proportion of Hb.
1-2% Normal
Less than 10% metHb - No symptoms
10-20% metHb - Skin discoloration only (most notably on mucous membranes)
20-30% metHb - Anxiety, headache, dyspnea on exertion
30-50% metHb - Fatigue, confusion, dizziness, tachypnea, palpitations
50-70% metHb - Coma, seizures, arrhythmias, acidosis
Greater than 70% metHb - DeatH
Diagnostic Considerations
Because the initial symptoms of methemoglobinemia can be vague, especially with low
levels of methemoglobinemia, this condition can easily be misdiagnosed or go
unrecognized. Lack of awareness of this condition often leads to delayed and missed
diagnosis.
Cyanosis (presence of more than 5 g/dL of deoxygenated hemoglobin) associated with
hypoxia may be caused by cardiac or pulmonary disease. Cyanosis may also be present
in polycythemia but is generally without hypoxia. The hallmark of methemoglobinemia
is cyanosis that is unresponsive to high oxygen concentrations in the absence of cardiac
or pulmonary disorders. Pulmonary diseases generally respond to oxygen
administration, whereas cardiac disease may not. Right-to-left shunts in the
cardiovascular system, especially when large, do not respond to oxygen administration.
Sulfhemoglobinemia, skin contamination with blue/gray/black-colored dyes, or
ingestion/treatment with methylene blue causes cyanosis that is unresponsive to oxygen.
Darkish discoloration of the skin may be due to excessive exposure to silver compounds
(argyria) and can mimic methemoglobinemia.
Treatment & Management
Initial Management
Early clinical recognition of methemoglobinemia is paramount, as patients often have
only vague, nonspecific complaints, especially in the initial phase. High levels of
methemoglobinemia can be life-threatening and necessitate emergency therapy. Patients
with chronic mild increases in methemoglobin level may be completely asymptomatic
and require no specific therapy (provided that there is no evidence of end-organ
damage).
Once the diagnosis of methemoglobinemia has been confirmed and appropriate
management has been initiated, the underlying etiology should be sought. In acquired
methemoglobinemia, the toxin or drug may be identified by obtaining blood levels,
performing gastric lavage, or both. In asymptomatic patients with low levels of
methemoglobin, monitoring serial serum levels may be all that is necessary. The levels
normalize over time unless recurrent or chronic exposure to the offending agent occurs.
After acute exposure to an oxidizing agent, it is advisable to treat patients with
methemoglobin levels of 20% or higher. Patients with significant comorbidities (eg,
coronary artery disease [CAD] or anemia) may require therapeutic intervention at lower
methemoglobin levels (eg, 10%), especially if end-organ dysfunction (eg, cardiac
ischemia) is present.
If methemoglobinemia is the result of toxin exposure, then removal of this toxin is
imperative. Further ingestion or administration of the drug or chemical should be
avoided. If the substance is still present on the skin or clothing, the clothing should be
removed and the skin washed thoroughly. These patients may be unstable and should be
cared for in a closely monitored situation, with oxygen supplementation provided as
needed.
Pharmacologic Therapy, Exchange Transfusion, and Hyperbaric Oxygen
Methylene blue is the primary emergency treatment for documented symptomatic
methemoglobinemia [10]. It is given in a dose of 1-2 mg/kg (up to a total of 50 mg in adults,
adolescents, and older children) as a 1% solution in IV saline over 3-5 minutes.
Administration may be repeated at 1 mg/kg every 30 minutes as necessary to control
symptoms. Methylene blue is itself an oxidant at doses greater than 7 mg/kg and thus
may cause methemoglobinemia in susceptible patients; hence, careful administration is
essential.
Exchange transfusion (which replaces abnormal hemoglobin with normal hemoglobin)
may be considered for G6PD-deficient patients who are severely symptomatic or
unresponsive to methylene blue. Patients who are on long-acting medication (eg,
dapsone) may have initial treatment success with subsequent relapse of symptoms.
Gastric lavage followed by charcoal administration may decrease this prolonged drug
effect. These patients should be monitored closely and retreated with methylene blue as
necessary. [11]
Hyperbaric oxygen treatment is another option for situations where methylene blue
therapy is ineffective or contraindicated. This approach permits tissue oxygenation to
occur through oxygen dissolved in plasma, rather than through hemoglobin-bound
oxygen. [12]
Infants with methemoglobinemia due to metabolic acidosis should be treated with IV
hydration and bicarbonate to reverse the acidosis. The NADPH-dependent
methemoglobin reductase enzyme system requires glucose for the clearance of
methemoglobin. Therefore, IV hydration with dextrose 5% in water (D5W) is often
effective. [13]
Patients with mild chronic methemoglobinemia due to enzyme deficiencies may be
treated with oral medications in an attempt to decrease cyanosis. These medications
include methylene blue, ascorbic acid, and riboflavin. The methylene blue dosage in this
setting is 100-300 mg/day, which may turn the urine blue in color. The ascorbic acid
dosage is 200-500 mg/day.
Long-Term Monitoring
Close outpatient follow-up care is required in patients treated for methemoglobinemia.
Discharged patients should be reevaluated by a physician within 24 hours for any signs
or symptoms of recurring disease. Patients should also be provided with strict discharge
instructions detailing symptoms that should prompt immediate medical reevaluation,
such as shortness of breath, increasing fatigue, or chest pain.
Clear instructions to avoid future exposure to the precipitating agent (and related agents)
should be given to the patient. If treatment is indicated on an ongoing basis, patients
should be observed for therapeutic and toxic effects of treatment.
An outpatient followup should be done as long term toxicity of sodium nitrate is not
clear.
Medication Summary
Unless methemoglobinemia is severe or symptomatic, treatment is purely for cosmetic
or psychological reasons. Various agents can reduce the methemoglobin levels to within
the reference range (1%) or at least to acceptable levels (5-10%).
Methylene blue is the first-line antidotal therapy. Ascorbic acid and riboflavin have
been used. N -acetylcysteine reduces methemoglobin levels but is not yet approved for
the treatment of methemoglobinemia. Cimetidine can be used in dapsone-induced
methemoglobinemia. Hyperbaric oxygen and exchange transfusion should be
considered when methylene blue treatment is ineffective or contraindicated.
References
https://pubchem.ncbi.nlm.nih.gov/compound/Sodium-nitrite
https://www.cancertherapyadvisor.com/home/tools/fact-sheets/dietary-nitrates-nitrites-and-cancer/
https://ec.europa.eu/environment/water/water-nitrates/index_en.html
https://www.longdom.org/open-access/drugs-may-be-induced-methemoglobinemia-2329-8790-1000270.pdf
https://nj.gov/health/eoh/rtkweb/documents/fs/2258.pdf
https://www.medicalnewstoday.com/articles/320396#what-are-the-symptoms
