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.
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.
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.
Known groundwater contaminants, as designated by the state of California (for actively registered pesticides) or from historic groundwater monitoring records (for banned pesticides).
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.
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.
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.
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.
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).
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)AcidosisSymptoms associated with cardiac and/or neurologic ischemiaSkeletal 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. [55, 56]
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. 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.
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.
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.
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.
