Introduction: Nitrobenzene, an aromatic nitro-compound, used as solvent in shoe and metal polishes, pesticide and screen printing in India. Its toxicity is due to its ability to induce methemoglobinemia. Clinical Picture: A 42 year female patient survived a suicidal consumption of 250ml of 20% Nitrobenzene. On presentation to the hospital, the patient was unconscious and showed typical symptoms of cyanosis, abnormal arterial blood gas (ABG) showing metabolic acidosis with SpO2 of 83%, and the arterial blood sample was chocolate brown in colour. The patient suspected of methemoglobinemia showed the formation of 17.7% methemoglobin (normal: 0-3 % of Hb), and normalized fully within 10 days due to quick extensive treatment. Outcome: She underwent supportive treatment and was given 1% methylene blue and 1gm ascorbic acid which acts as an oxygen scavenger. The patient eventually made a complete recovery and the ABG was entirely normalized within 10 days due to quick and extensive treatment. Conclusion: Acute Methemoglobinemia is usually associated with high mortality; hence an early aggressive management of poisoning should be attempted. RBC exchange transfusion and hyperbaric oxygen therapy are usually reserved for patients who are resistant to standard treatment and for those with severe symptoms.
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Nitrobenzene Poisoning, Acute Methemoglobinemia, Methylene Blue, Ascorbic Acid, Cyanosis
Intentional exposure is a major cause of premature mortality globally and 113914 suicides are recorded annually from India for which a variety of chemicals have been used.1 Nitrobenzene is a pale yellow oily liquid, with an odour of bitter almonds is used in the synthesis of solvents, like paint removers, manufacture of dyes, lubricating oils and synthetic rubber. It's also known as nitrobenzol or oil of mirbane.2 In India, 20% nitrobenzene emulsion is widely used as pesticides and marketed under the brand name Synflower offered by Mandar agrotech. The lethal dose is reported to range from 1 to 10gm by different studies.3-5 Methemoglobinemia is the primary acute effect that subsequently occurs after nitrobenzene ingestion. The toxic dose resulting in methemoglobinemia was estimated in one case study at 4.3 to 11gm based on urinary p-nitrophenol levels.6
A 42 year old woman was rushed to a local hospital and given first aid after a suicidal attempt of consuming 250ml 20% Nitrobenzene Pesticide an hour ago. After 8 hours she became centrally and peripherally cyanosed, unconscious and gasping, and was quickly transferred to a mission hospital. She was intubated; her arterial blood sample drawn was found to be chocolate brown in colour and was suspected of methemoglobinemia. Her blood sample analysis suggested metabolic acidosis with pH -7.10, PaO2 -134mmHg, PaCO2 -42.6mmHg, and HCO3 -12.9meq/L. She was then lavaged via naso-gastric (NG) tube with sodium bicarbonate, followed by administration of activated charcoal (1 g/kg of 20% suspension) and started with IV fluids. Her blood sample analysis after 4 hours showed respiratory alkalosis with pH-7.49, PaO2-273mmHg, PaCO2 -33mmHg, and HCO3 -20.2meq/L. Her SpO2 was 83% and had respiratory distress. Due to non availability of intravenous methylene blue; specific antidote could not be given and was referred to our hospital. On examination her pulse was 106beats/min, blood pressure 90/60mmHg, and her SpO2 was still 85% with FiO2 - 100%.7 Urine was dark coloured, WBC count was 21,500/dL while all the other parameters and tests remained normal. MetHb spectrophotometry values gave the result as 17.7% (Normal 0-3% of Hb). It was diagnosed as Acute Nitrobenzene Poisoning with Severe Methemoglobinemia and treated with 1% solution of methylene blue 2mg/kg intravenously over a period of 5 minutes and slow intravenous infusion of 1gm ascorbic acid in 5% dextrose thrice a day. MetHb spectrophotometry values on the 6th day gave the result as 13.8% and SpO2 was 90%. After 3 days of ICU stay patient condition was stabilized, slowly recovered, SpO2 gradually increased and was discharged on the 10th day.
Methemoglobinemia is a condition in which the iron within haemoglobin is oxidized from the ferrous (Fe2+) state to the ferric (Fe3+) state, resulting in the inability to transport oxygen and resulting in brownish discoloration of blood.8 The low level of methemoglobin is maintained by two important mechanisms. One that occurs within the erythrocyte is the hexose-monophosphate shunt pathway which reduces oxidizing agents by glutathione prior to the formation of methemoglobin. The second mechanism against methemoglobin formation uses two enzymes systems: diaphorase -I and diaphorase -II which requires NADH and NADPH enzymes respectively to reduce methemoglobin to its original ferrous state. The NADH-dependent reaction is catalysed by cytochrome b5 reductase enzyme.9, 10
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Normal level of methemoglobin is 0 to 3% and acute intoxication shows 10 to 15% methemoglobin which is usually asymptomatic sometimes with only cyanosis. Beyond 20% headache, dyspnea, chest pain, tachypnea, and tachycardia develops and above 40% confusion, lethargy, and metabolic acidosis leading to coma, seizures, bradycardia, ventricular dysrythmia, and hypertension. More than 70% is highly fatal and leads to death.4, 10
It also causes hepatosplenomegaly, elevated liver function, and haemolytic anaemia. Tools of diagnosis include characteristic smell of bitter almonds, persisting cyanosis on continuous oxygen therapy without pre-existing cardiopulmonary disease, low arterial oxygen saturation, and abnormal arterial blood gas (ABG) analysis. Chocolate brown colour that fails to turn bright red on shaking is the main distinguishing feature suggesting methemoglobinemia. Presence of nitrobenzene compound can be detected spectrophotometrically by different techniques like pulse-oximeter, co-oximetry, Evelyn- Malloy method and enzyme assay.9, 11, 12
Methemoglobinemia can be congenital or acquired; antidote of choice for acquired (toxic) methemoglobinemia is methylene blue, 1-2 mg/kg administered as a 1% solution undiluted as direct IV over 3-5 minutes, repeated at 1 mg/kg in 1 hour as necessary to control fluctuating symptoms. Toxic dose of methylene blue is more than 7mg/kg which can cause dyspnea, chest pain, and hemolysis.4,13 It is known to cause erroneous SpO2 measurements.14 NADPH-dependent methemoglobin reductase system is effective in reducing methemoglobin to ferrous form and methylene blue accelerates it by acting as an electron donating exogenous cofactor. At higher doses even methylene blue has reverse action causing methemoglobinemia. It should not be given in patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency as it leads to severe haemolysis. Other uses of methylene blue include treatment of urolithiasis, cystitis, herpes simplex infection and antidote of choice in cyanide poisoning.4, 9, 10
Other treatment includes ascorbic acid which is an antioxidant; free radical scavenger which reduces the NAD+ at doses of 0.5-1gm given 8th hourly.5, 9 There is very less evidence from recent studies that suggested N-acetyl cysteine is effective in reversing methemoglobin. RBC exchange transfusion and hyperbaric oxygen therapy are usually reserved for patients who are resistant to standard treatment and for those with severe symptoms. 10 Dextrose is the major source of NADH in the red blood cells which catabolises sugar through glycolysis and also a source of NADPH through the hexose-monophosphate shunt, which is necessary for enhanced effectiveness of methylene blue. Hence, dextrose should also be administered.15
The treatment of poisoning caused by an uncommon compound is a challenge and the situation becomes graver when the patient does not respond properly on treatment. Acute Methemoglobinemia is usually associated with high mortality; hence an early aggressive management of poisoning should be attempted.11, 13 Methylene blue and ascorbic acid are the treatment of choice, while RBC exchange transfusion and hyperbaric oxygen therapy are usually reserved for patients who are resistant to standard treatment and for those with severe symptoms. The authors wish to point out the non availability of intravenous methylene blue should not be a hindrance, as methylene blue powder is available and can be made into 1% solution and sterilized in CSSD.10