Abstract
Sodium chlorite is a household and industrial cleaning agent that can cause oxidative stress leading to methemoglobinemia and severe hemolysis when ingested. There is a scarcity of published literature reporting this in humans. We report a case of intentional sodium chlorite ingestion for homeopathic purposes that resulted in methemoglobinemia and hemolysis, requiring admission to the intensive care unit. Following successful treatment with methylene blue, the patient developed worsening hemolytic activity. Outpatient testing later revealed she was non- glucose-6-phosphate dehydrogenase (G6PD) deficient. Hemolysis precipitated by methylene blue is an underrecognized side effect that can be observed in individuals both with and without G6PD deficiency.
Sodium chlorite is an inorganic salt that acts as an oxidizing agent; it is typically used as a household detergent or in an industrial setting to clean drinking water. While sodium chlorite ingestion is known to cause methemoglobinemia, there is a scarcity of published literature reporting this in humans.1–6 Methylene blue is used as an antidote to methemoglobinemia; however, as an oxidizing agent, methylene blue can paradoxically precipitate methemoglobinemia or induce hemolysis in high doses or when methemoglobin is ineffectively reduced. While hemolysis following methylene blue administration is classically seen in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to decreased endogenous levels of nicotinamide adenine dinucleotide phosphate (NADPH),7 this may also be observed in non-G6PD deficient individuals. Here, we report a case of intentional sodium chlorite ingestion for homeopathic purposes resulting in methemoglobinemia and hemolysis that was treated with the administration of methylene blue, resulting in worsening hemolysis in a non-G6PD deficient individual.
Case Presentation
A woman, aged 60 years, presented to the emergency department with gastrointestinal upset after ingesting two tablespoons of sodium chlorite and citric acid for homeopathic purposes at approximately 0200 hours. She reported taking three drops of this solution daily for several months but accidentally ingested 50 mL of the sodium chlorite solution prior to presentation. She was also taking the following prescribed medications at the time of ingestion: escitalopram 20 mg, mirtazapine 30 mg, trazodone 50 mg as needed, and valacyclovir 500 mg twice daily as needed. Poison Control had been called enroute to the Emergency Department by the patient and her family member. She was hypoxic at presentation, with oxygen saturation below 80% on room air, and she was placed on high-flow nasal cannula and Ventimask with a FiO2 of 100%. A venous blood gas was drawn at 0304 hours, which showed a methemoglobin level of 21%; her hemoglobin at presentation was 140 g/L with a normal peripheral blood smear (Figure 1). Hemoglobin levels prior to admission were noted to be normal. A chest radiograph was also completed at 0306 hours to assess for alternative causes of hypoxia (Figure 2), and this demonstrated bilateral infiltrates in keeping with aspiration from vomiting. Her initial liver enzymes drawn at 0316 hours were as follows: alanine aminotransferase (ALT) 37 units/L (reference 0-34 units/L), aspartate aminotransferase (AST) 33 units/L (reference 18-34 units/L), and alkaline phosphatase (ALP) 124 units/L (reference 38-126 units/L). A gamma glutamyl transferase (GGT) level was not available at that time. A dose of methylene blue at 2 mg/kg (110 mg) was administered at 0335 hours. Her oxygen saturation transiently improved but given her persistent hypoxia and the risk of aspiration in the context of ongoing emesis, she was intubated. A second dose of methylene blue at 2 mg/kg (110 mg) was administered at 0400 hours, given no appreciable and lasting clinical improvement was noted after the first dose. A repeat venous blood gas showed a methemoglobin level of 9% at 0403 hours, and then 2% at 0727 hours.
Hemoglobin and venous methemoglobin levels from time of presentation to discharge from hospital.
Initial chest radiograph demonstrating infiltrates in the left mid/lower zone and right lower zone with normal heart size and mediastinal contours.
The patient was admitted to the intensive care unit (ICU). Her mirtazapine, escitalopram, and trazadone were held given the risk of serotonin syndrome associated with methemoglobinemia. A follow-up phone conversation with Poison Control occurred at approximately 0430 hours with the recommendation of ongoing monitoring of bloodwork and supportive care, as the methemoglobinemia was attributed to the sodium chlorite ingestion. It was recommended that if the methemoglobin level were to rise to 30%, or if there was a rise to >20% with symptoms of severe anemia, an additional dose of methylene blue could be considered. If the maximum dose of methylene blue was reached (4 mg/kg), and the patient was requiring ongoing treatment, then exchange transfusion could be initiated. At 1750 hours, she was noted to have a hemoglobin drop to 107 g/L, with an elevated lactate dehydrogenase (LDH) of 850 units/L (reference 120-250 units/L). Hemolytic workup revealed reduced haptoglobin, the presence of free hemoglobin, hemopexin-heme complexes, and methemalbumin with a negative direct antiglobulin test. Reticulocytes were elevated at 95 × 109/L (reference 10–86 × 109/L), and initial unconjugated bilirubin was normal at 9 umol/L (reference ≤19 μmol/L). Poison Control was contacted again by ICU staff to further review the case given the results of her hemolytic workup. They believed the hemolysis may have been due to methemoglobinemia from an oxidative process versus G6PD deficiency, as the patient had received large amounts of methylene blue. As per Poison Control’s recommendations, her ongoing treatment consisted of supportive care, monitoring for liver and kidney injury, and providing blood transfusions as needed. A G6PD assay was not drawn during admission, as test results are often falsely negative during acute hemolysis due to increased reticulocytes that tend to contain more G6PD enzymes. By day 2 of admission, hemoglobin was 86 g/L, and she underwent an endoscopy to assess for caustic injury, which showed only nonspecific duodenitis. She also developed mild transaminitis, which was felt to be secondary to ingestion. Given her clinical improvement, she was successfully extubated on day 3. By day 4–5, reticulocytes were 211 × 109/L, LDH 1549 units/L, unconjugated bilirubin 50 μmol/L with normal conjugated bilirubin, and peripheral blood smear demonstrated red blood cells with blister cell morphology, spherocytes, Howell-Jolly bodies, and a leukoerythroblastic picture. At day 5, her transaminitis peaked with an ALT of 162 units/L and AST of 213 units/L. Hemoglobin reached a nadir of 60 g/L by day 5, treated with 2 units of packed red blood cells and started on empiric folic acid 5 mg daily. Following this, her hemoglobin increased to 89 g/L and remained stable for the remainder of her admission. There was no evidence of disseminated intravascular coagulation with normal coagulation parameters. Her liver enzymes continued to downtrend. She did not require initiation of renal replacement therapy. She was discharged on day 8. At 3 months after discharge, repeat bloodwork demonstrated a normal hemoglobin at 138 g/L, no evidence of hemolysis, and normal G6PD assay at 9.6 units/g (reference 4.6–13.5 units/g).
This patient developed an acquired methemoglobinemia following sodium chlorite ingestion due to induced oxidant stress. Strong oxidizing agents such as sodium chlorite can also precipitate hemolysis, which became evident during admission based on her hemolytic workup. Treatment of the methemoglobinemia with methylene blue was successful, but this can also precipitate hemolysis. The observed increase in non-immune hemolytic activity (reticulocytosis, elevated LDH, elevated unconjugated bilirubin, reduced or absent haptoglobin, and presence of heme complexes with negative direct antiglobulin test) in the days following methylene blue administration were attributed to the methylene blue, with no evidence of G6PD deficiency.
Discussion
Sodium chlorite is a white, flaky, odorless salt commonly found in household detergents, water purification processes, and as a bleaching agent in some industrial operations due to its powerful oxidizing properties. More recently, sodium chlorite has been marketed online as a natural health remedy, and, therefore, it has gained popularity despite inadequate clinical evidence.2,5 Human intoxication with sodium chlorite remains rare, with data limited only to case reports. Initial signs and symptoms following ingestion typically include gastrointestinal upset (abdominal cramping, nausea, vomiting, and diarrhea) likely from irritation of the gastric mucosa by chlorite, irritability, confusion/altered level of consciousness, generalized cyanosis, and refractory hypoxemia.1–6 Ingestion is also associated with laboratory findings of methemoglobinemia, often with further complications such as intravascular hemolysis, disseminated intravascular coagulation, and acute renal failure.1–6 Given that methemoglobinemia is a crucial diagnosis made early in the clinical course of sodium chlorite ingestion, its management must be prioritized.
As in our case, exposure to substances that produce direct or indirect hemoglobin oxidation can cause acquired methemoglobinemia.8 Oxidizing agents such as sodium chlorite trigger the conversion of the oxygen-carrying ferrous (Fe2+) iron ion of hemoglobin to the ferric (Fe3+) state, producing methemoglobin.3,4,8 This change results in the inability of the Fe3+ site to bind oxygen in the lungs and shifts the oxygen-hemoglobin dissociation curve to the left. The resulting shift causes an increased oxygen affinity of ferrous iron, and subsequent impairment of oxygen release to tissues.4,8 Hypoxia and “functional anemia” without a decrease in hemoglobin occurs.8
The clinical presentation of methemoglobinemia is variable; however, the diagnosis should be suspected in patients presenting with unexplained cyanosis and hypoxemia.8 Typical signs and symptoms of methemoglobinemia can be found in Table 1.3,8 Several factors affect the severity of presentation including the percentage of methemoglobin, rate of increase in methemoglobin levels, a patient’s functional status and their inherent ability to clear methemoglobin, and the duration and amount of exposure to the oxidizing agent.8
The primary treatment of methemoglobinemia is the administration of intravenous methylene blue, particularly for symptomatic methemoglobin concentrations over 20%.7,8 Methylene blue predominantly acts as a reversal agent, ultimately reducing the Fe3+ state back to the Fe2+ state in erythrocytes via its reduced state of leucomethylene blue in the presence of NADPH.3,7,8 Typically, the initial dose of methylene blue is 1-2 mg/kg, infused over 5-10 minutes.7,8 If methemoglobinemia does not significantly decrease within the first 30-60 minutes, a 1 mg/kg dose can be repeated.7,8 However, in sodium chlorite ingestion, the reduction of methemoglobin to hemoglobin is only reversible in the early phase, postulated to be within 6 hours after ingestion, and methylene blue often fails when methemoglobin levels exceed 70%.1,3 If there is no improvement in the patient’s condition after repeated doses of methylene blue (not exceeding the toxic dose of >7 mg/kg), therapeutic whole blood exchange or hyperbaric oxygen therapy can be considered.8
Hemolytic anemia as a side effect of methylene blue is well recognized among toxicologists and hematologists; however, this side effect may not be widely known among emergency room, general internal medicine, or critical care physicians who provide the initial care. Hemolytic anemia from methylene blue is classically described in G6PD deficient individuals; however, it has also been described in non-G6PD deficient neonates, and one report in a non-G6PD deficient adult, as in our case.9–13 When methylene blue interacts with erythrocytes it is metabolized to leucomethylene blue, which produces hydrogen peroxide. When high doses of methylene blue are used, the production of hydrogen peroxide overwhelms the erythrocyte ability to cope, leading to hemolysis occurring up to a week post exposure.13 Our patient’s ongoing hemolysis and anemia after successful treatment of her methemoglobinemia was attributed to methylene blue.
Previous case reports have described acquired G6PD deficiency after ingestion of sodium chlorite.2,4 The G6PD enzyme plays a crucial role in protecting erythrocytes from oxidative stress.14 Although most cases of G6PD deficiency are inherited in a X-linked recessive manner, acquired G6PD deficiency can also occur in the setting of nutrient deficiency, in association with different medical conditions, or following medication/toxin ingestion.15 This is thought to occur due to oxidative damage to the G6PD enzyme itself or by overwhelming the anti-oxidative mechanisms of erythrocytes.15 In patients with inherited or acquired G6PD deficiency, hemolysis and the formation of methemoglobin occurs during times of oxidative stress due to glutathione depletion.14 During a hemolytic episode, inherited and acquired G6PD deficiency are best distinguished by history, with prior or recurrent episodes of hemolysis occurring with the inherited type. Inherited and acquired G6PD deficiency are indistinguishable on routine investigations, with both demonstrating signs of hemolysis with a blood smear demonstrating bite cells, blister cells as well as Heinz bodies, and with specific G6PD testing demonstrating reduced enzyme activity and levels.14,15
In the reported cases of adult sodium chlorite ingestion, patients experienced hemolysis both with and without the use of methylene blue to correct methemoglobinemia.1–6 Importantly, the cases in which methylene blue was not administered had less severe methemoglobinemia with peak levels of 5.2%4 and 6.7%,2 respectively. In these cases, methylene blue was not used for concerns of worsening hemolysis due to acquired G6PD deficiency;2,4 instead, one patient received N-acetylcysteine to replenish depleted glutathione stores.2 The efficacy of methylene blue on reducing methemoglobinemia caused by sodium chlorite ingestion was varied, with the best effect seen in those patients who received methylene blue closer to the time of ingestion.1,3,5,6 Notably, for the cases of sodium chlorite ingestion in which G6PD deficiency testing was performed, enzyme activity and levels were low in the acute phase, but they normalized within days or months.2,4 In our case, G6PD testing was not performed in the acute phase, but the worsening hemolysis subsequent to methylene blue administration suggests methylene blue, irrespective of G6PD, can precipitate and/or exacerbate hemolysis.
Conclusion
Sodium chlorite toxicity is a rare but important cause of methemoglobinemia in humans, particularly given its increasing popularity as a natural health remedy despite lack of clinical evidence. Methemoglobinemia and severe hemolysis can develop due to oxidative stress caused by sodium chlorite. Acquired G6PD deficiency has been reported in two cases, and routine laboratory testing in the acute phase is unable to distinguish acquired from inherited G6PD deficiency. Treatment of methemoglobinemia with methylene blue can precipitate or exacerbate red cell hemolysis, and it is an important side effect to recognize with methylene blue. To the best of our knowledge, this is the first reported case of intentional sodium chlorite ingestion for homeopathic purposes resulting in methemoglobinemia and hemolysis, with the methemoglobinemia successfully treated with methylene blue but complicated by worsening hemolysis following treatment.
- Received August 10, 2024.
- Revision received January 27, 2025.
- Accepted February 25, 2025.
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