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Year : 2020  |  Volume : 18  |  Issue : 3  |  Page : 175-178

Acquired methemoglobinemia in cases of intentional exposure to agrochemicals: Our 4 years experience

Department of Emergency Medicine, CMC, Vellore, Tamil Nadu, India

Date of Submission02-Jan-2020
Date of Decision02-Feb-2020
Date of Acceptance10-Feb-2020
Date of Web Publication10-Jul-2020

Correspondence Address:
Dr. Darpanarayan Hazra
Department of Emergency Medicine, CMC, Vellore - 632 004, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmi.cmi_3_20

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Background: Intentional exposure to agrochemicals is a major cause of premature mortality globally. Many such agrochemical compounds contain solvents that may result in severe methemoglobinemia that may be fatal. Acute methemoglobinemia is usually associated with high mortality; hence, an early aggressive management of poisoning in the emergency department (ED) should be attempted. Materials and Methods: This was a single-center, retrospective, cohort study analyzing patients with a history of ingestion of agrochemicals and significant methemoglobinemia in a period of 4 years that presented to our ED. Results: The total number of patients presenting to the ED following ingestion of agrochemicals with a motive of deliberate self-harm was 2491 during the 4-year study period, among which 24 patients had significant levels of methemoglobin. Majority of the patients presented following ingestion of nitrobenzene compounds (37%), followed by organic herbicides and larvicidal compounds (17%). The most common clinical features were that of low oxygen saturation on pulse oximetry not improving with oxygen therapy and central cyanosis. Most of these patients, i.e., 91.6%, were treated with intravenous (IV) methylene blue, to which 81.8% patients responded favorably and had methemoglobin <20% at 1-h interval from administering. Among the total study population, most (83.3%) patients required admission in the ward or intensive care for further stabilization and management, whereas the rest (16.7%) opted for discharge against medical advice. There was no mortality in the ED. Conclusions: Methemoglobinemia can be caused by a wide variety of agrochemicals that are potentially life-threatening. The most common clinical signs in the ED are those relating to hypoxemia. Use of IV methylene blue resulted in a significant reduction of methemoglobinemia. With this characterization, we hope to guide protocols in the future for the management of agrochemical poisoning.

Keywords: Acquired methemoglobinemia, acquired methemoglobinemia and acute poisoning, acute poisoning, intravenous methylene blue

How to cite this article:
Nekkanti AC, Hazra D, Kumar S, Rajenesh A. Acquired methemoglobinemia in cases of intentional exposure to agrochemicals: Our 4 years experience. Curr Med Issues 2020;18:175-8

How to cite this URL:
Nekkanti AC, Hazra D, Kumar S, Rajenesh A. Acquired methemoglobinemia in cases of intentional exposure to agrochemicals: Our 4 years experience. Curr Med Issues [serial online] 2020 [cited 2021 Nov 27];18:175-8. Available from: https://www.cmijournal.org/text.asp?2020/18/3/175/289415

  Introduction Top

Methemoglobin is an oxidized derivative of hemoglobin. It is generated by oxidization of the ferrous form of iron (Fe2+) in the heme molecule to the ferric form (Fe3+). A molecule of methemoglobin is incapable of binding and carrying oxygen.[1],[2],[3] Methemoglobinemia should be suspected in patients who present with drowsiness and cyanosis following ingestion of toxicants.[4],[5] Over the last few decades, agricultural pesticides have become a common household item in rural areas of the developing world. Due to this easy availability, they have been commonly used for intentional self-poisoning and are important cause of morbidity and mortality worldwide. Organophosphates are the most common agrochemical poisons followed closely by herbicides.

Methemoglobinemia is an increased concentration of methemoglobin in the blood above 2% and results from exposure to a wide variety of chemicals, including many commonly prescribed drugs (usually in an overdose situation) or may be congenital due to deficiency or lack of specific enzymes protecting hemoglobin from oxidization or abnormal structure of the hemoglobin molecule.[2],[3],[4]

Cyanosis resistant to oxygen therapy and dyspnea occur in patients with methemoglobin concentration more than 20%. Consciousness disorders, respiratory and circulatory failure, and liver and kidney damage may occur in patients with methemoglobin concentration more than 50%. Most cases require only supportive therapy and assessment for other toxic complications. Severe cases may result in hypoxia and require treatment with methylene blue.[6],[7],[8] However, not all cases respond to methylene blue, and methylene blue itself may produce serious side effects. This article is an addition to the already reported literature of clinical features, laboratory findings, course in hospital, and outcome of patients with severe methemoglobinemia following intentional ingestion of toxicants.

  Materials and Methods Top


The study was a single-center, retrospective, observational study conducted in the emergency department (ED).


The study was conducted in the ED of Christian Medical College Hospital, Vellore, which is a tertiary medical care center. The ED is a 49-bed department and tends to about 300 patients/day, including trauma and nontrauma patients.


All patients with intentional ingestion of poisons and features of methemoglobinemia were included in the study. Patients were triaged into priority 1 and 2 based on their hemodynamic stability. Patient in shock i.e. Quick Sequential Organ Failure Assessment (qSOFA) score ≥ 2, low Glasgow Coma Scale (GCS) or patients with impending respiratory or circulatory arrest were triaged as priority 1.

Study period

January 2013 to January 2017 (4 years).


Data of the patients were obtained from the electronic hospital records and the details of history and physical examination findings of all patients were recorded on a standard data collection sheet. The following were extracted: type of compound ingested, methemoglobin levels on co-oximetry, clinical features at presentation, and outcome.

Outcome variable

Outcome of ED visit was categorized as hospital admission or leave against medical advice. In-hospital management and outcome of these patients were also analyzed.


This is a retrospective study, and therefore we could not control exposure or outcome assessment, and instead relied on others for accurate recordkeeping.

Sample size calculation

During the study period, 24 patients with acute poisoning, all of which were deliberate self-harms, had significantly elevated methemoglobin levels.

Laboratory tests

Investigations such as complete blood count, serum electrolytes, liver and renal function tests, and methemoglobin levels on arterial blood gas were done as applicable, based on the initial history and clinical examination.

Statistical analysis

All categorical variables were expressed as frequencies and percentages. The data were extracted from ED triage software and Clinical Workstation and entered into Statistical Package for the Social Sciences (SPSS Inc., Released 2018) software, version The data were summarized using mean with standard deviation for continuous variables and frequencies with percentages.

  Results Top

A total of 2491 patients with a history of deliberate ingestion of agrochemicals presented to ED during the study period of 4 years, of which 24 patients had significant levels of methemoglobin and hence were included in the study. Among these, majority were triaged as priority 2, i.e., 22 (91.7%) patients, whereas 2 (8.3%) were triaged as priority 1 [Figure 1].
Figure 1: STROBE diagram.

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Clinical features and methemoglobin levels on co-oximetry

The patients presented with a multitude of symptoms, including central cyanosis, altered mental status, and shock as given in [Table 1]. Majority of the patients, i.e., 11 (45.8%), had moderate (50%–70%) methemoglobinemia. Mild methemoglobinemia (20%–50%) was seen in 8 (33.3%) patients and severe methemoglobinemia (≥70%) was noted in 5 (20.8%) patients as given in [Table 2]. Dark coffee-brown colored arterial blood was noted in 9 (37.5%) patients [Figure 2].
Table 1: Clinical features at presentation

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Table 2: Methemoglobin levels on co-oximetry

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Figure 2: Dark coffee–brown-colored arterial blood.

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Types of compound ingested

Majority of the patients presented following ingestion of nitrobenzene compounds, i.e., 9 (37%) cases followed by organic herbicides and larvicidal compounds, i.e., 4 (17%) cases, details of which are shown in [Figure 3].
Figure 3: Types of compound ingested.

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Emergent management in emergency department

Most of these patients, i.e., 22 (91.6%), were treated with intravenous (IV) methylene blue (2 mg/kg), to which 18 (81.8%) patients responded favorably and showed methemoglobin levels of <20% at 1-h interval from administering. The remaining four patients required a second dose of IV methylene blue, after which the methemoglobin levels dropped to <20% at 2-h interval. Two patients among the study population were not treated with IV methylene blue for unknown reasons. However, these two patients as well as the four that required two doses of methylene blue were all given IV ascorbic acid.

Emergency department and hospital outcome

Among the total study population, 20 (83.3%) patients were admitted, of which 16 (80%) patients were admitted in the ward and 4 (20%) patients in the intensive care unit (ICU). Two patients with severe methemoglobinemia required invasive ventilation, among which one of them required inotropic supports and hemodialysis. While majority of the patients, i.e., 18 (90%), were discharged in a stable condition, 2 (10%) patients with severe methemoglobinemia succumbed to the toxicant during ICU stay.

  Discussion Top

Methemoglobinemia is a condition in which the ferrous (Fe) 2+ state of iron within hemoglobin gets oxidized to the ferric (Fe) 3+ state, resulting in the incapability of hemoglobin to transport oxygen. Normal level of methemoglobin is 0%–2%. Acute intoxication shows 10%–15%, which is usually asymptomatic but occasionally presents with only cyanosis. Beyond 20%, symptoms such as headache, dyspnea, chest pain, tachypnea, and tachycardia develop and above 40%, confusion, lethargy, and metabolic acidosis leading to coma, seizures, bradycardia, ventricular dysrhythmias, and hypertension are seen. More than 70% levels are highly fatal and often lead to death.[1],[2],[3],[8],[9],[10]

Like the other studies in the past, majority of our study population that had presented with mild-to-moderate levels of methemoglobin had good hospital outcome, whereas patients with methemoglobin of more than 70% had poor hospital outcome.[10],[11]

Indoxacarb, aluminum phosphide, and paraquat are the commonly implicated insecticides for methemoglobinemia. These agrochemicals contain biological extracts, stabilizers, and fillers. Biological extracts are rich in nitrogenous products and hence can potentially cause methemoglobinemia. Methemoglobinemia is a clinical diagnosis that is made based on history and presenting symptoms. The presence of hypoxemia refractory to supplemental oxygen therapy and of chocolate-colored blood strongly supports the diagnosis. The confirmatory test is an arterial or venous blood gas with co-oximetry that can speciate the hemoglobin to determine the methemoglobin level in the blood.[12],[13],[14]

Methylene blue is the antidote of choice for toxic methemoglobinemia. It acts as an exogenous cofactor, which greatly accelerates the NADPH-dependent methemoglobin reductase system.[9],[11] Methylene blue is indicated for acquired methemoglobinemia when the level is >35%–40% and the patient has cardiorespiratory symptoms. However, in this study population, methylene blue was used with a level of more than 20% and showed a good clinical outcome. The initial dose is 1–2 mg/kg or 0.1–0.2 ml/kg of the 3% solution, given intravenously over 5 min. Response occurs within 1 h and reduces the elimination half-life of severe methemoglobinemia to 90-120 minutes, which was observed in our patients as well. According to the current recommendations, methemoglobin levels should be checked 1 h after infusion and a repeat dose may be warranted if levels remain high and the patient is still symptomatic. Physicians should also consider the fact that methylene blue is itself an oxidant when administered at doses >7 mg/kg and thus may cause methemoglobinemia in susceptible patients. Repeated doses may cause acute hemolysis and may worsen the methemoglobinemia. Treatment with methylene blue can also be complicated by the presence of underlying enzyme deficiencies, including glucose-6-phosphate dehydrogenase deficiency; hence, the role of methylene blue infusion needs to be explored in such cases. Nonpathological side effects such as discoloration of urine can be expected. Methylene blue interacts with teratogenic drugs; hence, caution should be exerted in pregnancy to minimize fetal risk.[4],[5],[8],[13],[14]

In cases where methylene blue is contraindicated, or ineffective, ascorbic acid is often used as an alternative therapy. Ascorbic acid or Vitamin C is a natural water-soluble vitamin and is a potent reducing and antioxidant agent. It functions in fighting bacterial infections, in detoxifying reactions, and in the formation of collagen in the fibrous tissue, teeth, bones, connective tissue, skin, and capillaries. Exchange transfusion is another modality of treatment shown to be beneficial in severe cases.[5],[6],[14]

  Conclusions Top

The treatment of poisoning caused by an uncommon/unknown compound is a challenge and the situation become graver, when the patient does not respond properly to treatment. Sudden onset of cyanosis with symptoms of hypoxia (low SpO2 on pulse oximeter) that does not improve with an increased fraction of inspired oxygen and abnormal dark red, chocolate, or brownish coloration of the blood observed during phlebotomy are the red flag signs of methemoglobinemia. Acute methemoglobinemia is usually associated with high mortality; hence, an early aggressive management in the ED should be attempted. Methylene blue and ascorbic acid are the treatment of choice in such cases.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

Research quality and ethics statement

The authors of this manuscript declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation was determined to require Institutional Review Board/Ethics Committee review, and the corresponding protocol/approval number is IRB Min No.: 10345 dated October 19, 2016. We also certify that we have not plagiarized the contents in this submission and have done a plagiarism check.

  References Top

Ash-Bernal R, Wise R, Wright SM. Acquired methemoglobinemia: A retrospective series of 138 cases at 2 teaching hospitals. Medicine (Baltimore) 2004;83:265-73.  Back to cited text no. 1
Falkenhahn M, Kannan S, O'Kane M. Unexplained acute severe methaemoglobinaemia in a young adult. Br J Anaesth 2001;86:278-80.  Back to cited text no. 2
Dahshan A, Donovan GK. Severe methemoglobinemia complicating topical benzocaine use during endoscopy in a toddler: A case report and review of the literature. Pediatrics 2006;117:e806-9.  Back to cited text no. 3
Abhilash KP. Methemoglobinemia: When to suspect and how to treat. Curr Med Issues 2019;17:125-8.  Back to cited text no. 4
  [Full text]  
Patnaik S, Natarajan MM, James EJ, Ebenezer K. Methylene blue unresponsive methemoglobinemia. Indian J Crit Care Med 2014;18:253-5.  Back to cited text no. 5
[PUBMED]  [Full text]  
Bhat P, Sisler I, Collier AB 3rd. Exchange transfusion as treatment for rasburicase induced methemoglobinemia in a glucose-6-phosphate dehydrogenase deficient patient. Pediatr Blood Cancer 2008;51:568.  Back to cited text no. 6
Skold A, Cosco DL, Klein R. Methemoglobinemia: Pathogenesis, diagnosis, and management. South Med J 2011;104:757-61.  Back to cited text no. 7
George T, Shaikh AI, Thomas L, Kundavaram AP. Severe methemoglobinemia due to insecticide poisoning. Indian J Crit Care Med 2014;18:113-4.  Back to cited text no. 8
[PUBMED]  [Full text]  
Bradberry SM. Occupational methaemoglobinaemia. Mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev 2003;22:13-27.  Back to cited text no. 9
Beutler E. Methemoglobinemia and other causes of cyanosis. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams Hematology. 5th ed. New York: McGraw-Hill; 1994. p. 654-62.  Back to cited text no. 10
Top WM, Gillman PK, de Langen CJ, Kooy A. Fatal methylene blue associated serotonin toxicity. Neth J Med 2014;72:179-81.  Back to cited text no. 11
Warang PP, Kedar PS, Shanmukaiah C, Ghosh K, Colah RB. Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India. Clin Genet 2015;87:62-7.  Back to cited text no. 12
Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia. Treatment issues. Drug Saf 1996;14:394-405.  Back to cited text no. 13
Sohn CH, Seo DW, Ryoo SM, Lee JH, Kim WY, Lim KS, et al. Life-threatening methemoglobinemia after unintentional ingestion of antifreeze admixtures containing sodium nitrite in the construction sites. Clin Toxicol (Phila) 2014;52:44-7.  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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