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Hemolysis and acquired methemoglobinemia associated with lidocaine and benzocaine topical application: a case report



Topical anesthetics are commonly used over the counter, and one of the adverse effects of these medications is methemoglobinemia, which is a serious and life-threatening condition.

Case presentation

We describe a 25-year-old Persian male presenting with generalized weakness, dizziness, headache, and cyanosis. In addition, he had genital warts starting 3 weeks ago, which were self-treated with podophyllin, resulting in itching and pain. He used over-the-counter topical anesthetics, including benzocaine and lidocaine, to reduce the symptoms. According to the lab data, signs and symptoms of methemoglobinemia and hemolysis were diagnosed. Considering the hemolysis, ascorbic acid was used for treatment. The patient was discharged after 5 days with normal arterial blood gas and pulse oximetry and no signs and symptoms.


This case highlights that self-administration of some topical anesthetics may lead to potentially fatal conditions.

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Hemoglobin A (Hb), the main type of the hemoglobin in adolescents, contains ferrous iron (Fe2+) and four heme groups [1]. Oxidization of the ferrous iron (Fe2+) to ferric iron (Fe3+) produces methemoglobin [1]. Methemoglobin is incapable of binding, transporting, and releasing oxygen into the tissues effectively, resulting in hypoxia and functional anemia [2]. Physiological mechanisms and enzymatic systems protect the red blood cells against oxidative stress and try not to let the methemoglobin levels exceed 1–2% of the total hemoglobin [2, 3]. Methemoglobinemia, which means high levels of methemoglobin in the blood, is a rare but life-threatening condition, presenting in hereditary or acquired forms [4]. Hemoglobin M disease, cytochrome b5 reductase deficiency, and glucose-6-phosphate dehydrogenase (G6PD) deficiency are causes of hereditary methemoglobinemia [5]. Furthermore, some drugs, such as dapson, nitroglycerine, nitroprusside, nitric oxide, sulfanamides, phenazopyridine, chloroquine, lidocaine, prilocaine, and benzocaine, may cause acquired methemoglobinemia [4, 5]. Cocaine-derived anesthetics, including lidocaine and benzocaine, are extensively used in medical procedures, such as endoscopy and bronchoscopy [6]; moreover, they may be used topically [6]. In this study, we present a unique and atypical case of methemoglobinemia and hemolysis induced by self-administration of topical lidocaine and benzocaine.

Case presentation

A 25-year-old self-employed Persian male with no past medical history presented to the hospital with generalized weakness, dizziness, and headache for almost 7 days. After an accurate history taking, he also reported some genital warts that appeared starting 3 weeks ago. He started self-treatment of the warts with podophyllin, which is an over-the-counter topical ointment. Self-administration of the excessive podophyllin caused severe pain and itching of the genitalia. To reduce the noticed symptoms, he started using over-the-counter topical anesthetics, such as benzocaine and lidocaine, for approximately 2 weeks. The patients surprisingly reported that he used four ointment tubes daily: two tubes of benzocaine ointment 5% (60 g/10 g) and two tubes of lidocaine ointment 5% (70 g/10 g). He did not smoke, and his family history of polycythemia and hematologic, cardiovascular, and pulmonary disorders was negative. On physical examination, he was alert and not distressed, and skin pallor and perioral and acral cyanosis were remarkable. Examination of the heart and lungs was normal. The vital signs revealed 37 °C (98.6 °F), blood pressure of 115/75 mmHg, heart rate of 80 beats per minute, and respiration of 18 breaths per minute. Oxygen saturation (SpO2) was 75% on room air, increasing to almost 85% when using an oxygen mask. Electrocardiogram (ECG) and chest X-ray were normal. Laboratory findings indicated that anemia and renal and liver functional tests and inflammatory markers [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)] were normal. Additionally, the urine analysis was not remarkable, and the urine culture was negative. G6PD was sufficient. Viral markers, including human immunodeficiency virus (HIV) Ab, hepatitis C virus (HCV) Ab, hepatitis B surface (HBS) Ag, and HBS Ab were nonreactive. Prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) were normal. Furthermore, the lactate dehydrogenase (LDH) and the total and direct bilirubin increased up to 3500 U/L, 2.8 mg/dL, and 1.2 mg/dL, respectively. The arterial blood gas (ABG) had chocolate-brown appearance and measured pH of 7.51, pCO2 26.8 mmHg, pressure of O2 (pO2) of 189.2 mmHg, HCO3 of 21.1 mEq/L, and arterial oxygen saturation (SaO2) of 99.4%. CO-oximetry revealed total calculated hemoglobin of 7.5 g/dL, oxyhemoglobin of 70.9%, carboxyhemoglobin of 8.2%, and methemoglobin of 19.5%. Considering that abnormal LDH and bilirubin levels may be due to hemolysis, direct and indirect Coombs tests were taken, which were negative, and splenomegaly was not detected in abdominopelvic ultrasonography. Considering the normal cardiovascular and pulmonary findings (ECG and chest X-ray) and according to the excessive application and the discrepancy between SaO2 and SpO2, the final diagnosis was lidocaine- and benzocaine-induced methemoglobinemia and hemolysis. According to the hemolysis, methylene blue was not the choice of the treatment. The anesthetic ointment was discontinued, and 3 g ascorbic acid (vitamin C) was intravenously administered daily for 3 days. After 2 days, repeated CO-oximetry showed decreased methemoglobin (12.3%) and increased oxyhemoglobin (76.1%). The cyanosis and hemolysis symptoms disappeared within 3 and 5 days, respectively. At the time of discharge, all signs and symptoms were resolved so that SpO2 was 97–98%, LDH and bilirubin levels returned to normal ranges, methemoglobin was 0.3%, and oxyhemoglobin increased up to 91.6%.


The acquired form of methemoglobinemia may be induced by medication overdose following ingestion, skin absorption, and inhalation [4]. Drugs may oxidize the hemoglobin directly or indirectly by producing superoxide free radicals [4]. Route of administration, prolonged use, body surface area, age, accompanying use of oxidative drugs, comorbidity, and high doses of oxidizing drugs are related to the occurrence and severity of methemoglobinemia [4]. A methemoglobin level up to 15% of total hemoglobin is asymptomatic in healthy patients; headache and fatigue is associated with a level ranging from 15% to 30%; dizziness, dyspnea, and syncope occur at levels of 30–50%; and at levels higher than 50%, central nervous system (CNS) depression, coma, and death are expected [2, 7]. Symptoms may be worsened due to cardiovascular, hematologic, and pulmonary disorders, as well as infection and renal or liver failure [4]. Prilocaine, lidocaine, and benzocaine are anesthetics that may cause methemoglobinemia [8]. In the current case, the excessive use of topical benzocaine and lidocaine resulted in methemoglobinemia presenting with dizziness, cyanosis, and generalized weakness. Nappe et al. reported a case of methemoglobinemia in a patient who used benzocaine gel three times daily for 3 days [7]. The gel was self-administered to reduce the toothache [7]. One study conducted by Hahn et al. demonstrated that the use of five tubes of EMLA cream (lidocaine and prilocaine) before laser epilation resulted in methemoglobinemia [9]. Furthermore, Lavergne et al. [10] presented a case of methemoglobinemia and acute hemolysis induced by tetracaine lozenges. Several studies reported methemoglobinemia induced by inhalation of anesthetics [11, 12]. Methemoglobinemia is diagnosed by pulse oximetry, patient symptoms, and ABG with CO-oximetry [7]. Oxygen saturation gap between SaO2 measured in ABG and SpO2 predicts methemoglobinemia [7]. In calculating SaO2, all the hemoglobin is assumed normal, whereas SpO2 shows the percentage of oxyhemoglobin compared with the total hemoglobin [7]. In this regard, methylene blue and ascorbic acid are used to treat hyperoxia [2]. Methylene blue, which is not used in hemolysis and G6PD deficiency, oxidized the nicotinamide adenine dinucleotide phosphate (NADPH) and reduced to leukomethylene blue, which turns methemoglobin to hemoglobin [7]. Ascorbic acid acts directly as an electron donor and reduces methemoglobin to hemoglobin [2]. Considering the strengths of the current study, in this case acquired methemoglobinemia was accompanied with hemolysis, which was not detected in previous studies and is more likely to be noticed in patients presenting with methemoglobinemia. At first, due to cultural concerns, the patient avoided letting us know about the genital warts, and this could have deviated us from the correct diagnosis; thus, cultural differences should be observed.


Commonly used drugs may cause acquired methemoglobinemia. Over-the-counter topical anesthetics, including benzocaine and lidocaine, are supposed to induce methemoglobinemia. Self-administration of these drugs is an important issue that may cause life-threatening conditions. Thus, methemoglobinemia should be considered in patients presenting with dyspnea, dizziness, hypoxia, and cyanosis.

Availability of data and materials

The datasets analyzed in the current study are available from the corresponding author on reasonable request.



Over the counter


Arterial blood gas




Glucose-6-phosphate dehydrogenase

SpO2 :

Saturation of peripheral oxygen




Erythrocyte sedimentation rate


C-reactive protein


Human immunodeficiency virus


Hepatitis C virus


Hepatitis B surface


Prothrombin time


Activated partial thromboplastin time


International normalized ratio


Lactate dehydrogenase

pCO2 :

Pressure of CO2

pO2 :

Pressure of O2

SaO2 :

Arterial oxygen saturation


Central nervous system


Nicotinamide adenine dinucleotide phosphate


  1. Cortazzo JA, Lichtman AD. Methemoglobinemia: a review and recommendations for management. J Cardiothorac Vasc Anesth. 2014;28(4):1043–7.

    Article  CAS  PubMed  Google Scholar 

  2. Taleb M, Ashraf Z, Valavoor S, Tinkel J. Evaluation and management of acquired methemoglobinemia associated with topical benzocaine use. Am J Cardiovasc Drugs. 2013;13(5):325–30.

    Article  CAS  PubMed  Google Scholar 

  3. Faust AC, Guy E, Baby N, Ortegon A. Local anesthetic–induced methemoglobinemia during pregnancy: a case report and evaluation of treatment options. J Emerg Med. 2018;54(5):681–4.

    Article  PubMed  Google Scholar 

  4. Alanazi MQ. Drugs may be induced methemoglobinemia. J Hematol Thrombo Dis. 2017;5(3):1–5.

    Google Scholar 

  5. Cefalu JN, Joshi TV, Spalitta MJ, Kadi CJ, Diaz JH, Eskander JP, et al. Methemoglobinemia in the operating room and intensive care unit: early recognition, pathophysiology, and management. Adv Ther. 2020;37(5):1714–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Barash M, Reich KA, Rademaker D. Lidocaine-induced methemoglobinemia: a clinical reminder. J Am Osteopath Assoc. 2015;115(2):94–8.

    PubMed  Google Scholar 

  7. Nappe TM, Pacelli AM, Katz K. An atypical case of methemoglobinemia due to self-administered benzocaine. Case Rep Emerg Med. 2015;2015: 670979.

    PubMed  PubMed Central  Google Scholar 

  8. Wang S, Giannakopoulos H, Lowstetter J, Kaye L, Lee C, Secreto S, et al. Lack of methemoglobin elevations after topical applications of benzocaine alone or benzocaine plus tetracaine to the oral mucosa. Clin Ther. 2017;39(10):2103–8.

    Article  CAS  PubMed  Google Scholar 

  9. Hahn I-H, Hoffman RS, Nelson LS. EMLA®-induced methemoglobinemia and systemic topical anesthetic toxicity. J Emerg Med. 2004;26(1):85–8.

    Article  PubMed  Google Scholar 

  10. Lavergne S, Darmon M, Levy V, Azoulay E. Methemoglobinemia and acute hemolysis after tetracaine lozenge use. J Crit Care. 2006;21(1):112–4.

    Article  PubMed  Google Scholar 

  11. Mir WAY, Shrestha DB, Reddy VK, Gaire S, Verda L. A case report of acute transient encephalopathy following a trans-esophageal echocardiography. Cureus. 2021;13(10): e18580.

    PubMed  PubMed Central  Google Scholar 

  12. Riaz S, Kudaravalli P, Saleem SA, Heisig D. Methemoglobinemia: a life-threatening complication of topical pharyngeal anesthetics. Cureus. 2020;12(4): e7900.

    PubMed  PubMed Central  Google Scholar 

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We appreciate Tehran University of Medical Sciences. The authors also express their appreciation to the patients of this study.


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NKH and MR analyzed and interpreted the data. GHD and NKH drafted the initial manuscript. NKH supervised the project. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ghazal Daftari.

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This study was conducted per the Declaration of Helsinki and was approved by the Imam Khomeini Hospital Complex, Tehran University of Medical Science, Tehran, Iran. The patient was informed of the study, and a consent form was obtained.

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Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

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Khajavirad, N., Daftari, G. & Jelodar, M.R. Hemolysis and acquired methemoglobinemia associated with lidocaine and benzocaine topical application: a case report. J Med Case Reports 17, 146 (2023).

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  • Topical anesthetics
  • Methemoglobin
  • Lidocaine
  • Benzocaine
  • Hemolysis