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Cetacaine induced methemoglobinemia: overview of analysis and treatment strategies.


Methemaglobinemia is a commonly occurring clinical condition with its etiology related to either inherited or acquired causes. Congenital or inherited causes of methemoglobinemia result due to decreased activity of the enzyme cytochrome b5 reductase resulting in diminished enzymatic reduction of the hemoglobin molecule. Acquired causes are more prevalent and familiarity with known precipitants is necessary to address any acute presenting symptomology. (1) Conversion of heme iron to its ferric state makes the heme particle incapable of binding oxygen, resulting in a firmer binding of the oxygen molecule to the heme particle. This situation results in inadequate oxygen delivery to the tissues leading to hypoxia and other life-threatening conditions.

Cetacaine spray is a benzocaine based topical anesthetic which is commonly used in endoscopic procedures. Although, methemaglobinemia is a known side effect of benzocaine based anesthetics, the acuity and the variability in presentation requires quick understanding of the complaints and a specific solution. Presenting complaints mask a myriad of other differentials and although uncommon, immediate recognition is necessary for this potentially fatal condition.

Case Presentation

A 70 year old patient with streptococcus bacteremia was scheduled for a transesophageal echocardiogram (TEE). This patient had earlier denied any history of, IV drug abuse or any other cardiac interventions in the past. Physical examination findings were negative for any noticeable murmurs, dermatological findings or any other vascular phenomenon. Topical cetacaine was utilized as part of the operative protocol with a decline noted in the oxygen saturations within 20 minutes of administration. The patient at this point denied any significant complaints such as chest pain or shortness of breath. Patient also did not demonstrate any neurological or mental status changes during this episode. An ABG was then obtained which confirmed adequate oxygenation with PaO2 levels of 148. A methemoglobin level was then collected which returned with elevated levels of 33%. Decision was then made to give methlene blue at 1mg/kg dosing with improvements noted within 1 hour of administration. Repeat ABG's demonstrated methemoglobin levels of 16.8%. Patient was transferred to the ICU and was kept on continuous pulse oximetry for the next 36 hours. No further interventions with methlene blue were made given the patients asymptomatic status. Other differentials for this patient's hypoxia/hypoxemia could include hypoventilation, right to left shunt, atrioseptal defects or a ventilation perfusion mismatch. These were excluded by the patient's normal echocardiographic findings, chest X-ray and arterial blood gas results.


Methemoglobinemia leads to a diminished oxygen supply resulting in a "saturation gap" between the oxygen saturations on a pulse oximetry and the arterial blood gas. (5) Presenting complaints could include fatigue, malaise, dyspnea, headaches, dysrhythmias, coma and or death. (7) This condition could be secondary to a genetic defect involving the cytochrome b5 reductase pathway (Figure 1). Reduction of methemaglobin to hemaglobin involves two pathways: 1) Cytochrome b5 reducatase pathway 2) NADPH glucose 6 phosphate dehyrogenase in the hexose monophosphate shunt pathway (Figure 1). (8) Other more commonly seen causes could be from exposure to a potential inciting agent (Table 1).

Symptoms usually occur between 15 to 60 minutes of product administration with delayed reaction typically seen in products involved with slow absorptive mechanisms, such as with powder application. Sites of systemic absorption include broken skin tissue, inflamed gastric sites, eczematous skin and respiratory mucosa with the risk of a reaction increasing with number and duration of sprays administered. (2) Package instructions typically recommend a 1-2 second spray but given human performance limitations, no reliable estimate fractions can be predicted. Symptoms are typically noticed at methemoglobin concentrations of greater than 15%. (5) List of potential inciting agents are listed below.

Clues at the bedside include: persistent cyanosis, tachypnea, low pulse oximetry with normal Pa[O.sub.2] levels on an ABG and a classic chocolate brown appearance of the arterial blood. (9)

Confirmation of the diagnosis requires CO-oximetry testing, which utilizes multiple wavelengths of light to detect serum methemoglobin levels. Other diagnostic modalities include a positive Kronenberg test and the presence of an oxygen saturation gap. (2) Confirmation with the Evelyn-Malloy assay is required as follow up since the co-oximeter can falsely read methylene blue as if it was methemoglobin. (5) Recent advances in technology have led to the creation of a device (The Rainbow Rad 57) which possess the ability to measure methemoglobin and carboxyhemoglobin in a noninvasive manner allowing a significant improvement in the ability to quickly diagnose and address these medical emergencies. (3)

Treatment strategies employed are different for an acquired cause as compared to a congenital cause. The current mainstay of treatment for an acute presenting condition involves the utilization of methylene blue. Methylene blue directly reduces the quantity of methemoglobin in the blood and is administered intravenously in a dose of 1 to 2 mg/ kg given as a 1% solution over 5 minutes. (9) The dose maybe repeated if no resolution of symptoms is achieved within 1 hour. It should also be noted that doses of methylene blue in excess of 7mg/kg can precipitate and or worsen Methemoglobinemia. (5) Other treatment strategies include: Exchange transfusion, hyperbaric oxygen and ascorbic acid. Careful monitoring in the ICU is typically required for 24 to 36 hours given the possibility of rebound methemoglobinemia after exposure. (3)


Benzocaine related methemoglobinemia is an important clinical problem and requires physicians to be extra vigilant when utilized. Topical anesthetics have been reported to cause methemaglobinemia, but this adverse event is extremely rare and is not usually listed as one of the possible complications of procedures involving topical anesthetic use. Majority of patients are able to tolerate benzocaine based anesthetics but some patients will unfortunately develop methemoglobinemia upon exposure. Predicting the population at risk is not possible but given the severity of this condition, prompt recognition and treatment is needed.


(1.) Bittmann S, Kruger C. Benzocaine-Induced Methaemoglobinemia: A Case Study. British Journal of Nursing 2011, Vol. 20. No. 3: 168-70.

(2.) Conway R, Browne P, O'Connell P, et al. An Unusual Cause of Methaemoglobinemia. Irish Medical Journal 2009, Vol. 102 Number 6, Page: 184.

(3.) Guay J. Methemoglobinemia related to local anesthetics: a summary of 242 episodes. Anesthesia and Analgesia 2009; 108(3): 837-45.

(4.) Husseini AE, Azarov N. Is Threshold for treatment of Methemoglobinemia the same for all? A case report and literature review. American Journal of Emergency Medicine 2010, 748 e5 to 748 e10.

(5.) Moore TJ, Walsh CS, Cohen MR. Reported adverse event cases of methemoglobinemia associated with benzocaine products. Archives of Internal Medicine 2004; 164: 1192-1196.

(6.) Pallais CJ, Mackool BT, Pitman BM et al. A 52 year old Man with Upper Respiratory Symptoms and Low Oxygen Saturation Levels, New England Journal of Medicine 364; 10, March 10, 2011, Page 957-65.

(7.) Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, Pharmacology, and Clinical Management. Annals of Emergency Medicine 1999; 34(5): 646-56.

(8.) Yubisui T, Takeshita M, Yoneyama Y. Reduction of methemoglobin through flavin at the physiological concentration by NADPH-flavin reductase of human erythrocytes. Journal of Biochemistry. 1980; 87(6): 1715.

Rizwan Khan, DO

Camden Clark Medical Center, Department of Internal Medicine

Bairava S. Kuppaswamy, MD, FACP

Camden Clark Medical Center, Department of Internal Medicine

Corresponding author: Rizwan Khan, DO, Camden Clark Medical Center, Department of Internal Medicine, Parkersburg, WV 26101;

Table 1: Substances that can cause Methemoglobinemia (4)

Inorganic Agents               Nitrates, fertilizers,
                               chlorates, copper sulfates

Organic Agents                 Amyl Nitrate, Isobutyl
                               Nitrite, Sodium Nitrite,
                               Nitroglycerin, Nitroprusside,
                               Nitric Oxide, Nitrogen
                               Dioxide, Trinitrotoluene,
                               Combustion products

Drugs                          Local Anesthetics: Benzocaine,
                               Lidocaine, Prilocaine
                               Pyridium, Anti-malarials
                               --Primaquine, Chloroquine,
                               Rasburicase, Cyclophosphamide,
                               Ifosfamide, flutamide,
                               Acetaminophen, Acetanilid,
                               Phenacetic, celecoxib,
                               Zopiclone, Methlene Blue (high
                               doses in G6PD-Deficient
                               patients) Antibiotics:
                               Sulfonamides, Nitrofurantoins,
                               P-aminosalicylic acid, Dapsone

Industrial/Household Agents    Aniline Dyes, Nitrobenzene,
                               naphthalene (moth balls),
                               aminophenol, nitroethane (nail
                               polish remover)
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Title Annotation:Scientific Article
Author:Khan, Rizwan; Kuppaswamy, Bairava S.
Publication:West Virginia Medical Journal
Article Type:Case study
Date:May 1, 2013
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