noviembre 14, 2023

Cyanosis with refractory hypoxemia: a case report

AUTORES: Soto-Ramos M,1,4 Treviño-Zuñiga M,2,4 Hinojos-Gallardo LC,1,4 Hernández- Saldaña R,1 Guerrero-Lucio N,3,4 Colmenero-Rascón M,1 Aragón-Rico D,1 Carrillo-Rodríguez VM,1,4 Aldana-Vergara R4

1Facultad de Medicina y Ciencias Biomédicas, Universidad Autónoma de Chihuahua, Hospital Infantil de Especialidades de Chihuahua, Hospital Ángeles de Chihuahua, México

2Hospital Christus Muguerza de Chihuahua

3Centro Médico Internacional, Matamoros Tamaulipas, México

4Neumólogo Pediatra, México



La anestesia tópica se utiliza ampliamente para tratar el dolor localizado en procedimientos médicos y odontológicos. La lidocaína y la benzocaína son algunos de los anestésicos tópicos que se administran por vía oral, subdérmica o cutánea (crema, gel, spray).

Estos medicamentos generalmente se consideran seguros, con reacciones adversas mínimas, pero la exposición prolongada o el uso repetido aumentan el riesgo de absorción hacia el sistema circulatorio. El efecto secundario más común es la estimulación tisular, así como la alteración transitoria del gusto cuando se aplica en la cavidad oral.

La benzocaína puede causar metahemoglobinemia, que provoca alteraciones graves o incluso fatales con una sola aplicación o en forma inesperada después de aplicaciones repetidas. La sintomatología se presenta en minutos a horas después de su uso. Los anestésicos tópicos mixtos (lidocaína/prilocaína) también se han asociado con el desarrollo de metahemoglobinemia.

Este reporte presenta el caso de una niña de 13 años, previamente sana, que cursó con metahemoglobinemia inducida por anestésicos tópicos (MetHb), presentándose con cianosis central una semana después de haber sido operada de amigdalectomía y que usó anestésicos tópicos varias veces al día durante 7 días consecutivos. La saturación de oxígeno medida por oximetría de pulso fue de alrededor de 82%, a pesar de estar con oxígeno suplementario con cánula nasal de alto flujo, mientras que en el análisis de gases en sangre arterial mostró una presión parcial de oxígeno (PaO2) de 132 mmHg y una SatO2 de 94.7%. Esta desproporción en la saturación de oxígeno en las dos mediciones se produjo debido a la presencia de la variante de hemoglobina anormal (MetHb).

Palabras clave: metahemoglobinemia, cianosis, anestesia, saturación de oxígeno



Topical anesthesia is widely used to treat localized pain in medical and dental procedures. Lidocaine and benzocaine are some of the topical anesthetics that are administered orally, subdermally, or topically (cream, gel, spray).

These medications are generally considered safe, with minimal adverse reactions, but prolonged exposure or repeated use increases the risk of absorption into the circulatory system. The most common side effect is tissue stimulation, as well as transient taste alteration when applied in the oral cavity.

Benzocaine can cause methemoglobinemia, which leads to severe or even fatal complications with a single application or unexpectedly after repeated applications. Symptoms appear minutes to hours after use. Mixed topical anesthetics (lidocaine/prilocaine) have also been associated with the development of methemoglobinemia.

This report presents the case of a previously healthy 13-year old girl who experienced topical anesthetic-induced methemoglobinemia (MetHb), presenting with central cyanosis one week after undergoing tonsillectomy and using topical anesthetics multiple times a day for 7 consecutive days. Oxygen saturation measured by pulse oximetry was around 82%, despite receiving supplementary oxygen through a high-flow nasal cannula, while arterial blood gas analysis showed a partial pressure of oxygen (PaO2) of 132 mmHg and an oxygen saturation (SatO2) of 94.7%. This discrepancy in oxygen saturation between the two measurements occurred due to the presence of the abnormal hemoglobin variant (MetHb).

Keywords: methemoglobinemia, cyanosis, anesthesia, oxygen saturation



Hemoglobin is a protein in red blood cells that binds oxygen and transports it throughout the body. The oxygen-binding capacity of hemoglobin is 1.34 mL O2 per gram. One molecule of hemoglobin can reversibly bind four O2 molecules. The binding of oxygen to hemoglobin is determined by the partial pressure of oxygen.

Cyanosis is a bluish appearance of the skin, subungual skin, and mucous membranes of the mouth associated with increased levels of deoxygenated hemoglobin (>4 g/dL), sulfhemoglobin (>0.5 g/dL), or methemoglobin (>1.5 g/dL). There are two types of cyanosis. Central cyanosis is caused by a decrease in oxygen saturation (≤85 percent) and a systemic arterial concentration of deoxygenated hemoglobin in the blood above 5 g/dL. This is an indicator of underlying respiratory or cardiovascular conditions. Peripheral cyanosis is caused by a decrease in blood flow to the extremities, leading to a purple discoloration of the hands and feet. It is commonly seen in healthy infants in the first few days of life but can also occur in cardiovascular or respiratory conditions.

Methemoglobinemia can lead to alterations in hemoglobin’s oxygen concentration, and its production occurs in the body through three mechanisms:

  1. Auto-oxidation. When molecular oxygen binds to deoxyhemoglobin, one electron is partially transferred from the heme iron (Fe2+) to the bound oxygen. This process results in molecules in which the heme iron remains in its ferric (Fe3+) state. This occurs at a rate of 1%.
  2. Oxidative stress. Free radicals and endogenous compounds such as superoxide, nitric oxide, and hydrogen peroxide are produced during metabolic activity in the body, leading to the oxidation of the ferrous moiety in heme and subsequent methemoglobin formation.
  3. Exogenous causes. Nitrites that may be present in food and water can result in the production of superoxide radicals.

A combination of these factors results in the production of a small amount of methemoglobin every day.

The human body has at least three different mechanisms to effectively reduce methemoglobin, but the cytochrome b5-NADH pathway accounts for about 95% of erythrocyte-reducing capacity and is considered the only physiologically important pathway.

High concentrations of methemoglobin cause functional anemia through two mechanisms: by impairing the oxygen-carrying capacity of the blood and by shifting the oxygen dissociation curve to the left, resulting in tissue hypoxia due to impaired oxygen release.

Methemoglobinemia can be congenital or acquired, with acquired methemoglobinemia being much more common. It occurs as a result of exposure to substances that directly or indirectly cause oxidation of hemoglobin.

The diagnosis of methemoglobinemia is based on the clinical features observed in affected patients, including cyanosis that appears when MetHb levels exceed 1.5 g/dL (approximately 10% of total Hb), blood that appears brown or chocolate-colored, and anemia. Subclinical levels of MetHb below 25% can occur, while levels of 30-35% may cause mild symptoms such as dyspnea and headache. However, levels above 70% are life-threatening.

Case report

We present the case of a 13-year-old girl, originally from Mexico, who was brought to the Emergency Department with cyanosis and hypoxemia. She had undergone a tonsillectomy one week prior, and three days after the procedure, she developed cyanosis without any other related symptoms or fever. She had been using topical lidocaine and benzocaine at home for pain relief for several days.

During the physical examination, central and peripheral cyanosis were observed (figs. 1 to 3), while the respiratory and neurological systems appeared normal. The patient was provided with supplemental oxygen via a mask with a reservoir bag at a flow rate of 15 liters per minute, resulting in an improvement in oxygen saturation (SaO2) to 80%. Chest X-ray showed normal findings (fig. 4). Subsequently, the patient was treated with a high-flow nasal cannula at a flow rate of 30 L/min and fraction of inspired oxygen (FiO2) of 80%, leading to an improvement in SaO2 to 82% (figs. 5 and 6).

The arterial blood gas analysis revealed the following results: pH 7.42, pCO2 33, PO2 132, lactate 1.4, base excess (EB) -2.4, methemoglobin (MetHb) 30%, HCO3 21.4, and SaO2 94.7% (fig. 7).

Echocardiography showed normal cardiac structures, pulmonary artery (PA) systolic pressure from tricuspid regurgitation jet measuring 25 mmHg, and normal values for ventricular systolic and diastolic function.

Hematic biometry results were as follows: leukocytes 11.5, neutrophils 9.61, lymphocytes 1.4, hemoglobin 13.1, hematocrit 41.4%, platelets 292.8, D-dimer 2.71, ultra-sensitive troponin <0.03, NT-proBNP 361, and CRP 18.

There was a discrepancy between SaO2 measured by pulse oximeter and SaO2 measured by arterial blood gas, along with a high level of methemoglobin. As a result, the diagnosis of methemoglobinemia was made.

She was treated with intravenous methylene blue at a dose of 2 mg/kg, resulting in significant improvement (fig. 8).


Anesthetic-associated factors

Most cases reported in medical literature regarding acquired methemoglobinemia are related to benzocaine, which is an ester that works by blocking voltage-gated sodium channels on neurons. It is metabolized by plasma pseudocholinesterase, ethanol, and para-aminobenzoic acid. Animal studies have shown differences in the metabolism of benzocaine, leading to the production of a toxic metabolite —an aniline-containing N-hydroxyl derivative— which is capable of inducing methemoglobin.

The presence of mucosal trauma, particularly when the anesthetic is applied orally, such as in cases involving previous lesions associated with dental procedures or tracheal intubation, can lead to increased absorption of the anesthetic and cause methemoglobinemia.

The amount of anesthetic administered may also play a role in the pathophysiology of methemoglobinemia. Doses of 15 mg/kg in infants and between 150 to 300 mg have been implicated.

Patient-associated factors

Extremes of age are predisposing factors for the development of methemoglobinemia. The functional activity of NADH-cytochrome b5 reductase decreases with age.

According to a study by Kane et al., patients who developed methemoglobinemia were more likely to have an active systemic infection compared to the control group (68.4 vs. 6.8%; P < 0.001). Systemic infection is a significant cause of oxidative stress, which, in turn, increases methemoglobin production.

Pre-existing liver, cardiac, or lung diseases can also increase the risk of developing methemoglobinemia.


Clinical presentation

The clinical features observed in patients with methemoglobinemia include cyanosis, which appears when methemoglobin levels exceed 1.5 g/dLl (approximately 10% of total Hb), brown chocolate-colored blood, and anemia. Subclinical levels of methemoglobin below 25% may occur, while levels of 30-35% can cause mild symptoms such as dyspnea and headache. However, levels above 70% are considered fatal.

Other symptoms that may be present include pallor, fatigue, weakness, central nervous system depression, metabolic acidosis, seizures, dysrhythmias, and coma.



It should be considered in all patients who have undergone topical anesthetic treatment and present with these symptoms. The measurement of methemoglobin (MetHb) levels in arterial blood using co-oximetry is diagnostic. Pulse oximetry is not useful for the diagnosis of methemoglobinemia.



Once suspicion of methemoglobinemia is established in a patient previously treated with topical anesthetic, immediate suspension of the anesthetic is necessary.

The active treatment for methemoglobinemia involves the administration of methylene blue at a dose of 1-2 mg/kg over 5 minutes. Methylene blue, through its metabolite leukomethylene blue, helps activate the flavin-NADPH pathway and is recommended for patients with 30% or more of methemoglobin. The dose can be repeated after 30-60 minutes if significant symptoms persist or if methemoglobin levels remain above the treatment threshold.

If methylene blue administration is ineffective after the second dose, underlying conditions such as G6PD deficiency and NADPH-methemoglobin reductase deficiency should be considered as possible reasons for treatment refractoriness.

In cases where treatment with methylene blue is ineffective or not recommended, alternative options may include ascorbic acid, exchange transfusion, or hyperbaric oxygen therapy.



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