Toxic Methemoglobinemia Due to Prilocaine Injection After Circumcision

Introduction

Hemoglobin is categorized as methemoglobin if the iron of heme is oxidized to ferric (Fe+³) form. Methemoglobinemia is characterized by increased quantities of ferric iron containing hemoglobin over 1%. It is characterized clinically by cyanosis. Cyanosis suggests hypoxia in an infant or newborn. Several factors including hematological, cardiac or respiratory may be a cause of hypoxia. Since methemoglobin is useless as an oxygen carrier, it causes a varying degree of cyanosis. Methemoglobinemia may arise from hereditary disorders, but exposure to medication is the most common cause of methemoglobinemia.¹ We report cyanosis developing in three cases in newborns and early infancy due to use of prilocaine hydrochloride as a local anesthetic during circumcision.

Case Reports

Twenty-nine-day-old, 40-day-old and 3-month-old male infants were admitted with cyanosis. In their history, cyanosis appeared 60, 180, 30 minutes after prilocaine injection. Prior to circumcision, approximately 5 ml (5, 4 and 5 mg/kg respectively) prilocaine hydrochloride (Citanest® 0.5%) had been injected subcutaneous as local anesthesia to all patients. All of them had normal gestation and a history of uneventful spontaneous vaginal delivery. No abnormality was established in their physical examination except for cyanosis. Their arterial blood gases were within normal ranges. Glucose-6 phosphate dehydrogenases of all patients were normal. Chest radiograms and electrocardiograms were normal. Hemoglobin levels were 8.5 g/dl, 9 g/dl and 10.9 g/dl respectively. Methemoglobin levels were 20%, 29%, 27% respectively. Other biochemical analyses including renal and liver function tests were normal. Dextrose (5%) containing saline fluid intravenously was started to all patients and 1mg/kg of methylene blue orally plus ascorbic acid intravenously (100 mg/kg once a day) were given. Cyanosis completely disappeared at the 90, 100, 110 minutes of treatmentrespectively.

Discussion

Carrying of oxygen by hemoglobin to the tissues is vital. Methemoglobin has less oxygen carrying capability than functional hemoglobin. Heme iron autoxidized by several oxidant factors converts hemoglobin to methemoglobin during circulation.² Erythrocytes have some mechanisms to convert oxidized heme iron to normal ferrous (Fe+²) state. The major mechanism for this conversion is soluble NADH cytochrome b₅ reductase.¹ Deficiency of NADH cytochrome b₅ reductase and several abnormal hemoglobin variant as designated hemoglobin M may cause hereditary methemoglobinemias.¹

Methemoglobinemia manifests clinically by cyanosis if more than 1% of the hemoglobin pool is oxidized to the ferric form.³ It is well tolerated to methemoglobin concentration to 10%-20% but above 70% may cause death.¹ Because of lower activity of NADH cytochrome b 5 reductase in erythrocytes from infants aged less than 3 months, this age group may be more susceptible for methemoglobinemia.^4,5 As with our cases, the most common cause of methemoglobinemia is medication. Ingestion or exposures of skin or mucous membranes to oxidizing agents lead to methemoglobinemia.^1,6 Prilocaine as a local anesthetic is a well known oxidizing agent. It leads to an increase of methemoglobin concentration in 1 to 6-year-old children.⁷ Previously, Kara et al⁶ and Ozbek et al reported cases developing methemoglobinemia after prilocaine injection during newborn and infancy. They treated them with intravenous methylene blue. Unfortunately, because we could not find intravenous form of methylene blue, we had to give oral form. Although methylene blue is an oxidant, its reducing metabolic product is leukomethylene blue responsible for converting to ferric (Fe+³) iron to ferrous (Fe+²) state.¹ Dextrose should be given because it is a major source of NADH in erytrocytes.¹ Ascorbic acid decreased methemoglobin formation and can be used in treatment.⁹ Use of prilocaine is common during minor surgery in infancy and childhood. Circumcision during newborn and early infancy is a common religious practice especially in the Jewish and Islamic populations in our country (Turkey).

In conclusion, methemoglobinemia, a life-threatening condition, usually arises from use of oxidizing agents such as prilocaine in newborns and during early childhood, because infants less than 3 months of age are more susceptible to prilocaine. Physicians should be careful with this age group. When diagnosed, methylene blue should be given immediately.

From  Karadeniz Technical Universitys  Faculty of Medicine, Department of Pediatrics, Trabzon, Turkey (Dr Odemis, Dr Sonmez, Dr Aslan).

Address reprint requests to Ender Odemis, MD, Karadeniz Technical University, Faculty of Medicine Department of Pediatrics, 61080 Trabzon/Turkey.

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