EMLA Toxicity After Application for Allergy Skin Testing

Abstract

EMLA (eutectic mixture of local anesthetics) is a eutectic mixture of lidocaine and prilocaine used to provide topical anesthesia for various procedures. When used properly, EMLA can provide anesthesia to a depth of 5 mm in intact skin, allowing for better pain control during superficial procedures (eg, venipuncture and lumbar puncture).1 Its use has grown widely over the past few years.The adverse effects most commonly related to the use of EMLA are mild local reactions such as edema, erythema, and transient pallor. More-severe reactions, however, have been reported, including methemoglobinemia and seizures.1–6 Only 2 prior reports have described the association between the use of EMLA and the development of seizures.2 This case stands out from prior reports in that a proper amount of EMLA was used but applied to a large area of diseased skin.A healthy 3-year-old white female with a history of eczema was referred to an allergist because of seasonal and environmental allergy symptoms. She was scheduled for allergy skin testing. Her parents were given a prescription for a 5-g tube of EMLA to be applied to the patient’s back, which then was to be covered with plastic wrap, before arriving at the allergist’s office on the day of skin testing.On the morning of the scheduled visit, the parents applied the EMLA as instructed (covering a surface area of ∼1140 cm2). Approximately 1 hour later, as the family was driving to the allergist’s office, the patient’s mother noted that she had become less interactive and less responsive. Her parents then noticed that she was foaming at the mouth with her eyes open and fixed, jaw locked, and all extremities shaking. This activity lasted 3 to 5 minutes, and the father pulled to the side of the road. They took her out of the car and called for an ambulance. The father noticed a raised, erythematous rash covering her back. He removed the plastic wrap and the small amount of EMLA cream that was still present on her back.On arrival of emergency medical services, the patient was noted to have perioral and distal extremity cyanosis. She received supplemental oxygen and was transported to the local emergency department. In the emergency department, the patient was alert and playful. Initial vital signs were within the normal range for her age; however, during her stay in the emergency department, the patient developed mild bradycardia, hypotension (to 80/40), and worsening of her perioral cyanosis. She received an intravenous fluid bolus and was placed on 100% oxygen via nonrebreather face mask. Venous blood gas and co-oximetry (∼5 hours after application of EMLA) revealed: pH, 7.37; partial pressure of carbon dioxide, 42; partial pressure of oxygen, 90; HCO3, 24; oxyhemoglobin, 80%; and methemoglobin, 17.7%. A lidocaine level, drawn 2.5 hours after EMLA application, was 3.0 μg/mL. Complete blood count and electrolytes were within normal limits.The patient was transferred to the pediatric intensive care unit at the local children’s hospital for additional evaluation and management and received 100% oxygen overnight with close monitoring. She remained asymptomatic throughout her stay in the unit. Repeat co-oximetry the next morning revealed: oxyhemoglobin, 92.6%; and methemoglobin, 1.4%. She then was discharged from the hospital without incident.Additional discussions with the family revealed no other medications taken in the preceding 3 days, no ingestion of EMLA, no recent illnesses, and no personal or family history of seizures.EMLA is a eutectic mixture of 2.5% lidocaine and 2.5% prilocaine. Each gram of EMLA contains 25 mg of lidocaine and 25 mg of prilocaine. Dermal analgesia is achieved within 1 hour after application, with maximal effects at 2 to 3 hours and continued effects for 1 to 2 hours after removal. There are specific recommendations for the application of EMLA cream in children, which, in this case, would be a maximum of 5 g applied over an area of 100 cm2 (Table 1).7Lidocaine is an aminoacyl amide that is used as an anesthetic and antidysrhythmic agent. It undergoes metabolism in the liver to active the metabolites monoethylglycinexylidide and glycinexylidide, both of which have activity similar to, although weaker than, lidocaine.8–10 Lidocaine causes a wide spectrum of effects with a well-documented toxicity profile. At low levels (0.5–4 μg/mL), lidocaine has an anticonvulsive effect. At moderate levels (4.5–7.5 μg/mL), it may cause restlessness, dizziness, blurred vision, or tremors. At high levels (>7.5 μg/mL), it can produce generalized tonic-clonic seizures.9,11Prilocaine is an intermediate aminoamide with activity similar to lidocaine. It has a wider volume of distribution and a faster plasma clearance than lidocaine, causing lower serum levels after administration of similar doses of the 2 drugs. Despite these lower levels, prilocaine, in overdose, may contribute significantly to the development of methemoglobinemia. Prilocaine is metabolized in the liver to o-toluidine, which then oxidizes normal hemoglobin to methemoglobin. The effects of an elevated methemoglobin level can range from cyanosis and lightheadedness to seizures, arrhythmias, and even death (Table 2).12In our case, the patient had symptoms most consistent with lidocaine toxicity associated with a concomitant methemoglobinemia. The single lidocaine and methemoglobin levels drawn in this case, and the delay in drawing them, make it difficult to determine the patient’s lidocaine level at the time of the seizure. However, the patient had multiple factors that may have contributed to an increased lidocaine load and, therefore, a toxic lidocaine level. These factors include application of the EMLA cream over a surface area far exceeding recommendations and its application to eczematous skin. Prior studies have shown a dramatically increased absorption of topically applied lidocaine through diseased skin.13This case stresses the importance of patient and parental instructions when prescribing any medication, even medications that are used commonly without frequent complications. It is also important for practitioners to remember that any medication, even when used topically, may have significant potential for toxicity.“It is a maxim of medicine that ‘the therapeutic benefits of hope cannot be overstated.’ So, as part of his/her professional skill, a doctor must try to give Hope. … How, then, can the doctor discuss terror? Yet, if the doctor pretends there is no place for fear because all is well, he or she may not be a good liar; patients pick up body language, the over-practiced smile, the false tone. Or, does the doctor evade the subject of Hope? A patient may sense this, too.”Gearin-Tosh M. Living Proof. Scribner; 2002Submitted by Student