Methemoglobinemia Induced by Prilocaine in a Child With Noonan Syndrome

Abstract

Limited information is currently available on methemoglobinemia caused by the administration of prilocaine in children undergoing dental procedures in Japan. This case report presents the development of methemoglobinemia due to prilocaine overdose. The patient was a female aged 5 years 8 months with Noonan syndrome who also had pulmonary valve stenosis and hypertrophic cardiomyopathy. She presented with severe dental caries affecting 12 total teeth and required general anesthesia due to a lack of cooperation during dental treatment. General anesthesia was performed, during which 3% prilocaine with 0.03 IU/mL felypressin was administered intraoperatively via infiltration. Her SpO₂ gradually decreased after 30 minutes, and cyanosis was observed postoperatively. Several assessments including a 12-lead electrocardiogram, an anteroposterior chest radiograph, and venous blood gas analysis were performed to identify potential causes. However, there were no indications of acute respiratory or cardiovascular abnormalities. It was noted that a total of 192 mg prilocaine was administered during the procedure, and methemoglobinemia was suspected to have developed because of overdose. Further testing revealed an elevated serum methemoglobin of 6.9%, supporting methemoglobinemia as the cause of her decreased SpO₂. In dental procedures that require the use of prilocaine to treat multiple teeth, particularly for pediatric patients, it is important to carefully manage prilocaine dosing, as an overdose may lead to methemoglobinemia.

INTRODUCTION

Methemoglobin (MetHb) is an oxidized form of hemoglobin (Hb) in which heme iron configuration is in the ferric state (Fe³⁺) instead of the ferrous state (Fe²⁺). MetHb normally constitutes approximately 1% of all Hb. Several symptoms develop as the level of MetHb increases. Methemoglobinemia may be caused by a variety of substances that exert oxidative effects, such as nitrogen oxides, acetaminophen, and local anesthetics, most commonly prilocaine and benzocaine.^1,2 In Japan, there have been 3 case reports of methemoglobinemia in newborns resulting from infiltrative administration of prilocaine during dental procedures. However, limited evidence is currently available on methemoglobinemia in children. In the following case report, we describe a patient with Noonan syndrome who developed methemoglobinemia because of a prilocaine overdose during general anesthesia for a dental procedure. The patient and her parents provided their permission to publish the features of this case, and written informed consent was obtained.

CASE PRESENTATION

The patient was a girl aged 5 years 8 months who was below the average growth range for her age at the time of surgery (height 98 cm; weight 16 kg; body mass index 16.6 kg/m²). The patient had pain in her mouth that had persisted the year prior to surgery and upon visiting a private dental clinic was diagnosed with rampant dental caries involving multiple teeth. Because she was uncooperative during dental treatment, the patient was referred to our pediatric dentistry department for further examination. Her subsequent treatment plan included restoration of 8 teeth and 4 extractions to be completed under general anesthesia.

The patient was born at 40 weeks 2 days of gestation by normal delivery (3110 g). At 4 months of age, she was diagnosed with pulmonary valve stenosis and hypertrophic cardiomyopathy. The patient was diagnosed with Noonan syndrome at 4 years of age because she presented with short stature and a depression in her forehead midline that was suspected to have been caused by wound dehiscence of the coronal suture. She had since been followed by the pediatric cardiology department every 6 months. Obstructive sleep apnea was also suspected based on a history of loud snoring; however, a definitive diagnosis was lacking. The patient was not taking any medications and had no known allergies.

Routine preoperative blood tests were all within normal limits, and there were no abnormal findings on preoperative anteroposterior chest radiograph. An echocardiogram demonstrated mild pulmonary valve stenosis and hypertrophic cardiomyopathy Electrocardiography revealed a mild degree of left axis deviation with no other abnormalities noted.

During the preoperative anesthesia consultation, the patient's mother reported that she snored loudly at night. Physical examination revealed the patient had grade II palatine tonsil hypertrophy and was categorized as Mallampati class II.

Food intake was prohibited starting at 2100 hours the night before surgery, after which the patient was allowed to drink only clear liquids. She consumed 300 mL of water 2.5 hours before surgery and was orally administered 10 mg of midazolam 20 minutes before entering the operating room, where standard anesthesia monitors were applied. General anesthesia was induced using sevoflurane 8% with a mask and a continuous intravenous infusion of remifentanil at 0.5 μg/kg/min once intravenous access was obtained. After the administration of rocuronium 15 mg, the patient was orally intubated with a wire-reinforced size 5.0 oral endotracheal tube. General anesthesia was maintained with continuous intravenous infusions of propofol 12 mg/kg/h (200 μg/kg/min) and remifentanil 0.2 μg/kg/min along with oxygen 1.5 L/min and air 0.5 L/min. Before starting the surgical procedure, betamethasone 2 mg and ampicillin 0.5 g were administered intravenously, and an additional dose of ampicillin 0.5 g was administered 2 hours 45 minutes later.

At the start of surgery, local anesthesia was administered using 3% prilocaine with 0.03 IU/mL felypressin. A total of 6.4 mL was injected intraorally throughout surgery as follows: 1.5 mL at 1000 hours at the beginning of treatment, 1.8 mL at 1100 hours, 0.3 mL at 1110 hours, 1 mL at 1145 hours, and 1.8 mL at 1220 hours.

The patient's SpO₂ was maintained at 100% for the first 30 minutes of surgery. The endotracheal tube was moved from the left to the right corner of the mouth coincident with the start of treatment on the left side. Aspiration of possible airway secretions that consisted of clear sputum was performed at that time, and the patient's SpO₂ began to gradually decrease. Intravenous acetaminophen 250 mg was administered for postoperative pain relief at 1220 hours, 2.5 hours after the start of surgery. Her SpO₂ was 95% with an FiO₂ of 30% at the end of surgery at 1245 hours, and rhonchorous lung sounds were noted upon auscultation, which resolved completely following aspiration of a small amount of clear sputum from the endotracheal tube. However, tracheal aspiration did not effectively increase her SpO₂; therefore, a 12-lead electrocardiography and an anteroposterior chest radiograph were immediately obtained, which failed to show any abnormal findings. An arterial blood gas analysis was deemed necessary, but a clinical error resulted in venous blood being inadvertently collected. The obtained sample was judged to be venous blood as the pO₂ was 61 mm Hg at an FiO₂ of 100% and an SpO₂ 92% to 95% (Table). EtCO₂ was 35 mm Hg at the end of surgery and 48 mm Hg at extubation, which occurred at 1330 hours, roughly 40 minutes after surgery. Her SpO₂ remained within 92%–95% with supplemental oxygen administered via a face mask. The overall duration of anesthesia was 4 hours 22 minutes, and the total operative time was 2 hours 45 minutes.

Venous Blood Gas

Parameter	Value	Reference Range
pH	7.321	7.33–7.44
pO2, mm Hg	61	35–40 (on air)
pCO2, mm Hg	46.9	40–55
HCO3−, mEq/L	24.8	24–28
BE, mEq/L	−1.8	−2.0 to + 2.0

After returning to the ward, the patient was monitored via electrocardiography, pulse oximetry, and a noninvasive blood pressure monitor. Cyanosis of the lips was observed 15 minutes after she returned to the ward, and her SpO₂ decreased to 89% to 90%. At 1415 hours, approximately 1 hour after surgery, her SpO₂ further decreased to 83% to 84%, and her heart rate ranged between 127 and 136 beats per minute. A simple face mask was used for supplemental oxygen at 2 L/min, and her SpO₂ recovered to 91%. Since the patient had a productive cough, a nebulizer with saline was used for humidification. Although we initially suspected that her decreased SpO₂ was due to retention of airway secretions, the patient did not have abnormal breath sounds or altered consciousness. She was also able to sit up on her bed and move normally. These observations suggested that her reduced SpO₂ was not caused by respiratory or cardiovascular abnormalities. At that time, we did note the 6.4 mL of local anesthetic (total of 192 mg 3% prilocaine and 0.192 IU felypressin; 12 mg/kg prilocaine) that had been administered during the procedure and suspected that methemoglobinemia had developed as a result.

Another blood sample was collected from a venous line 3.5 hours after surgery (1630 hours) and sent to a medical center to be analyzed for MetHb. The level of MetHb was 6.9%, suggesting that the reduction in SpO₂ was in fact due to methemoglobinemia. The patient's SpO₂ at the time of blood collection was 88% to 90% with an FiO₂ of 30% to 40%. Because the patient rejected wearing the simple oxygen mask, we terminated oxygen administration at 1745 hours, and her SpO₂ remained constant at 88% to 90% on room air. The patient exhibited no symptoms of cyanosis, altered consciousness, respiratory compromise, nausea, or vomiting; therefore, we decided to continue monitoring her instead of administering methylene blue. Her SpO₂ recovered to 91% to 93% at 1800 hours. We confirmed that the patient was drinking water and allowed her to start eating. Urination was confirmed at 1920 hours, and her SpO₂ further recovered to 94% by 2020 hours and to 96% to 98% by 0700 hours the next morning. This patient's perioperative clinical course is detailed in the Figure.

Record of the patient's perioperative clinical course.

DISCUSSION

This report describes a case of methemoglobinemia caused by intraoperative prilocaine overdose. A total of 12 teeth with dental caries were treated, and the total operative time and anesthesia time were 2 hours 45 minutes and 4 hours 16 minutes, respectively. A total of 192 mg of prilocaine was administered during surgery. The use of prilocaine in children is accepted by the guidelines of the American Academy of Pediatrics, which recommend 6 mg/kg as the maximum weight-based dose.³ The calculated weight-based maximum dose for this patient was 96 mg; however, the total dose given was 192 mg or 12 mg/kg based on her body weight. Overdose was attributed to the lack of consideration given to the total amount administered throughout the long operation and a lack of awareness by both the surgeon and anesthesiologist.

Previous studies reported that the excretion of metabolites requires up to 24 and 48 hours; therefore, it was unclear how long metabolites remained in the blood.^4,5 Methemoglobinemia occurs when the iron moiety of Hb is oxidized from the ferrous state (Fe²⁺) to the ferric state (Fe³⁺), forming MetHb in concentrations beyond 1-2%. Unlike regular Hgb, MetHb is incapable of binding with oxygen. Furthermore, methemoglobinemia causes a leftward shift in the oxygen dissociation curve that decreases the release of oxygen within the tissues. As a result, oxygen supply is reduced, and patients become hypoxic. Therefore, a high MetHb concentration is associated with a number of clinical symptoms, including cyanosis, respiratory compromise, tachycardia, shakiness, seizures, hypertension, myocardial ischemia, and coma.¹ Methylene blue is required as an antidote when a patient's MetHb concentration reaches 30% or higher or in the presence of significant symptoms.^2,6 The possibility of congenital methemoglobinemia was not investigated in the present case; therefore, its relevance is unknown. There have been no case or featured reports of Noonan syndrome with congenital methemoglobinemia.

In normal RBCs, MetHb is primarily reduced by cytochrome-b5 reductase, which is a nicotinamide adenine dinucleotide (NADH)–dependent enzyme. NADH-cytochrome-b5 reductase activity is lower in newborns than in adults.⁷ Furthermore, because fetal hemoglobin (Hb-F) has a greater affinity for oxygen than adult hemoglobin (Hb-A) does, infants have a higher risk of methemoglobinemia. Limited information is available on methemoglobinemia in newborns as a result of the infiltrative administration of prilocaine during dental procedures in Japan.⁸ Furthermore, the incidence of methemoglobinemia in children remains unknown. Rechetzki et al⁹ compared MetHb concentrations in children (6–10 years) and adults (21–60 years) without a history of cyanosis and found that serum MetHb concentrations were higher in children (4.61%) than in adults (3.44%). This finding suggests that the activity of NADH-cytochrome-b5 reductase is lower in children, which increases the risk of methemoglobinemia.⁸

Guay et al⁶ examined 242 cases of methemoglobinemia induced by local anesthesia that were reported between 1949 and 2007 and identified 65 cases that were caused by prilocaine. Notably, they suggested that prilocaine is not suitable for administration to children younger than 6 years because 38.2% of all cases occurred in this population.⁶

Similar to other local anesthetics used in dentistry, the package insert for 3% prilocaine with 0.03 IU/mL felypressin indicates that the safety profile has not been established in children according to Japanese regulations. However, it is still used for children in clinical settings.⁸ For example, a survey administered by the Japanese Society of Pediatric Dentistry (2005) revealed that approximately 7.0% of dentists use prilocaine. The use of prilocaine for children is accepted by the guidelines of the American Academy of Pediatrics, which recommend 6 mg/kg as the weight-based maximum recommended dose and 400 mg as the absolute maximum recommend dose.³ In the present study, the patient had pulmonary valve stenosis and hypertrophic cardiomyopathy, which are characteristics of Noonan syndrome. Therefore, to prevent changes in circulation, we selected prilocaine as a local anesthetic instead of other agents that contain epinephrine as a vasoconstrictor. In general anesthesia, the use of local anesthetics with vasoconstrictors is important for enhancing the effects and slowing the systemic update of local anesthetics. Local anesthesia with an epinephrine-free vasoconstrictor is performed only in Japan using prilocaine with felypressin.

Among the number of medications used in the present case, the acetaminophen administered postoperatively for analgesia may have affected the onset of methemoglobinemia. Acetaminophen is a derivative of acetanilide and phenacetin, which are metabolized to the MetHb-producing by-products aniline and ethoxyaniline.¹⁰ In addition to acetaminophen, these antipyretics are also metabolized to N-acetylbenzoquinoneimine, both of which are structurally related to several molecules that produce methemoglobinemia, most notably aniline.¹⁰ In the setting of massive acetaminophen administration, acetaminophen, N-acetylbenzoquinoneimine, or para-aminophenol may oxidize Hb to MetHb.¹⁰ Acetaminophen may elicit oxidative effects that exceed the reductive effects of Hb during the process of metabolism, thereby leading to the development of methemoglobinemia.

Noonan syndrome is a congenital anomaly caused by the mutation of genes in the RAS/MAPK signaling pathway.¹¹ It is clinically characterized by distinctive facial features, developmental delays, learning difficulties, a short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties.¹¹ Approximately 50% of patients with Noonan syndrome develop heart disease; hypertrophic cardiomyopathy has been reported in 20% of patients with Noonan syndrome.^11,12 The aggressive progression of hypertrophic cardiomyopathy may lead to a poor prognosis in some cases.¹³ In the present case, we performed echocardiography prior to surgery to confirm that the patient did not have left ventricular outflow tract obstruction at rest. However, we noted the risk of hypotension and hypoxia due to a sudden decrease in systemic vascular resistance or preload. Therefore, pain management with appropriate local anesthesia was required to (1) maintain the level of anesthesia and circulation while minimizing the risk of cardiac depression and (2) prevent left ventricular outflow tract obstruction by controlling the level of cardiac contractility. Furthermore, because the patient had congenital heart disease, it was important to prevent hypoxemia as a result of increased MetHb. Therefore, clarifying with surgeons the maximum dose of prilocaine prior to surgery would have been beneficial.

CONCLUSION

Prilocaine overdose resulted in methemoglobinemia in a patient with Noonan syndrome and congenital heart disease. When a dental procedure requires the use of prilocaine to treat multiple teeth, it is important to carefully manage the dose of prilocaine as overdose may lead to methemoglobinemia.