When Is a Gray Baby Not a “Gray Baby”?

A 10-day-old boy presents to the Emergency Department with concern for “gray” color. He was born at term via uncomplicated vaginal delivery to a 23-year-old primiparous mother whose pregnancy was complicated by gestational diabetes. She had a subsequent diagnosis of group B streptococcal urinary tract infection treated with antibiotics the week following delivery. The patient did not receive Vitamin K or Hepatitis B immunization at birth. Postnatal course at home was uncomplicated and included a circumcision on day of life 8.On the evening of presentation, his parents noticed that the patient appeared gray in color. With the color change, his parents checked his temperature and found it to be 101°F. Parents noticed faster breathing, that he had been more sleepy than usual, and that he had gone several hours without feeding well. The parents called emergency medical services, and he was transported to the closest pediatric emergency department.The infant is awake and crying on his arrival at the emergency department. His extremities are “gray” in color. He is hypoxemic with postductal oxygen saturations of 89%. He is tachycardic with a capillary refill over 3 seconds. Blood pressure is normal for age. No evidence of bruising or other rashes. Circumcision is healing.He is placed on a 15L 100% nonrebreathing mask. Postductal SpO2 remains 85% to 93%. Laboratories reveal an elevated C-reactive protein of 1.59 mg/dL (15.90 mg/L), elevated procalcitonin of 0.69 ng/mL (0.69 μg/L), elevated erythrocyte sedimentation rate of >130 mm/h (>130.00 mm/h), and elevated white blood cell count of 34 800 cells/μL (34.80 x109/L). Hemoglobin is 15.8 g/dL (158.00 g/L) and platelets 500 000 cells/μL (500.00 × 109/L). Arterial blood gas reveals a normal pH of 7.43, CO2 of 32 mm Hg (4.26 kPa), and paO2 of 321 mm Hg (42.69 kPa). Comprehensive metabolic panel is normal. Rapid Influenza A and B, respiratory syncytial virus, and COVID-19 testing are negative. A blood culture is obtained. A 10 mL/kg normal saline bolus is given, and he is started on intravenous fluids. Vancomycin and ceftazidime are ordered. Prostaglandin E is also ordered to the bedside. The patient is placed on bubble Continuous Positive Airway Pressure. He is transferred to the neonatal intensive care unit (NICU) for ongoing evaluation and management.In the NICU, the patient has persistently low SpO2 between 85% and 93%, both pre- and postductally, on 100% FiO2. He is intubated because of hypoxemia. The chest radiograph is without focal findings. Vitamin K is administered intramuscularly. Newborn metabolic screen is collected, and urine and cerebrospinal fluid (CSF) cultures are obtained. Herpes simplex virus blood, surface, and CSF cultures sent. Antibiotics are continued, and acyclovir is started. An echocardiogram is normal. Ammonia is normal, and lactate is mildly elevated at 21.1 mg/dL (2.34 mmol/L). Respiratory pathogen panel and CSF meningitis/encephalitis panel both return normal. Both pre- and postductal SpO2 remain 85% to 93% on 100% FiO2 without any significant difference between the 2 values. Titrating supplemental oxygen down to 40% FiO2 and then down to 21% FiO2 does not significantly change the pre- and postductal oxygen saturations.Differential diagnosis includes bacterial sepsis, viral sepsis, viral bronchiolitis, critical congenital heart disease, persistent pulmonary hypertension, methemoglobinemia, carboxyhemoglobinemia, and sulfhemoglobinemia. The infectious and cardiac etiologies are diagnoses that are relatively common and cannot be missed. Although rare, the latter 3 above come into the differential with the low SpO2 and high Pao2.Methemoglobin level was elevated at 8.2% (0.08), and the patient was diagnosed with methemoglobinemia. The patient is treated with methylene blue with improvement in oxygen saturations to normal and return of pink coloring within 10 minutes of infusion. He extubates to room air. Repeat methemoglobin level is 1.5% (0.01) after treatment. All infectious testing is negative. Toxicology and genetics are in consultation. The patient is monitored for hemolysis after receiving methylene blue, with a trough hemoglobin level of 12.2 g/dL (122.00 g/L) and no evidence of significant hemolysis. Methemoglobin level is 1.0% (0.01) at the time of discharge. Newborn metabolic screen is normal. Genetic testing sent for specific enzyme deficiencies that cause methemoglobinemia is negative. Family is counseled to avoid topical anesthetics.Methemoglobin formation results from the oxidation of the heme iron in hemoglobin from the ferrous (Fe2+) to the ferric (Fe3+) state. Methemoglobin cannot carry oxygen and changes the remaining ferrous hemes in the tetramer so they do not release oxygen (shifting the oxygen-hemoglobin dissociation curve to the left). These changes lead to poor oxygen delivery to the tissues, causing this patient’s gray discoloration in the setting of a high Po2 arterially. Neonatal methemoglobinemia has many possible etiologies. There are genetic as well as acquired causes, which are typically exposure to oxidizing agents, such as medications, food products, or chemicals, such as nitrates/nitrites. On additional history, this patient has been receiving topical lidocaine 2.5% and prilocaine 2.5% to his penis with every diaper change for 2 days following circumcision, as prescribed by a provider. The family also uses well water, but the patient is exclusively breastfed and has not had any exposure to well water.Based on no genetic etiology being found and no exposure to other inciting agents, it is likely that this infant developed methemoglobinemia from topical lidocaine and prilocaine exposure to his healing circumcision site. There are previous case reports and case series of individuals who had received topical anesthetics developing acute toxic methemoglobinemia.1–4 This has not previously been described in topical anesthetics used for postcircumcision care.Consider checking Pao2 with an arterial blood gas in an infant with persistent hypoxemia despite oxygen delivery. If elevated, consider dysfunctional hemoglobins: methemoglobinemia, carboxyhemoglobinemia, or sulfhemoglobinemia.This case highlights the importance of returning to the history—taking process throughout a patient’s hospital stay, both if an initial diagnosis doesn’t fit as time progresses and as new information arises.American Board of Pediatrics Neonatal–Perinatal Content SpecificationUnderstand definitions and principles of pharmacokinetics.