Anesthetic Management of a Pediatric Patient with Congenital Methemoglobinemia

A 15-year-old girl with congenital methemoglobinemia and no prior anesthetic history presented for the extraction of multiple impacted molars. Pulse oximetry values were expected to complicate the accurate monitoring of her oxygenation status in the perioperative period. An arterial line was placed for hemodynamic monitoring, arterial blood gas (ABG) analysis, and obtaining the methemoglobin (MetHgb) level and additional blood gases if clinically indicated. A continuous CO-oximeter was also used. Her intraoperative course was uneventful and she was discharged home on the same day of the procedure. This report reviews this rare condition and describes the monitoring methods utilized to assess her oxygen and methemoglobin levels, as well as the anesthetic techniques and pharmacologic agents employed. With appropriate intraoperative monitoring and careful drug selection, pediatric patients with this unusual condition can safely undergo general anesthesia.


Introduction
Congenital or hereditary methemoglobinemia is a rare condition which was frst described in 1845 that prevents the reduction of the iron molecule contained in hemoglobin (Hb) from an oxidized state (Fe 3+ , ferric) to a reduced state (Fe 2+ , ferrous), resulting in decreased oxygen carrying capacity and tissue hypoxia [1]. To date, the literature on anesthesia has primarily described the perioperative management of adult patients with acquired methemoglobinemia or that of cyanotic patients who were later found to have previously undiagnosed congenital methemoglobinemia. We report the frst case report of the perioperative management of a pediatric patient with known congenital methemoglobinemia undergoing general anesthesia.

Case Presentation
Te patient was an otherwise healthy 15-year-old, 60 kg, Caucasian female (Figures 1 and 2), diagnosed with methemoglobinemia at birth after she was noted to have a "blue hue" without any accompanying symptoms. Her father, paternal grandmother, and paternal uncle had all been diagnosed with the same condition. Her functional status was high, as she was active in track and swimming while remaining asymptomatic. She was not taking any prescription medications. She presented for the extraction of multiple impacted molars under general anesthesia. Her preoperative hemoglobin and hematocrit values were 14.6 g/ dL and 44.4%, respectively. Available outpatient MetHgb values varied between 3% and 15%. A preoperative interdisciplinary discussion was held before scheduling her procedure, and as the use of local anesthetics had the potential to cause methemoglobinemia, their use was avoided [2].
Te patient's preinduction vital signs were as follows: blood pressure, 127/68; heart rate, 79; and respiration, 18 breaths/min. A nasal cannula was placed with an oxygen fow rate set at 2 L/min; a remifentanil and propofol infusion was started at 0.5 mcg/kg/hr and 100 mcg/kg/min, respectively, primarily in order to facilitate the placement of an arterial catheter without local infltration, as well as to promote hemodynamic stability as a maintenance anesthetic. An initial arterial blood gas analysis, measured by a point-of-care GEM 3500, revealed a pH of 7.39, a PaO 2 level of 110 mmHg, a PaCO 2 level of 46 mmHg, an HCO 3 level of 27.8 mmol/L, and a base defcit of 2.2 mmol/L. Te patient was preoxygenated, and after an induction dose of propofol (150 mg) without neuromuscular blockade, the patient was intubated with a nasal RAE endotracheal tube on the frst attempt, facilitated by the elective use of a fexible fberoptic bronchoscope. Anesthesia was maintained with isofurance delivered with oxygen and air, and remifentanil.
Pulse oximetry on room air revealed an oxygen saturation (SpO 2 ) of 12%-35% (Figure 3), taken on all extremities. Cerebral oximetry, measured with an O 3 near-infrared spectroscopy (NIRS) module, revealed values between 40% and55% ( Figure 4). In an attempt to minimize arterial blood gas sampling, a Masimo Root monitor was utilized in conjunction with the Radical-7 Pulse CO-Oximeter (Masimo Inc., Irvine, CA) with the goal of measuring continuous MetHgb. As shown in Figure 4, cerebral oximetry values were visible, but the monitor was unable to detect the patient's methemoglobin level.
Te patient received 4 mg each of dexamethasone and ondansetron as prophylaxis for postoperative nausea and vomiting, as well as 50 mcg of fentanyl for analgesia.
A second arterial blood gas at FiO 2 level of 1.0 was drawn after intubation and sent to the hospital's main laboratory, which revealed a pH of 7.40, a PaO 2 level of 452 mmHg, a PaCO 2 level of 44 mmHg, an HCO 3 level of 27.3 mmol/L, a base defcit of 2.1 mmol/L, and a serum methemoglobin level of 13.1%. End-tidal carbon dioxide (EtCO 2 ) and NIRS values remained stable.
Approximately 15 minutes later, a repeat arterial blood gas at an FiO 2 level of 0.7 revealed a pH of 7.38, a PaO 2 level of 443 mmHg, a PaCO 2 level of 43 mmHg, an HCO 3 level of 25.2 mmol/L, a base defcit of 0.7 mmol/L, and a serum methemoglobin level of 13.2%. Te case proceeded uneventfully, and the patient was extubated     Characterized by chronic cyanosis, otherwise asymptomatic Case Reports in Anesthesiology and taken to the post-anesthesia care unit (PACU). Te total operative time was 40 minutes.
One fnal arterial blood gas was drawn in recovery with the patient being extubated and awake at 6 L/min of oxygen by facemask, demonstrating a pH of 7.39, a PaO 2 level of 176 mmHg, a PaCO 2 level of 40.5 mmHg, an HCO 3 level of 24.3 mmol/L, a base defcit of 0.1 mmol/L, and a serum methemoglobin level of 13.8%. She was monitored for an additional four hours prior to being discharged home.

Discussion
Methemoglobinemia can result from various etiologies, including dietary, idiopathic, chemical, and toxicologic sources. It can also be congenital in nature and can be broadly classifed into two categories, the frst being methemoglobinemia due to an enzyme defciency, specifcally NADH reductase I defciency, also referred to as cytochrome b5 reductase or diaphorase I defciency. Tere are four known types of these disorders, all of which are autosomal recessive with respect to inheritance patterns [2]. Mutations of the alpha or beta globin chains can also result in an altered form of hemoglobin, which results in hemoglobin M disease, a condition that is inherited in an autosomal dominant fashion [3]. Our patient's family history suggested an autosomal dominant pattern of inheritance and in addition to her cyanosis present at birth, suggested that her diagnosis was hemoglobin M disease. However, her genetic workup had not been completed. Te major characteristics of each subtype of congenital hemoglobinemia are summarized in Table 1.
Cyanosis is generally present when serum MetHgb levels reach approximately 5-15%. Patients with methemoglobinemia tend to present with symptoms such as dyspnea, headaches, dizziness, and/or confusion when MetHgb levels reach 30%. Increasing levels of neurologic decline, cardiovascular collapse, and death result from levels above 60-70%. Clinically, type II cytochrome b5 reductase defciency is the most severe. While patients with other forms of congenital methemoglobinemia tend to remain asymptomatic with the exception of cyanosis, they are more susceptible to acquired forms of methemoglobinemia [4].

Anesthetic Considerations for Patients with Congenital
Methemoglobinemia. Te primary considerations in the perioperative care of patients with congenital methemoglobinemia relate to the assessment of oxygenation through the use of appropriate monitoring modalities and avoiding known triggering/oxidizing agents that could exacerbate their baseline methemoglobinemia.
Pulse oximetry devices rely on the diference in capacity for light absorption of oxygenated hemoglobin (HbO 2 ) and deoxygenated hemoglobin (HHb). HbO 2 absorbs more light in the infrared spectrum and HHb absorbs more red light. A fnger pulse oximetry probe emits high-frequency light every 5-10 microseconds at two wavelengths: 660 nm (red) and 940 nm (infrared). A photo detector senses the pulsatile (AC) component of absorbed wavelengths, subtracts the nonpulsatile (DC) component, and generates a voltage proportional to the transmitted light. A microprocessor compares the absorption ratio of HbO 2 and HHb by the two diferent wavelengths and converts this to a percentage using an algorithm of known values, which generates an SpO 2 reading. Te reading will be inaccurate if the pulsatile fow is very small (such as in hypotension or vasospasm), if the pulsatile fow is irregular (as in arrhythmias), or if nonstandard Hb components (such as CO or MetHgb) significantly interfere with wavelength absorbency.
MetHgb demonstrates light absorption at two peaks, 630 nm and 960 nm, i.e., absorption in each spectrum. As levels of MetHgb in the blood increase, equal absorption at these wavelengths corresponds to an SpO 2 output by the microprocessor of 85% [5]. Even in the absence of increased methemoglobin levels, severe oxyhemoglobin desaturation can occur with even minimal durations of hypoventilation given these patients have only a modest amount of normal hemoglobin in addition to the left shift in their individual oxyhemoglobin dissociation curve, impairing oxygen delivery [6].
Te utility of continuous CO-oximetry and cerebral oximetry has previously been described in the care of an adult with congenital methemoglobinemia and was utilized to guide the intraoperative management of increasing serum methemoglobin and ultimately methylene blue administration [7]. If such a device is unavailable, or reliable readings cannot be obtained, serial arterial blood gas measurements utilizing a laboratory-based CO-oximeter in conjunction with continuous end-tidal capnography can provide an adequate assessment of global oxygen delivery and tissue perfusion. Our Masimo device was calibrated and checked by a representative from the company, and the cause of the monitor's inability to measure MetHgb in our particular case remains unknown. Te Masimo representative responded by suggesting that the blue discoloration of her fngers, or indeed, the low SpO 2 measurement, may have contributed to this.
With respect to oxidizing agents, though many are known to trigger episodes of methemoglobinemia or an underlying condition, medications such as local anesthetics, antibiotics (dapsone), and nitrites (nitroglycerin/nitric oxide) are most commonly encountered by anesthesiologists in their clinical practice. Benzocaine and prilocaine account for the vast majority of local anesthetics associated with methemoglobinemia in the literature; however, bupivacaine's and lidocaine's roles in this regard are controversial and not defnitively considered universally safe [8][9][10]. As discussed, patients with congenital methemoglobinemia, even if asymptomatic, are more likely to develop an acquired form when exposed to an oxidizing agent due to their decreased ability to reduce free radicals at the baseline, thus our reason to avoid the use of any local anesthetics in this patient's care [11,12].
Te mainstay of emergency therapy for acquired methemoglobinemia consists of intravenous administration of methylene blue, dosed at 1-2 mg/kg, given over 5-10 minutes, repeatable every half hour, up to a maximum of 7 mg/kg due to its own oxidant activity. It is generally indicated when MetHgb levels exceed 30% or earlier if the patients are symptomatic. Methylene blue works by activating nicotinamide adenine dinucleotide phosphate (NADPH) MetHgb reductase, ultimately reducing MetHgb to functional hemoglobin. In patients with glucose-6-Pdehydrogenase (G-6PD) defciency, or chlorate poisoning, which inhibits G-6PD, methylene blue can actually exacerbate methemoglobinemia induced by intravascular hemolysis. In such cases, ribofavin can be efective in reducing MetHgb [12,13].
Besides the enzyme-dependent pathways, there are bimolecular reactions that act to reduce MetHgb indirectly. For example, ascorbic acid reduces MetHgb in erythrocytes; it is oxidized to dehydroascorbic acid, which is then reduced by glutathione or DHA reductase, efectively transferring an electron to MetHgb. Tus, ascorbic acid can reduce oxidative stress and reduce MetHgb levels in patients with congenital methemoglobinemia after methylene blue treatment. Glutathione also plays a role in MetHgb reduction and is helpful in treating nitrite-induced methemoglobinemia [13].

Conclusion
Patients with congenital or inherited methemoglobinemia represent a challenge with respect to perioperative assessment of oxygenation and global tissue perfusion. Te avoidance of potential oxidizing agents should be discussed, as well as the availability of emergency treatment modalities such as methylene blue or exchange transfusions, when applicable in the setting of an individual patient's specifc disorder. When possible, the measurement of continuous MetHgb should be a consideration in their management, and when unavailable or not feasible, serial CO-oximetry via serial blood gas measurements in conjunction with other surrogate measures of oxygen delivery such as cerebral oximetry can be utilized to safely guide their care.

Data Availability
Te data used to support this study are included within the article.

Consent
A written HIPAA authorization to use/disclose existing protected health information was obtained. Te patient's legal guardian provided consent as she is a minor.

Conflicts of Interest
Te authors declare that there are no conficts of interest.