Keywords
methemoglobinemia - methemoglobin - hypoxia - co-oximetry
Introduction
Methemoglobin (metHb) is an abnormal hemoglobin where the ferrous iron in the hemoglobin
is oxidized to a ferric state. Hemoglobin in this state cannot carry oxygen, resulting
in hypoxemia that does not respond to oxygen supplementation. Congenital methemoglobinemia
occurs due to deficiency of cytochrome-5-reductase and the acquired variant occurs
due to the ingestion of oxidizing agents. The normal level of metHb is less than 2%.
Few anesthesiologists are aware of this condition and do not know when to suspect
it. In patients with methemoglobinemia, there is a discrepancy between peripheral
oxygen saturation (SpO2) and partial pressure of oxygen (PaO2) by arterial blood gas (ABG) analysis. The pulse oximeter gives erroneous values
as it recognizes only wavelengths of oxyhemoglobin and deoxyhemoglobin.[1] In this case series, we present two patients of undiagnosed methemoglobinemia with
primary neurological pathology who had intraoperative hypoxemia, which were misdiagnosed
or nearly missed.
Case 1
A 9-year-old child presented with complaints of headache, projectile vomiting, and
weakness of the right-sided upper and lower limbs (Medical Research Council [MRC]
grade ⅘). Magnetic resonance imaging of the brain showed multiple serpiginous flow
voids in the cervicomedullary junction. Bilateral vertebral artery angiogram showed
arteriovenous malformation (AVM) measuring 19.5×13 mm, in the cervicomedullary junction,
with feeders from both right and left posterior inferior cerebellar arteries (PICA),
right and left vertebral arteries and draining via dilated latero-medullo-pontine
veins into the petrosal vein, superior petrosal sinus, bilateral cavernous, and transverse
sigmoid sinus. The patient had initially visited another hospital, where SpO2 of 85% was documented. Chest X-ray and two-dimensional echocardiogram with bubble
test for the evaluation of the cause of hypoxia were unremarkable. Given the diagnosis
of brainstem AVM, hypoxia was attributed to central hypoventilation without any confirmation
by polysomnography, ABG, or pulmonary function tests.
The child visited our hospital and was scheduled for the embolization of the AVM.
Preinduction, the patient's SpO2 on room air was 88 to 90%, which improved to 98% after oxygen supplementation. After
induction of anesthesia and tracheal intubation, the SpO2 dropped to 92% and cyanosis of hands and lips was seen, despite ventilation with
fractional inspiratory oxygen (FiO2) of 1 ([Fig. 1A]). Since the patient was now being ventilated with 100% oxygen, diagnosis of central
hypoventilation was ruled out. The color of the arterial blood (drawn for ABG) was
chocolate brown. The PaO2 was 460 mm Hg on two consecutive samples, which were appropriate for FiO2 of 1. Due to acute angulation of the right distal PICA, navigation until the AVM
nidus failed, and the procedure was abandoned. Anesthesia was reversed and the patient's
trachea was extubated. In the recovery room, SpO2 was 89 to 90%, which improved to 94 to 95% with oxygen supplementation. The cause
of the mismatch between SpO2 and PaO2 and unexplained hypoxemia was evaluated using pulse co-oximetry (Radical-7, Masimo,
Irvine, California, United States) and the metHb level was found to be 21.1% ([Fig. 1B]). Since the child was not on any medications, acquired methemoglobinemia was ruled
out and a provisional diagnosis of congenital methemoglobinemia was made.
Fig. 1 (A) Low peripheral oxygen saturation despite ventilation with fractional inspiratory
oxygen (FiO2) of 100%. (B) Cyanosis of hands and high methemoglobin level (21.1%) detected by co-oximetry in
the first case.
Case 2
A 30-year-old female presented with a 3 months history of convulsions, headache, and
altered sensorium. She had been receiving antiretroviral treatment for the past 4
months. The patient was conscious, with power in right side limbs of MRC grade 3.
She had neck stiffness and Kernig sign was positive. A computed tomography scan of
the brain showed multiple ring-enhancing lesions in bilateral parietal lobes with
significant perilesional edema suggestive of brain abscess. Burr hole and tapping
of the abscess was planned on an emergent basis. Laboratory investigations were unremarkable
except for the low CD4 count (15 cells per mm3).
In the operating room, her heart rate was 58 beats/minute with SpO2 of 85%, without any signs of respiratory distress. Lung and cardiac auscultation
were normal. SpO2 did not rise above 90% despite preoxygenation for 5 minutes.
The tracheal was intubated after induction of anesthesia and the patient was mechanically
ventilated with FiO2 of 1. However, the SpO2 did not improve beyond 90 to 91%. Arterial blood appeared dark brown with a normal
PaO2 (246 mm Hg) and saturation (98.6%). The difference between PaO2 and SpO2 was investigated using co-oximeter, which showed a metHb of 18.7% ([Fig. 2]).
Fig. 2 Co-oximetry showing elevated methemoglobin (18.9%) in the second case.
The intraoperative course was uneventful except for low SpO2. After surgery and tracheal extubation, with oxygen supplementation at 6 L/min, SpO2 was maintained at 88%. A detailed history from the patient revealed the ingestion
of sulfamethoxazole–trimethoprim for more than a month to treat fever. Methemoglobinemia
has been reported with sulfamethoxazole–trimethoprim.[2] The incidentally observed methemoglobinemia is most likely the acquired type due
to prolonged use of sulfamethoxazole.
Discussion
In the first case, when low SpO2 was encountered, the presence of any cardiac and pulmonary causes was ruled out.
Hypoxia was present throughout the procedure. Postprocedure, we found the cause of
low saturation to be methemoglobinemia by co-oximetry. When hypoxemia occurred again
in the second case, after ruling out systemic causes, co-oximetry showed a metHb level
of 18.7%. Now, methylene blue was kept available for emergency use. The early diagnosis
and adequate preparation reduced the stress and increased the confidence in managing
this case.
Therefore, from these cases, we learnt that abnormal hemoglobin should be suspected
whenever PaO2 is normal, with low SpO2. Generally, only patients with metHb levels above 30% are symptomatic.[3]
Patients with unexplained hypoxia warrant co-oximetry evaluation. Co-oximetry helps
determine the percentages of various forms of hemoglobin in the blood in relation
to total hemoglobin. These include oxygenated, deoxygenated, carboxy-, and metHb.
It uses four to eight wavelengths and therefore is able to distinguish between the
different hemoglobin. Blood gas analyzers with integrated co-oximetry modules are
available or they can be done using noninvasive technology similar to a peripheral
pulse oximeter. Indications for co-oximetry are known or suspected exposure to drugs
that cause hemoglobin conversion to metHb or in patients who have been exposed to
carbon monoxide. Patients with high levels of carboxyhemoglobin have normal SpO2 values because pulse oximeters cannot differentiate carboxyhemoglobin from oxyhemoglobin.[4] Drug-induced methemoglobinemia can occur with drugs like nitrates and nitrite derivatives,
sulfonamides, and dapsone. Dapsone is administered for the treatment of leprosy, endemic
to countries like India. These patients will be asymptomatic preoperatively but will
challenge the anesthesiologist intraoperatively with cyanosis and desaturation.[5] Therefore, any history of ingestion of such drugs if positive should alert the anesthesiologist
to make arrangements accordingly.
Methemoglobinemia of higher severity can cause tissue hypoxia. In a neurological patient,
consequences can range from mild cognitive disturbances, seizures, stroke, to permanent
brain ischemia and coma in worst scenarios. If the diagnosis is priorly known, measures
can be taken to prevent severe hypoxemia. Methylene blue, which activates Nicotinamide
adenine dinucleotide phosphate hydrogen (NADPH) diaphorase, can help reduce metHb
to hemoglobin. This can be kept ready for use in life-threatening hypoxemia, as its
onset of action is quick. However, methylene blue should not be used in patients with
glucose-6-phosphate dehydrogenase (G6PD) deficiency. Known or suspected G6PD deficiency
is a contraindication to the use of methylene blue. In fact, methylene blue triggers
hemolysis in such patients.[6]
[7] Dextrose-containing fluids and the administration of vitamin C can help provide
substrate to produce NADH. Oxidants like local anesthetics should be avoided.[8] The use of drugs such as fentanyl, dexmedetomidine, nitrous oxide, and drugs metabolized
by the P450 system is controversial and these drugs should be avoided. Remifentanil,
propofol, benzodiazepines, and inhalational agents are safer choices.[9] Blood transfusion or exchange transfusion can also help in improving oxygen delivery.
Conclusion
The learning point from these cases is that hypoxia in any patient should be thoroughly
investigated, and if there is any mismatch between pulse oximetry and arterial oxygen
tension, suspicion of abnormal hemoglobin should be raised. This can be diagnosed
with a simple bedside co-oximeter. However, availability of co-oximeter may not be
possible at many centers. ABG, on the other hand, is more widely and easily available
method.
