Severe Methemoglobinemia, Unresponsive to Methylene Blue

Department of Emergency and Critical Care Team, Kauvery Hospital, Cantonment, Trichy, India

Abstract

Acquired methemoglobinemia occurs due to various poisonings such as plant fertilizers. We report a 28-years-aged female patient who consumed a plant energizer containing oligosaccharide resulting in methemoglobinemia. This was a challenging case that required modalities apart from regular treatment of methemoglobinemia with methylene blue. In spite of maximum dose of Methylene Blue (MB), methemoglobinemia was very high warranting the use of other ways. We used exchange transfusion, successfully treated and discharged in neurologically good status, and normal blood gas values.

Background

Methemoglobin is a form of hemoglobin that has been oxidized, changing its heme iron configuration from the ferrous (Fe2+) to the ferric (Fe3+) state. Unlike normal hemoglobin, methemoglobin does not bind oxygen and as a result cannot deliver oxygen to the tissues. Formation of methemoglobin and conversion back to the normal ferrous state (by reduction [addition of an electron]) occurs at low levels during normal red blood cell (RBC) metabolism. Normally, the formation and reduction of methemoglobin are balanced, and the steady-state level of methemoglobin is approximately 1 percent of total hemoglobin.

The typical presentation of Acquired Methemoglobinemia is of relative abrupt development of symptoms of hypoxia (low tissue oxygen) upon exposure to an oxidizing substance that induces methemoglobin formation. In contrast to tissue hypoxia, hypoxemia may be absent (the partial pressure of oxygen in the blood [PaO2] may be normal).

Institution of appropriate supportive care is required as needed. This may include intravenous access, hydration for hypotension, ventilator support for respiratory compromise, or treatments targeted to neurologic complications (antiseizure medications). Individuals with any symptoms of concern (eg, more than mild headache or lethargy) and/or a methemoglobin level >30 percent are usually treated with MB. MB acts faster than ascorbic acid and thus is the treatment of choice for symptomatic acute toxic methemoglobinemia. The effectiveness of MB is also better established than that of ascorbic acid and its use more widespread. Exchange transfusion and hyperbaric oxygen have been reported to be beneficial in severe diseases according to case reports, but there are no controlled trials of these approaches [1,2].

Case Presentation

A 28-year-old female was brought to ED with alleged history of consumption of a plant energizer containing 2% oligosaccharide around 200ml @6 pm on 23/7/21 at her home. Patient was taken to nearby hospital where first aid was given during which she had multiple episodes of seizure and poor saturation. Patient was intubated and put on ventilator. Gastric lavage done and ABG showed methemoglobinemia, Inj. Methylene blue was given. Methylene blue was given multiple times (1 mg/kg) to maximum of 7 mg/kg and still methemoglobinemia was very high hence referred to our hospital.

No known comorbidities. No H/O seizures in the past.

Married life, 10 years; P1L1; LCB, 8 years; prev. LSCS; LMP, 24/7/21; 3/1-3 months cycle – irregular

On arrival at our hospital, GCS, E1VTM1, SpO2, 77%; on bag and mask ventilation with 100% oxygen, BP, 110/60 mmHg; PR, 90.

Her G6PD levels were normal.

Table 1. Daily monitoring

Parameter	On admission	Post exchange D1	After ^2nd exchange	Post extubation	After ^3rd exchange	On discharge
pH	7.40	7.48	7.49	7.46	7.42	7.38
PaO2	380	499	413	200	100	100
Met Hb	38.7%	33.5%	8.7%	15%	11.6%	8%
SPO2	75%	80	85	85	89	92
PR	90	86	90	85	82	80
BP	110/70	110/74	112/70	110/72	120/80	130/70

ABG analysis had saturation gap/resp. alkalosis/hypokalemia and methemoglobin level of 33.5%. Central line secured and planned for exchange transfusion. Exchange transfusion was done with 10 units of PRBC. Inj. Methylene blue was continued. Methemoglobin levels were persistently more than 30 % with oxygen saturations around 80%, hence next day one more cycle of exchange transfusion with 10 units of packed RBCs done. The methemoglobin levels decreased and the levels fluctuated around 15%. Oxygen saturation improved to 85-88%. Inj. methylene blue was continued. Patient was extubated the next day. Now third cycle of exchange transfusion with 3 units of packed RBCs given. Inj. methylene blue was continued upto sixth day. Methemoglobin levels steadily came down to normal with lactate levels also. Other transfusions done are 6 units FFP, 2 units SDP and 4 units Platelet. Urologist opinion obtained for large renal pelvic calculus. Patient had methemoglobin levels less than 10 % with saturation of 99%. On becoming conscious, oriented and neurologically stable she was shifted to the ward where was followed up with further care and discharged.

Discussion

Pathophysiology:

Formation of methemoglobin and conversion back to the normal ferrous state occurs at low levels during normal red blood cell (RBC) metabolism. Normally, the formation and reduction of methemoglobin are balanced, and the steady-state level of methemoglobin is approximately 1% of total hemoglobin.

Formation of methemoglobin

The following processes contribute to oxidation of heme (removal of an electron) and formation of methemoglobin.

Auto-oxidation converts a small portion (less than 3%) of the available hemoglobin to methemoglobin [3,4].
- Reactions with endogenous free radicals and compounds including hydrogen peroxide(H2O2), nitric oxide (NO),O2-, and hydroxyl radical (OHâ€¢) also generate methemoglobin [5,6].
- Exogenous chemicals can increase methemoglobin, either directly or by means of a metabolic derivative or by generating O2- and H2O2 during their metabolism.
Reduction of methemoglobin – Methemoglobin levels are kept low (approximately 1 percent) by the RBC enzyme cytochrome b5 reductase (Cyb5R), which reduces (adds an electron to) the heme in hemoglobin, converting it back to the ferrous (Fe2+) state.
- Cyb5R: The only physiologically important pathway for methemoglobin reduction is via Cyb5R (previously called methemoglobin reductase or methemoglobin diaphorase. Cyb5R is a housekeeping enzyme, a member of the flavoenzyme family of dehydrogenases-electron transferases present in all cells; in RBCs it reduces ferric heme to ferrous heme [7-11].
- NADPH methemoglobin reductase and G6PD: An alternative pathway for methemoglobin reduction, which is not physiologically active, uses NADPH methemoglobin reductase. In this pathway, electrons are derived from NADPH that is generated by glucose-6-phosphate dehydrogenase (G6PD) in the hexose monophosphate (pentose phosphate) shunt. However, there is normally no electron acceptor present in RBCs to interact with NADPH. As a result, the pathway is only activated by extrinsic electron acceptors such as methylene blue (MB) and riboflavin [12-14]. This is the mechanism by which MB therapy reverses methemoglobinemia in severely affected individuals.
- Other pathways: Other compounds that can promote reduction of methemoglobin include electron donors such as ascorbic acid, reduced glutathione, riboflavin, tetrahydropterin, cysteine, cysteamine, 3-hydroxyanthranilic acid, and 3-hydroxykynurenine.

Clinically significant methemoglobinemia occurs when there is an imbalance between two processes, increased production of methemoglobin or decreased reduction. Acquired causes of methemoglobinemia are more common than congenital causes. In some cases, an underlying genetic predisposition to methemoglobin formation can greatly exacerbate methemoglobinemia after an exposure to an oxidant.

SaO2 (Oxyhemoglobin saturation of arterial blood) given by ABG analyzers is derived from the PaO2 and will be near 100% if PaO2 is more than 100 (as per the oxygen dissociation curve). This oxygen â€œsaturation gapâ€ between the SaO2 and SpO2 greater than 5%, is a diagnostic clue to the presence of MetHb [15].

CO-Oximetry is the gold standard in estimating methemoglobin levels.

Initial evaluation consist of arterial blood gas analysis, pulse oximetry, methemoglobin specific quantification if required. Complete blood count, haemoglobin, haematocrit and basal renal and liver function tests are done.

Management

Methylene blue is the treatment of choice for acute toxic methemoglobinemia with methemoglobin levels >30%. MB is also appropriate for those who are symptomatic with methemoglobin levels between 20 and 30 percent, especially those with pulmonary or cardiac comorbidities. For asymptomatic patients with methemoglobin levels <30%, with or without cyanosis, it is prudent to follow the patient without therapy after the offending drug or agent is withdrawn. Methylene blue can also be used cosmetically to lessen cyanosis in individuals with congenital (chronic) methemoglobinemia due to cytochrome b5 reductase (Cyb5R) deficiency. The recommended dose is 2 mg/kg for infants, 1.5 mg/kg for older children and 1 mg/kg for adults diluted in 1% sterile aqueous solution infused over 5 min. MetHb levels are generally brought below 10% within 30 min. The dose can be repeated hourly up to a maximum of 7 mg/kg over 24 h [16,17]. However, administration of more than 2 to 3 doses (>7 mg/kg) is generally avoided due to the possibility of causing hemolysis, even in individuals who do not have G6PD deficiency.

Most individuals have rapid clinical improvement with MB and reduction of methemoglobin levels to <10 percent within 10-60 minutes. Those who improve rapidly and whose cyanosis subsides do not need to have their methemoglobin level rechecked; the accuracy of methemoglobin measurement is impaired by MB interference at the same absorption wavelength. For those whose cyanosis returns and symptoms of hypoxia recur (likely due to continuous presence of offending agent), repeated doses of MB may be needed.

If rapid improvement does not occur, confirm that the original diagnosis is correct, and consider other interventions such as transfusion, exchange transfusion, or hyperbaric oxygen.

Erythrocytapheresis/red blood cell (RBC) exchange involves removing of a large number of RBCs from the patient and returning the patient’s plasma and platelets along with compatible allogenic donor RBCs. The donor RBCs selected for transfusion should be ABO- and Rh-compatible, relatively fresh (<10 days is preferable to allow maximum in vivo survival) and partially phenotype matched for Rh (C, c, E, e) antigen to avoid future alloimmunization. In general, one red cell volume (RCV) exchange will remove 70% of patient’s RBCs (percentage [fraction] of cells remaining of 30%) and two RCV exchange will remove about 90% [18].

In our case we have considered exchange transfusion as other intervention for persistent high methemoglobinemia. The treatment has been very helpful for the patient and had good recovery following which discharged.

Conclusion

Exchange transfusion of packed red cells are used in persistent high methemoglobinemia and found to be effective. Few studies of case reports are found to be effective. Randomised control trial is required regarding superiority and definitive estimation of benefits of exchange transfusion in alternative treatments of methemoglobinemia.

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Severe Methemoglobinemia, Unresponsive to Methylene Blue