Cyanosis of central origin can have different causes, as summarized in the table below. In our clinical case, the cause was methemoglobinemia of toxic origin.
Causes of central cyanosis [1, 2, 7] |
|---|
Cardiac | ∙ Hemodynamic pulmonary edema |
∙ Cardiac malformations with arteriovenous shunt |
Pulmonary | ∙ Pneumonia |
∙ Respiratory insufficiency |
∙ Pulmonary embolism |
Methemoglobinemia |
Congenital | ∙ NADH diaphorase enzyme deficiency, transmitted in an autosomal recessive mode, in these subjects the methemoglobin level varies between 20% and 45% |
∙ Structural abnormalities of hemoglobin that will favor the ferric form of heme |
Nonorganic causes | ∙ Poppers, nitrates (plant fertilizers, Ajax), gunpowder, chlorates |
Organic causes | ∙ Anesthetics (benzocaine, lidocaine, prilocaine) quinines and derivatives, metoclopramide, sulfonamides and sulfone (dapsone), phenazopyridine, phenylacetamide and derivatives, aminobenzene (aniline, naphthalene), nitrobenzene and derivatives, nitrotoluene. |
Methemoglobin is an oxidized form of hemoglobin where ferrous iron Fe2+ is converted to ferric iron Fe3+, making it unsuitable for oxygen (O2) transport [2,3,4,5, 8]. During normal metabolism, a slight proportion of methemoglobin exists in the blood, for example, 1% in adults, 1.5% in newborns, and 2% in premature babies. It is permanently reduced by various enzymatic mechanisms.
The main mechanism is the nicotinamide adenine dinucleotide (NADH)-dependent methemoglobin reductase I or diaphorase, which captures electrons from NADH to reduce methemoglobin to hemoglobin. NADH is produced by the main pathway of glucose degradation. This system ensures the reduction of 95% of the physiological circulating methemoglobin, coming from methemoglobinizing products of the food of nitrifying bacteria [2,3,4,5].
Symptomatology according to methemoglobin level [8, 1, 2, 9] |
|---|
15–30% | ∙ Cyanosis, asthenia, dizziness, headache |
30–50% | ∙ Dyspnea, tachypnea, syncope |
50–70% | ∙ Obnubilation, coma, convulsions, circulatory failure, rhythm disorders |
Over 70% | ∙ Risk of death |
The accessory mechanism uses the nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase. The NADPH is supplied by the accessory pathway of glucose degradation, of which glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme [2,3,4,5].
NADPH will allow the reduction of methylene blue to leucoblue, which will, in turn, reduce methemoglobin to hemoglobin. In the physiological state, this pathway is little used because it requires an electron carrier that is not available in the body (vitamin C or methylene blue) [2,3,4,5]. The treatment with methylene blue will allow maximum use of this pathway (Fig. 1) [1, 2, 4].
A French study in 2018 showed that more than 50% of cases of methemoglobinemia with values above 25% in the blood are linked to the use of poppers [8]. In the adult population as in teenagers, poppers are the second recreational drug taken after cannabis, confirming that it is not restricted to the homosexual community [11].
Poppers are an aliphatic nitrite (amyl, butyl, isobutyl, propyl), vasodilator, and oxidant [3, 5]. They come in the form of a volatile liquid to be inhaled in 10–15 mL vials and are sometimes used as a spray. The pop is the characteristic noise made by the vial being uncorked that gave them their name. Their euphoric and muscle-relaxing properties make it a very popular drug, particularly among the male homosexual population. The half-life is 14 minutes and has very short onset of action. It has hepatic metabolization. Vasodilatation will lead to some side effects, including facial flush, hypotension, tachycardia, headache, and nausea [3, 5].
The way that poppers work is through the rapid decomposition of the aliphatic nitrate, which is most commonly amyl nitrite to nitrous oxide. Another less common aliphatic nitrite is isopropyl nitrite, and it has a slower decomposition. The exact content of the amyl nitrate in poppers is not known. The nitrous oxide produced is responsible for the smooth-muscle relaxation among users. However, nitrous oxide is also responsible for the oxidation of ferrous iron to ferric iron that will transform hemoglobin into methemoglobin, making it unfit for oxygen transport [2,3,4,5, 8].
The cyanosis caused by methemoglobinemia is explained by a decrease in O2 bound to hemoglobin, causing a leftward shift in the Hb dissociation curve owing to an increased affinity of the unoxidized heme to O2, thus resulting in a decrease in oxygen supply to the periphery [8].
Generalized cyanosis is characteristic; in the absence of respiratory pathology, it suggests methemoglobinemia [4, 7,8,9, 12]. The chocolate color of the blood sample due to ferrous iron is also characteristic of methemoglobinemia [7,8,9, 12].
Methemoglobinemia will therefore cause respiratory distress that is unresponsive to O2 administration at normal oxygen pressure. Usually, arterial blood gas discloses a normal PaO2 [4, 5, 9, 13].
Hypoxia is a common clinical sign, even though arterial blood gas (ABG) discloses normal PO2. This physiologically appropriate PaO2 on ABG with low pulse oximeter saturation is called saturation gap.
In this case, the patient fulfilled all the clinical signs, and the other clinical investigations such as the blood test, chest x-ray, and EKG being normal, together with his history of poppers use, made this diagnosis very plausible. The treatment of methemoglobinemia consists of the intravenous administration of methylene blue that acts as a cofactor in the intra-erythrocyte reduction of methemoglobin in the presence of NADPH in non-G6PD-deficient subjects [1, 2, 4, 8].
When methemoglobinemia is symptomatic or if the level is over 30%, a methylene blue intravenous perfusion is given at the dose of 1–2 mg/kg over 15 minutes, possibly repeated after 1 hour if clinical signs persist, with a maximal dose of 7 mg/kg. More than this dose of methylene blue may also cause methemoglobinemia hemolysis. When methylene blue is ineffective, such as in cases of G6PD deficiency, a complete blood exchange can be performed [1, 2, 4, 8].
