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Lab Rounds

Lab Rounds. Yael Moussadji Feb 12, 2009. Case. A previously healthy 3 y/o male (15kg) presented to the ED with perioral and nail bed cyanosis The morning prior he had been complaining of tooth pain and was treated with a topical local anesthetic

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Lab Rounds

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  1. Lab Rounds Yael Moussadji Feb 12, 2009

  2. Case • A previously healthy 3 y/o male (15kg) presented to the ED with perioral and nail bed cyanosis • The morning prior he had been complaining of tooth pain and was treated with a topical local anesthetic • That morning, his mother had seen him swallow a small amount of topical anesthetic, and within 2 hours became “dusky” with clearly demonstrated cyanosis on the lips and nail beds • He has had no recent viral or diarrheal illnesses and no ill contacts

  3. Case • On examination, he had central and peripheral cyanosis, but no evidence of respiratory distress • He was playing quietly by himself in the room • Initial vital signs were HR 90, BP 100/50, RR 25, T 37.1, and SpO2 74% on R/A • A non-rebreather mask with 15L/min O2 was applied with no improvement in the child’s colour or oxygen saturation • As the nurse began to draw blood, she noted that the blood was dark brown in colour

  4. Ddx of Cyanosis • Cyanosis is most commonly caused by 2 mechanisms • An excess of deoxygenated hemoglobin • A significant amount of abnormal hemoglobin • With an abrupt onset of central and acral cyanosis in this previously healthy boy in the absence of significant respiratory distress, this is more likely to be due to a toxicologic or environmental cause

  5. Investigations • Mom pulls out a tube of topical anesthetic which is labeled 20% benzocaine gel • A blood gas is sent, and demonstrates the following • pH 7.33, PCO2 32, PaO2 400, HCO3 24 • Electrolytes are normal, no anion gap • SpO2 82%, MHb 48%

  6. Methemoglobinemia • Methemoglobin refers to the oxidation of ferrous iron (Fe++) to ferric iron (Fe+++) within the hemoglobin molecule • This reaction causes a leftward shift in the O2-Hb dissociation curve and impairs the ability of Hb to transport oxygen and CO2 leading to tissue hypoxemia and in severe cases, death • It commonly results from exposure to an oxidizing chemical, but may also arise from genetic, dietary, or even idiopathic etiologies

  7. Physiology • A number of reduction systems are in place to reduce iron from the ferric state to the ferrous state and maintain oxygen transport and delivery • In the presence of these reduction systems and under normal oxidative stress, RBCs are able to maintain a baseline MHb concentration of 0.5-1% by reconverting MHb to Hg at a maximal rate of about 15%/hr using first order kindetics • The cytochrome-b5-MHb reductase system is the predominant system, accounting for 95% of the daily MHb reduction

  8. Cytochrome MHb Reductase

  9. Other pathways • A second pathway uses NADPH and NADPH-dependent MHb reductase to reduce MHb • This pathway is dependent on the generation of NADPH through a process that involves G6PD • This is the conduit for the reduction of MHb by the administration of methylene blue

  10. Pathophysiology • The accumulation of excess MHb within RBCs overwhelms the baseline reduction rate and produces a conformation change to the Hb tetramer • This limits oxygen binding, and increases the binding affinity of the remaining ferrous iron • The resulting leftward shift in the oxygen-Hb dissociation curve and decreased oxygen carrying capacity produces a cellular hypoxia • Because oxidized Hb is incapable of carrying O2 and CO2, excess MHb causes cyanosis, impaired aerobic respiration, metabolic acidosis, and possibly death

  11. Etiology • Etiology can be thought of congenital or acquired • Acquired methemoglobinemia can be toxin induced, idiopathic (related to acidosis), or dietary

  12. Congenital • Results from one of 2 inherited pathways • An inhereted amino acid substitution at one of the binding sites on the Hb molecule creates an environment that favours the ferric state (autosomal dominant) • A second inherited deficiency is cytochrome b5 reductase reduces the ability of the RBC to reduce ferric iron (autosomal recessive) • These patients present very early in life with cyanosis

  13. Acquired • The most common cause of MHb is ingestion or skin exposure to an oxidizing agent • MHb is most common in children >6mo • Drugs themselves are usually not causative agents, but are metabolized to an oxidative free-radical • Agents commonly associated with methemoglobinemia • Benzocaine • Dapsone • Lidocaine • Nitrates • Nitrites (inhalent abuse) • Phenazopyridine • Primaquine • Prilocaine • Sulfonamides • (Chlorates)

  14. Benzocaine • Benzocaine is a member of the ester class of topical anesthetics and is found in numerous over the counter products marketed for the relief of teething, burns, hemorrhoids, sore throats • It is available in liquids, gels, sprays, lozenges, suppositories, creams, which typically contain between 5-20% benzocaine by volume • Benzocaine and other such drugs are all potent oxidative stressors because of their underlying amine constituent • Doses >15 mg/kg in infants are known to induce methemoglobinema

  15. Acquired • Other acquired causes include idiopathic MHb that is related to systemic acidosis • It can occur in young infants who develop severe metabolic acidosis as a results of sepsis, diarrhea, or dehydration • A third cause is related to well water nitrates (think about this in young infants who live in rural areas)

  16. Clinical Presentation • Generally, symptoms do not appear until MHb levels rise above 15-20% of the total Hb concentration, although some cyanotic skin discolouration may be present • At levels above between 20-30%, individuals may develop headaches, dizziness, lightheadedness, anxiety, sinus tachycardia, and tachypnea • At levels of 50-60%, myocardial ischemia, dysrhythmias, coma, seizures, and acidosis develop • At levels >70%, death usually results from severe cellular hypoxia

  17. Clinical Presentation • Small infants with MHb may present similarly to children with cyanotic congenital heart disease that fails to respond to supplemental oxygen • A distinguishing feature is an elevated PO2 despite clinical cyanosis, and a normal calculated oxygen saturation • Infants with sepsis may present in a similar fashion, but will respond to supplemental oxygen

  18. Investigations • The concentration of MHb, which is expressed as a % of total Hg, must be interpreted in the context of the blood Hg concentration • An anemic patient may have greater symptoms at a level of 20% than a non-anemic patient • Patients with underlying conditions that make them more susceptible to relative hypoxia (heart disease) may also cause them to manifest symptoms at lower levels

  19. Pulse Oximetry • The ratio of absorbance of two wavelengths, or the relative difference in light absorption between oxyHb and deoxyHg, reflects the percentage of Hb that is oxygenated at any given time • MHb will absorb light equally at both wavelengths • At a MHb of 100%, the ratio is 1.0, and the pulseoximeter reads 85% oxygen saturation • At lower levels of MHb the oxygen saturation will read slightly lower, but once MHb levels reach 30-35%, the light absorbance reaches a plateau and the pulse oximetry reading stabilizes at 82-86% • Therefore, significant levels of MHb will result in only mild to moderate oxygen desaturation

  20. ABG • The ABG is also limited in MHb because the oxygen saturation is derived from a nomogram and the PO2 • This conversion relies on the assumption that normal Hg is present • The presence of dyshemoglobins (MHb, COHg) will therefore result in falsely elevated oxygen saturations on the arterial blood gas analysis • If there is no access to co-oximetry, a saturation gap between the oxygen saturation obtained by pulse-oximetry and that obtained by ABG suggests the presence of abnormal hemoglobin

  21. Co-oximetry • The lab method of choice and will confirm the diagnosis of MHb • A spectrophotometer that measures light absorbance at 4 different wavelengths, which corresponds to the characteristics of deoxy-Hb, oxy-Hb, CO-Hg, and hemoglobin, using a specific peak absorbance to characterize MHb • These machines actually measure oxygen saturation instead of calculating it

  22. Treatment • After an exposure to an oxidizing agent, the actionable treatment level is considered to be approximately 20% if symptomatic or 30% if asymptomatic • Patients who are compromised due to underlying illness may need to be treated at lower levels • The treatment of choice is methylene blue, which is provided as a 1% solution (10mg/ml) • The dose is 1-2 mg/kg infused intravenously over 3-5 minutes, and may be repeated at 1 mg/kg if symptoms and levels do not resolve after 30 minutes • Methylene blue is excreted by the kidneys, resulting in blue-green discolouration of urine

  23. Complications • Complications have been reported in patients with G6PD deficiency and infants • Patients with G6PD deficiency may not respond to treatment because they can’t produce sufficient NADPH to reduce methylene blue to leukomethylene blue; they may also develop a paradoxically worsening MHb and hemolytic anemia because methylene blue, if not reduced, is an oxidant • This effect can be seen in the administration of large doses (>4mg/kg) as well, which has occurred in infants

  24. Other therapies • Supportive care • Removal of oxidative stressor • Dextrose (major source of NADH in the RBC is the catabolism of sugar through glycolysis) • NAC is being studied (electron donor)

  25. Case • The diagnosis was suggested by cyanosis that did not improve with supplemental oxygen, and exposure to an oxidizing agent • The gross appearance of his blood as a chocolate brown colour that did not change when exposed to oxygen was also suggestive of MHb • The patient was treated with 15 mg of methylene blue, based on a MHb level of 48%, which resulted in a dramatic improvement of his colour and oxygen saturation • A MHb level drawn before discharge was 1.7%

  26. Conclusion • Think of methemoglobinemia is patients who present with cyanosis with an appropriate exposure history (lots of oxidative toxins!) • Remember this in your approach to the cyanotic infant • Lack of response to supplemental oxygen and chocolate coloured blood that does not turn red on exposure to air is highly suggestive • Easily diagnosed with Co-oximetry • Treat with methylene blue 1-2 mg/kg if levels >20%

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