Lab RoundsYael Moussadji

Feb 12, 2009

CaseCase 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

CaseCase 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

Ddx of CyanosisDdx 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

InvestigationsInvestigations 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%

MethemoglobinemiaMethemoglobinemia 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

PhysiologyPhysiology 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

Cytochrome MHb ReductaseCytochrome MHb Reductase

Other pathwaysOther 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

PathophysiologyPathophysiology 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

EtiologyEtiology Etiology can be thought of congenital or

acquired Acquired methemoglobinemia can be toxin

induced, idiopathic (related to acidosis), or dietary

CongenitalCongenital 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

AcquiredAcquired 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)

BenzocaineBenzocaine 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

AcquiredAcquired 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)

Clinical PresentationClinical 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

Clinical PresentationClinical 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

InvestigationsInvestigations 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

Pulse OximetryPulse 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

ABGABG 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

Co-oximetryCo-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

TreatmentTreatment 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

ComplicationsComplications 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

Other therapiesOther 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)

CaseCase 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%

ConclusionConclusion 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%