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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 - PowerPoint PPT Presentation
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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%