The Story of The Blue and The Blue
The Story of the Blue and the Blue
Morbidity and Mortality Conference
Shadwan Alsafwah, MD
Cardiology fellow
The University of Tennessee at Memphis
Case
44 Y/O M with hx of cocaine and ETOH abuse presented to the ED with few
weeks history of right foot pain with foul smelling discharge, fevers at home,
and feeling ill
 PMH:
HTN
IDDM with CRI and BLE neuropathy
Gastric CA
PUD
 PSH:
Billirouth II surgery in 2004
Ray amputation of left 3rd toe
 SH:
Cocaine and ETOH abuse, with recent binge
smokes 2-3 cig/day since age 14
Case
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Meds:
Was not taking any of his meds:
HCTZ
Felodipine
Insulin
Omeprazole
Allergies:
NKDA
FH:
Positive for DM and HTN
ROS:
Other than the R foot pain and fever, was negative
Case
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Physical Exam:
204/106, 15, 105, 100.3, 97% on RA
Head: NC, AT
ENT: dry mucous membranes
Neck: No JVD
Chest: CTAB
CVS: tachycardic, RRR, accentuated A2, no murmurs,
no gallops
Abdomen: midline scar, soft, NT, ND, NABS
Ext: R foot: inflamed 2-5 toes, eschar on planter
surface of the great toe, (+) subcutaneous gas
Case
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Labs:
WBC 35,500 Hem 9 HCT 27.3 (at baseline) Plt 573000
MCV 70
Na 118 K 4.4 CL 80 HCO3 22.7 BUN 69 Cr 4.9 (baseline 2.4)
Glucose 585
Lactate 1.4
Urine: (+) ketones
tox screen: (+) cocaine
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Right foot X-ray: (+) gas in the soft tissue of the 2nd and 3rd toes
Case
Admitted to SICU to Surgery Service with Medicine on consult
and was started on:
IVF
Insulin drip
Broad spectrum Abx (Pip/Tazo and Vanc)
BP control (labetolol, felodipine)
 Had transmetatarsal amputation the same day
 His blood cultures grew: MRSA and Beta hemolytic Strep
 POD#5: started to have temp spikes
U/A, CXR were negative
Repeat blood cultures and urine cultures were negative (on Abx)
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Case
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2D echo requested to R/O endocarditis, showed:
Normal LVSF, EF 70%
Normal chamber sizes
Mild concentric LVH
Possible diastolic dysfunction
Mild-mod TR, mild MR, mild AI, mild PI
Mild pulmonary HTN (peak systolic PAP 40 mmHg)
Mild nodular thickening of the anterior tricuspid leaflet seen on
the apical 4-chamber view, suspicious but not definite for
vegetation
TEE may be indicated if clinical suspicion is strong
Case
TEE was scheduled
 The patient was kept NPO post midnight
 His PE on the morning of the TEE exam:
157/91, 103, 15, Temp 100.7, Sat 97% on RA
Neck: no JVD
Chest: CTAB
CVS: RRR, No murmurs
Abdomen: soft, NT, ND, NABS
Ext: S/P R TMT amp.
 Labs:
WBC 11.300 Hemog 8.4 HCT 25.8 PLT 518
Na 133 K 3.7 CL 100 HCO3 25.7, BUN 36 Cr 2.8 Glucose 122
Coags WNL
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Case
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Prep for TEE included:
Lidocaine hydrocholoride 2% viscous 20 ml x 2
Benzocaine 20% spray (Hurricaine) x2
O2 2L/min NC
Conscious sedation included:
Meperidine (Demerol) 25 mg IVP
Midazolam (Versed) 2 mg IVP
The patient experienced discomfort and nausea when the TEE
probe introduction was attempted, so 2 more sprays of
Benzocaine were administered
The TEE probe was eventually advanced, and the study started
Case
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After 10 minutes, the patient became cyanotic, O2 Sat by pulse
oximetry dropped down to 89%
O2 increased to 6L NC. However the pt became tachypnic,
more cyanotic and pulse ox dropped further to 85%
PE: cyanotic, tachypnic
Vitals: 165/95, 25, 120s, Sat 85% on 6LNC
ENT: no stridor
Lungs: CTAB
CVS: tachycardic, RRR
Neuro: sedated/obtunded
Monitor: sinus tachycardia
What Happened!!!
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Narcotic/benzodiazepine induced respiratory
depression!
Brochospasm/aspiration!
Esophageal rupture!
Something else!!!
Case
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The procedure was terminated
Flumazenil (romazicon) 0.2 mg IVP x2
Naloxone (narcan) 1 mg IVP were given
100% NRM administered, but the patient remained cyanotic,
obtunded with pulse oximetry still 85%!!!
Anesthesia and respiratory care were called for emergent
intubation
CXR ordered stat
ABGS blood drawn and sent was noted dark brown in color, so
it was repeated even before waiting for the results:
7.49/31.2/363.1/25/100%
Case
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Methemoglobinemia was suspected
IV methylene blue at 1 mg/kg IVP was given in the
echo lab
Pt. responded well with quick reversal of his MS
changes, cyanosis, and hypoxemia
Was transferred to ICU for close observation
Blood was sent out for Methemoglobin level which
came back later: Methemoglobin level 31% (reference
range: 0.4-1.5%)
The patient did well overnight and the next morning
repeat Methemoglobin level was 0.9%
Outline
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Safety of TEE
Historical background
Physiologic background
Pathophysiology
Methemoglobinemia
types
Benzocaine formulation
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Risk factors
Clinical presentation
Diagnosis
Treatment
Conclusion
Daniel et al. Safety of Transesophageal Echocardiography. Circulation 1991;83:817-821
Khandheria et al. Mayo Clin Proc 1994; 69:856-863
Historical Background & Incidence
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The first case of benzocaine induced methemoglobinemia was
documented by Bernstein in 1950
Up to 1994 fewer than 100 cases has been reported in literature
Between Nov 1997 through March 2002, 132 cases of
benzocaine induced methemoglobinemia was reported to FDA :
107 serious (81.1%)
2 deaths (1.5%)
In the pulmonary literature topical anesthetics (benzocaine and
lidocaine) induced methemoglobinemia occurred in an incidence
of 1/7000 bronchoscopies
Physiologic Background
Hemoglobin contains 4 heme groups with each
containing an iron in it’s ferrous state (Fe2+)
Physiologic Background
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It is this ferrous state (Fe 2+) that allows O2 to
be transported and delivered to the tissues.
With 4 heme groups having an iron in the
ferrous state, one O2 molecule may be carried
on each heme.
Methemoglobin is an altered state of
hemoglobin in which the ferrous (Fe2+) irons
of heme are oxidized to the ferric (Fe3+) state
Pathophysiology
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The ferric hemes of methemoglobin are unable
to bind and carry oxygen, resulting in functional
anemia
In addition, the oxygen affinity of any
accompanying ferrous hemes in the hemoglobin
tetramere is increased
As a result, the oxygen dissociation curve is left
shifted, and oxygen delivery to the tissues is
impaired
Methemoglobin
Pathophysiology
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RBC are continuously subjected to oxidative
stressors that result in the formation of
methemoglobin spontaneously in normal
individuals at a rate of 0.5-3% of the available
hemoglobin per day
Reduction of methemoglobin maintains a steady
state level of methemoglobin of about 1% of
total hemoglobin
Pathophysiology
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The most physiologically important pathway for
reducing methemoglobin back to hemoglobin is the
NADH-dependent reaction catalyzed by
methemoglobin reductase enzyme [cytochrome b5
reductase (b5R)], this accounts for 95% of the reducing
activity
Less important alternative pathway in Methemoglobin
reduction is by an enzyme utilizing NADPH pathway
Glutathione and ascorbic acid are slow-acting pathways
that play minor roles in the direct reduction of
methemoglobin
Methemoglobinemia Types
Methemoglobinemia occurs when an imbalance due to either
increased methemoglobin production or decreased
methemoglobin reduction is present
 Inherited:
1. Cytochrome b5 reductase deficiency:
type I: limited to RBC
type II: All cells (most die in infancy)
2. Hemoglobin M disease: mutation in either alpha or beta
globin molecule
 Acquired:
More common, result from increased methemoglobin formation
by various exogenous (most of the time pharmacologic) agents
more than the rate of its reduction.
The Fugate Family
“The Blue People of Troublesome Creek”
Agents implicated in Acquired Methemoglobinemia
Agents implicated in Acquired Methemoblobinemia
Amyl nitrite
Aniline derivatives
Butyl nitrite
Bismuth subnitrite
Dapsone
Lidocaine
Benzocaine
Menthol
Naphthalene
Phenytoin
NTG
Nitrophenol
Nipride
Nitrites
Nitrates
Phenacetin
Phenols
Pyridium
Quinones
Silver nitrate
Sulfonamides
Benzocaine Formulations
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Benzocaine is available in spray form, throat
lozenges, and liquid and gel preparations
The spray form is prepared as 14% to 20%
The average expulsion rate is 200 mg/sec
The average dose that can produce
methemoglobinemia is>300 mg in adults
The package insert: “spray for ½ second, may
repeat as needed”
Risk Factors
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Excessive dose
Concurrent use of multiple oxidizing agents
Mucosal damage or inflammation are contributing
factors
Absorption is particularly rapid from the
tracheobronchial tree, as it is technically equivalent to
IV administration
Differences in the metabolism of benzocaine may
explain the variability of benzocaine-induced
methemoglobinemia
High Risk Populations
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Patients with methemoglobin reductase
deficiency or G6PD deficiency
Pediatric population and especially neonates: due
to low levels of functional NADP
methemoglobin reductase
Elderly: NADP becomes less efficient
Impaired hepatic or renal function
Low Oxygen transport states: anemia, acidosis,
low cardiac output state, pulmonary disease
Clinical Presentation
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Onset of symptom is usually within 20 to 60 minutes
of drug administration
The symptoms and signs of methemoglobinemia
correlate to the amount of abnormal hemoglobin
present
Usually, 5 g/dL (>30% of total hemoglobin) of
reduced hemoglobin (deoxyhemoglobin) produces
clinical cyanosis; but only 1.5 g/dL (>10%) of
methemoglobin produces noticeable cyanosis due to
the combined:
1. Decrease in O2 carrying capacity
2. shift in oxyhemoglobin dissociation curve to the left
Methemoglobin
Symptoms and Signs
15-20%
Asymptomatic cyanosis
20-45%
Headache, dyspnea, weakness,
dizziness, lethargy, syncope
45-60%
60-70%
>70%
Decrease level of
consciousness, metabolic
acidosis, tachypnea
Seizures, cardiac arrhythmias,
homodynamic instability and
shock
Fatal
Diagnosis
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Diagnostic suspicion of methemoglobinemia is based
on clinical findings: generalized cyanosis out of
proportion to respiratory status and normal PaO2, and
doesn’t improve with administration of O2
Arterial blood drawn for blood sampling is chocolate
brown, blue, or black and fail to change color when
exposed to air (unlike deoxyhemoglobin) or when a
drop is dried on filter paper
The “oxygen saturation gap”
Cooximetry is the diagnostic test of choice
The cyanosis is generalized, and doesn’t improve
with 100% oxygen
The cyanosis has been referred to as “chocolate cyanosis”
The Oxygen Saturation Gap
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Refers to the difference between the high O2 sat
calculated from routine ABG analysis and the low
O2 sat measured by pulse oximetry
Methemoglobinemia should be suspected when
O2 Sat (ABG) >O2 Sat (pulse OX)
The Routine ABG in
Methemoglobinemia
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The PaO2 usually is normal or inappropriately
high
In routine ABG analysis O2 saturation is
calculated from PaO2 and pH, this leads to falsely
“normal” calculated O2 sat on the ABG analysis
Hence, the routine ABG by itself has no role in
the diagnosis of methemoglobinemia
Pulse Oximetry
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It usually yields information based on the ratio
of light absorbance of oxyhemoglobin (940 nm)
and reduced hemoglobin (660 nm)
Methemoglobin absorbs light equally at both
wavelengths (940 and 660), with pulse oximetry
displaying a O2 Sat of 85%
Hence; the higher the methemoglobin
concentration, the closer the O2 Sat to 85%,
regardless of patient status
Multiple Wavelength
Spectrophotometry (Cooximetry)
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Is the diagnostic test of choice for methemoglobinemia
It is based upon analysis of methemoglobin absorption
spectra which has peak absorbance at 631 nm
A fresh specimen should always be obtained as the
methemoglobin levels increase with storage
Hyperlipidemia interfere with the light absorption and
can cause falsely elevated methemoglobin
Treatment
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Discontinue the offending agent
Most of the cases resolve within 24-36 hours
after the clearing of the residual Benzocaine
General supportive measures (O2, close
observation) are appropriate when
methemoglobin level are <30%
Treatment
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In more severe cases
(methemoglobin>30%) methylene blue
in the dose of 1to 2 mg/kg of 1%
solution slow IV push over 5 minutes
is the preferred treatment.
Cyanosis resolve within 15-30 minutes
Marked reduction in the
methemoglobin concentration usually
by 50% is seen within 30 to 60 minutes
Methylene blue acts as a reducing
agent via the NADPH methemoglobin
reductase pathway It converts ferric
iron back to ferrous state, restoring the
O2 carrying capacity of hemoglobin
Treatment
Administration can be repeated in 1 hour if symptoms
do not resolve
 Methylene blue by itself has oxidizing properties at
higher doses, with toxic effects appearing in doses >7
mg/kg (dyspnea, chest pain, tremors, hemolysis)
 Hyperbaric O2 and exchange transfusion may be used
in:
1. Patients with G6PD deficiency who do not respond
to methylene blue
2. Severe cases (Methemoglobin level>70%)
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Conclusions
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Benzocaine-induced methemoglobinemia is a
rare but potentially fatal reaction that is
imminently treatable if the diagnosis is not
delayed
With the wide spread use of TEE, cardiologists
need to be able to identify and treat this serious
side effect
Identifying high-risk patients, and the judicious
use of topical benzocaine is crucial in
prevention
Conclusions
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The diagnosis is mainly clinical: with a chocolate-color
cyanosis unresponsive to O2 therapy, with a sudden
drop of pulse oximeter reading to 85%
The saturation gap should alert the physician, and the
diagnosis should be confirmed by cooxymetry
Methylene blue should be readily available in areas
where topical anesthetics are frequently used
End
The Story of the Blue
and the Blue