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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.

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the story of the blue and the blue

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


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:


IDDM with CRI and BLE neuropathy

Gastric CA


  • 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

  • Meds:

Was not taking any of his meds:





  • Allergies:


  • FH:

Positive for DM and HTN

  • ROS:

Other than the R foot pain and fever, was negative

  • 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

  • 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

  • Right foot X-ray: (+) gas in the soft tissue of the 2nd and 3rd toes
  • Admitted to SICU to Surgery Service with Medicine on consult and was started on:


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)

  • 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

  • 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

  • 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
  • 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
What Happened!!!
  • Narcotic/benzodiazepine induced respiratory depression!
  • Brochospasm/aspiration!
  • Esophageal rupture!
  • Something else!!!
  • 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:


  • 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%
Safety of TEE

Historical background

Physiologic background


Methemoglobinemia types

Benzocaine formulation

Risk factors

Clinical presentation





Khandheria et al. Mayo Clin Proc 1994; 69:856-863

historical background incidence
Historical Background & Incidence
  • 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
Physiologic Background

Hemoglobin contains 4 heme groups with each

containing an iron in it’s ferrous state (Fe2+)

physiologic background1
Physiologic Background
  • 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
  • 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
  • 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
  • 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 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”

benzocaine formulations
Benzocaine Formulations
  • 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
Risk Factors
  • 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
High Risk Populations
  • 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
Clinical Presentation

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

  • 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 oxygen saturation gap
The Oxygen Saturation Gap
  • Refers to the difference between the high O2 sat calculated from routine ABG analysis and the low O2 sat measuredby pulse oximetry
  • Methemoglobinemia should be suspected when O2 Sat (ABG) >O2 Sat (pulse OX)
the routine abg in methemoglobinemia
The Routine ABG in Methemoglobinemia
  • 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
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

Pulse Oximetry
multiple wavelength spectrophotometry cooximetry
Multiple Wavelength Spectrophotometry (Cooximetry)
  • 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
  • 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%
  • 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
  • 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%)

  • 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
  • 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


The Story of the Blue

and the Blue