Accepted Manuscript Methemoglobinemia: A Diagnosis Not to be Missed Kusum Lata, MD, Rajesh Janardhanan, MD, MRCP, FACC, FASE PII:
S0002-9343(15)00442-8
DOI:
10.1016/j.amjmed.2015.04.031
Reference:
AJM 12995
To appear in:
The American Journal of Medicine
Received Date: 27 April 2015 Accepted Date: 28 April 2015
Please cite this article as: Lata K, Janardhanan R, Methemoglobinemia: A Diagnosis Not to be Missed, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.04.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Tittle Page
Authors:
SC
Authors: Kusum Lata, MD
RI PT
Tittle: Methemoglobinemia: A Diagnosis Not to be Missed
M AN U
Rajesh Janardhanan, MD, MRCP, FACC, FASE
Institutional Affiliation:
Sarver Heart Center, Division of Cardiology,
TE D
Department of Medicine, University of Arizona
Conflict of interest: None Funding: None.
EP
Disclosures: None
AC C
Both thr authors had access to the data and a role in writing the manuscript.
First Author and Corresponding Author: Kusum Lata, MD Sarver Heart Center 1501 N. Campbell Avenue Tucson, AZ 85724
ACCEPTED MANUSCRIPT
Email: [email protected]
Second Author:
RI PT
Rajesh Janardhanan, MD, MRCP, FACC, FASE
Associate Professor of Medicine and Medical Imaging
Medical Director, Non-Invasive Cardiac Imaging, South Campus
SC
Sarver Heart Center, Box 245037 1501 N. Campbell Avenue
M AN U
Tucson, AZ 85724
Telephone: 520-626-3766 Fax: 520-626-4333
AC C
EP
TE D
Email: [email protected]
ACCEPTED MANUSCRIPT
Presentation
RI PT
A 60 year old female was referred for transesophageal echocardiography (TEE) for evaluation of endocarditis. Prior to TEE, the patient’s oxygen saturation by pulse
oximetry was 99% on room air and rest of the vital signs were normal. Conscious
SC
sedation was achieved with 3 mg of intravenous midazolam and 25 mcg of intravenous fentanyl. Topical 20% benzocaine (hurricaine) spray was utilized to achieve local
room air during the procedure.
Post procedure assessment
M AN U
oropharyngeal anesthesia. Her oxygen saturation was maintained to more than 95% on
TE D
After the TEE, she was easily arousable but looked tired. Vital sign assessment showed gradual fall in oxygen saturation despite increase in the oxygen supplementation. She was given intravenous naloxone to reverse sedation. However, her peripheral oxygen
EP
saturation did not improve. When the oxygen saturation dropped to 86%, a nonrebreather mask of 100% oxygen was applied (Figure-1). She looked cyanotic and pale
AC C
but able to respond to questions.
ACCEPTED MANUSCRIPT
Diagnosis and Management
Arterial blood gas analysis showed chocolate color blood with pH 7.43, SAO2 68, PO2
RI PT
416, pCO2 30 and elevated methemoglobin (MHb) levels of 32.1%. Immediate injection of methylene blue 1 mg/Kg intravenously was initiated. Repeat arterial blood gas analysis one hour later showed improving MHb levels of 9.1 % with oxygen saturation of 90%.
SC
She was much more alert and awake. Additional dose of methylene blue 1 mg/kg
intravenously was given. Two hours later venous blood gas analysis showed MHb level of
M AN U
0.4 % with complete resolution of cyanosis.
Discussion
Hemoglobin (Hb) carries iron in ferrous (Fe2+) state, which is the reduced state of iron. Methemoglobin (MHb) carries iron in oxidized form, which is Fe3+. Oxidized iron
TE D
(Fe3+) in MHb has high affinity for oxygen. Hence the release of oxygen to tissue is compromised. Abnormal elevation of MHb level in blood leads to reduced ability of red
EP
blood cells to release oxygen to tissues, resulting in methemoglobinemia.
Methemoglobinemia can be genetic due to deficiency of various enzymes and substrates
AC C
as well as acquired from various chemicals/drugs. Under normal physiologic circumstances MHb formed in the body gets reduced to deoxy-hemoglobin by nicotinamide adenine dinucleotide-dependent (NADPH) methemoglobin enzyme (Figure2).
Less than 2% of MHb level can be present under normal physiologic condition and does not cause any symptoms. Signs and symptoms of methemoglobinemia include headache,
ACCEPTED MANUSCRIPT
fatigue, dizziness, shortness of breath, cyanosis, mental status changes and loss of consciousness. Seizure, coma and death can occur in severe cases. Additional comorbidities in which oxygenation is already compromised like anemia, lung diseases,
RI PT
infection, hemoglobinopathies can result in severe symptoms even at lower levels of MHb. Risk factors predisposing to this condition in our patient were anemia and
bacteremia. Gold standard diagnosis is by co-oximetry blood gas analysis showing
SC
chocolate color blood, high or normal PO2 and high MHb level. The discrepancy
M AN U
between pulse oximetry and PO2 is due to presence of MHb in blood.
Apart from sedative medications, benzocaine (ethyl aminobenzoate) topical anesthetics are widely used prior to TEE. Though local benzocaine is a relatively safe anesthetic agent, methemoglobinemia is one of the extremely rare adverse events. The treatment of MHb is methylene blue, which can be initiated at a rate of 1-2mg/Kg intravenous over 3-
TE D
10 minutes. If MHb level is high > 50% or if the clinical condition worsens then higher dose of methylene blue 2mg/Kg initially can be given. The dose can be repeated if
EP
symptoms fail to improve or high MHb levels persist. Much higher level of MHb > 70% may require transfusion or dialysis. Recognition is critical, since delay in treatment can
AC C
lead to cardiopulmonary compromise, neurological sequelae, and even death.
Recent benzocaine exposure, lack of improvement of peripheral oxygenation to oxygen supplementation, high PO2 and high MHb levels were important diagnostic clues in our patient. Early diagnosis, prompt treatment, and careful monitoring lead to a positive outcome in our case.
RI PT
ACCEPTED MANUSCRIPT
99
99
99
90
9:06
9:25
9:36
9:57
EP
TE D
Time line (hh:mm)
AC C
SC
96
88
M AN U
Oxygen Saturation (%)
FIGURE 1: DECLINE IN OXYGEN SATURATION
10:30
10:42
86
10:44
ACCEPTED MANUSCRIPT
Methylene blue
NADPH MHb enzyme Reduced hemoglobin (Deoxy-Hb) Iron in Fe+2
SC
RI PT
Oxidized hemoglobin (MHb) Iron in Fe+3
Genetic, Acquired conditions
AC C
EP
TE D
M AN U
Figure 2: Methemoglobin formation pathway
S0002-9343(15)00442-8
DOI:
10.1016/j.amjmed.2015.04.031
Reference:
AJM 12995
To appear in:
The American Journal of Medicine
Received Date: 27 April 2015 Accepted Date: 28 April 2015
Please cite this article as: Lata K, Janardhanan R, Methemoglobinemia: A Diagnosis Not to be Missed, The American Journal of Medicine (2015), doi: 10.1016/j.amjmed.2015.04.031. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Tittle Page
Authors:
SC
Authors: Kusum Lata, MD
RI PT
Tittle: Methemoglobinemia: A Diagnosis Not to be Missed
M AN U
Rajesh Janardhanan, MD, MRCP, FACC, FASE
Institutional Affiliation:
Sarver Heart Center, Division of Cardiology,
TE D
Department of Medicine, University of Arizona
Conflict of interest: None Funding: None.
EP
Disclosures: None
AC C
Both thr authors had access to the data and a role in writing the manuscript.
First Author and Corresponding Author: Kusum Lata, MD Sarver Heart Center 1501 N. Campbell Avenue Tucson, AZ 85724
ACCEPTED MANUSCRIPT
Email: [email protected]
Second Author:
RI PT
Rajesh Janardhanan, MD, MRCP, FACC, FASE
Associate Professor of Medicine and Medical Imaging
Medical Director, Non-Invasive Cardiac Imaging, South Campus
SC
Sarver Heart Center, Box 245037 1501 N. Campbell Avenue
M AN U
Tucson, AZ 85724
Telephone: 520-626-3766 Fax: 520-626-4333
AC C
EP
TE D
Email: [email protected]
ACCEPTED MANUSCRIPT
Presentation
RI PT
A 60 year old female was referred for transesophageal echocardiography (TEE) for evaluation of endocarditis. Prior to TEE, the patient’s oxygen saturation by pulse
oximetry was 99% on room air and rest of the vital signs were normal. Conscious
SC
sedation was achieved with 3 mg of intravenous midazolam and 25 mcg of intravenous fentanyl. Topical 20% benzocaine (hurricaine) spray was utilized to achieve local
room air during the procedure.
Post procedure assessment
M AN U
oropharyngeal anesthesia. Her oxygen saturation was maintained to more than 95% on
TE D
After the TEE, she was easily arousable but looked tired. Vital sign assessment showed gradual fall in oxygen saturation despite increase in the oxygen supplementation. She was given intravenous naloxone to reverse sedation. However, her peripheral oxygen
EP
saturation did not improve. When the oxygen saturation dropped to 86%, a nonrebreather mask of 100% oxygen was applied (Figure-1). She looked cyanotic and pale
AC C
but able to respond to questions.
ACCEPTED MANUSCRIPT
Diagnosis and Management
Arterial blood gas analysis showed chocolate color blood with pH 7.43, SAO2 68, PO2
RI PT
416, pCO2 30 and elevated methemoglobin (MHb) levels of 32.1%. Immediate injection of methylene blue 1 mg/Kg intravenously was initiated. Repeat arterial blood gas analysis one hour later showed improving MHb levels of 9.1 % with oxygen saturation of 90%.
SC
She was much more alert and awake. Additional dose of methylene blue 1 mg/kg
intravenously was given. Two hours later venous blood gas analysis showed MHb level of
M AN U
0.4 % with complete resolution of cyanosis.
Discussion
Hemoglobin (Hb) carries iron in ferrous (Fe2+) state, which is the reduced state of iron. Methemoglobin (MHb) carries iron in oxidized form, which is Fe3+. Oxidized iron
TE D
(Fe3+) in MHb has high affinity for oxygen. Hence the release of oxygen to tissue is compromised. Abnormal elevation of MHb level in blood leads to reduced ability of red
EP
blood cells to release oxygen to tissues, resulting in methemoglobinemia.
Methemoglobinemia can be genetic due to deficiency of various enzymes and substrates
AC C
as well as acquired from various chemicals/drugs. Under normal physiologic circumstances MHb formed in the body gets reduced to deoxy-hemoglobin by nicotinamide adenine dinucleotide-dependent (NADPH) methemoglobin enzyme (Figure2).
Less than 2% of MHb level can be present under normal physiologic condition and does not cause any symptoms. Signs and symptoms of methemoglobinemia include headache,
ACCEPTED MANUSCRIPT
fatigue, dizziness, shortness of breath, cyanosis, mental status changes and loss of consciousness. Seizure, coma and death can occur in severe cases. Additional comorbidities in which oxygenation is already compromised like anemia, lung diseases,
RI PT
infection, hemoglobinopathies can result in severe symptoms even at lower levels of MHb. Risk factors predisposing to this condition in our patient were anemia and
bacteremia. Gold standard diagnosis is by co-oximetry blood gas analysis showing
SC
chocolate color blood, high or normal PO2 and high MHb level. The discrepancy
M AN U
between pulse oximetry and PO2 is due to presence of MHb in blood.
Apart from sedative medications, benzocaine (ethyl aminobenzoate) topical anesthetics are widely used prior to TEE. Though local benzocaine is a relatively safe anesthetic agent, methemoglobinemia is one of the extremely rare adverse events. The treatment of MHb is methylene blue, which can be initiated at a rate of 1-2mg/Kg intravenous over 3-
TE D
10 minutes. If MHb level is high > 50% or if the clinical condition worsens then higher dose of methylene blue 2mg/Kg initially can be given. The dose can be repeated if
EP
symptoms fail to improve or high MHb levels persist. Much higher level of MHb > 70% may require transfusion or dialysis. Recognition is critical, since delay in treatment can
AC C
lead to cardiopulmonary compromise, neurological sequelae, and even death.
Recent benzocaine exposure, lack of improvement of peripheral oxygenation to oxygen supplementation, high PO2 and high MHb levels were important diagnostic clues in our patient. Early diagnosis, prompt treatment, and careful monitoring lead to a positive outcome in our case.
RI PT
ACCEPTED MANUSCRIPT
99
99
99
90
9:06
9:25
9:36
9:57
EP
TE D
Time line (hh:mm)
AC C
SC
96
88
M AN U
Oxygen Saturation (%)
FIGURE 1: DECLINE IN OXYGEN SATURATION
10:30
10:42
86
10:44
ACCEPTED MANUSCRIPT
Methylene blue
NADPH MHb enzyme Reduced hemoglobin (Deoxy-Hb) Iron in Fe+2
SC
RI PT
Oxidized hemoglobin (MHb) Iron in Fe+3
Genetic, Acquired conditions
AC C
EP
TE D
M AN U
Figure 2: Methemoglobin formation pathway
