Author Information
Dudhe M*, Khadkikar R**, Saxena N*, Chauhan AR***
(*
Third Year Resident, ** Assistant Professor, *** Additional Professor.
department of Obstetrics and Gynecology, Seth GS Medical College & KEM
Hospital, Mumbai , India
Abstract
Methemoglobin is an oxidized form of hemoglobin with iron in
the ferric form instead of the usual ferrous form, which results in decreased
availability of oxygen to the tissues. Methemoglobinemia occurs when red blood
cells contain methemoglobin higher than 1%. It is a well-known but frequently forgotten
cause of hypoxia and respiratory distress in patients of all ages. [1]
As most patients are asymptomatic, congenital form may be
diagnosed for the first time during pregnancy. We report a primigravida with congenital
methemoglobinemia who was treated with injection methylene blue prior to emergency
lower segment cesarean section (LSCS) for abruptio placentae.
Introduction
Methemoglobin, along
with carboxyhemoglobin and sulfhemoglobin, are types of dyshemoglobin i.e. a
type of haemoglobin that does not bind with oxygen. [2]
Tissue
hypoxia is due to reduction in levels of free haemoglobin and hence difficulty in
release of oxygen. Congenital methemoglobinemia is a rare genetic abnormality in which patient
is mostly asymptomatic and only presents with cyanosis which may be present
since birth. [3] During pregnancy, it may lead to uteroplacental
insufficiency causing intrauterine growth retardation, oligohydramnios, severe
preeclampsia and abruption. [4]
Case
Report
A 23 year old primigravida, known case of congenital
methemoglobinemia was admitted in our tertiary care hospital at 34 weeks’ of gestation
for evaluation of pedal edema. Significant finding at this time was methemoglobin
level of 25%. Hematologist opinion was sought; no active treatment was advised except
to continue tablet vitamin C twice daily. Obstetric evaluation and other
investigations were normal hence patient was discharged.
On past history, patient
had mild cyanosis since birth but was diagnosed with congenital methemoglobinemia
only 4 years ago, when she presented with breathlessness not responding to
oxygen along with slate grey cyanosis. At that time, cardiovascular and respiratory
system examination were normal and all routine investigations were normal. G6PD
enzyme activity was normal. However, methemoglobin levels were significantly
elevated (44%), and nicotinamide adenine
dinucleotide (NADH) cytochrome b5
reductase activity was decreased. She was started on tablet vitamin C and
multivitamin twice a day. At 38 weeks
of gestation, patient was readmitted in early labour. On examination, she had
cyanosis, her pulse was 92/ min, blood pressure was 130/ 90 mm of Hg, urine
albumin was 2+. Blood drawn for investigations was chocolate brown in colour. ABG
showed oxygen saturation of 92 %. In view of foetal distress and signs of
abruption, decision for emergency LSCS was taken. Urgent haematology opinion
was sought; repeat urgent methemoglobin levels were not possible hence based on
recent report of methemoglobin 25 %, patient was given intravenous 1 mg/ kg (50 mg) methylene
blue in 500 ml normal saline over 30
minutes prior to commencement of LSCS. Patient underwent emergency LSCS in view of abruptio placenta
under general anaesthesia, with high doses of oxygen. LSCS was uneventful;
she delivered a male
child of
2.6 kg with Apgar score of 9/10.
Repeat methemoglobin level postoperatively was 3.3%. Patient was stable and was
discharged on day 7.
Discussion
Hemoglobin can transport oxygen only
when the iron is in ferrous form. When hemoglobin loses an electron, the iron
atom is converted to the ferric state, forming methemoglobin. This causes leftward
shift of the oxygen-hemoglobin dissociation curve, hence decreased release of
oxygen to the tissues, and hence clinical manifestations.
Normally, the
methemoglobin level is < 1 %; this low level is maintained by 2 mechanisms.
The first is the hexose-monophosphate shunt pathway within the erythrocyte,
where oxidizing agents are reduced by glutathione. The second mechanism requires
NADH and nicotinamide adenine dinucleotide phosphate (NADPH) to reduce
methemoglobin to its original ferrous state. Methemoglobinemia
results from a redox imbalance, either due to decrease in the activity of
reducing enzymes (congenital form) or excessive oxidization of haemoglobin (acquired
form).
Congenital methemoglobinemia is very
rare and is of
two types: one due to NADH methemoglobin reductase enzyme deficiency,
which is autosomal recessive and the other due to an abnormal oxygen affinity hemoglobin termed
hemoglobin M, which is autosomal dominant; our patient had
the former deficiency.[1]
Acquired form is more common, and may occur when
erythrocytes are affected by oxidizing agents like acetaminophen, anticonvulsants,
nitrofurantoin, sulphonamides, valproic acid, dapsone, nitroglycerin, topical
anaesthetic agents like benzocaine, and volatile organic compounds.[2]
Occasionally it may occur secondary to pathologic conditions like sepsis, sickle
cell crisis, and gastrointestinal infections in children.[2]
Presence of cyanosis
without any cardiopulmonary disorder or decrease in oxygen saturation, and an
appearance of “more blue than sick” are diagnostic.[1] Symptoms depend upon
percentage of methemoglobin in blood:
<3%
|
asymptomatic
|
3 – 15 %
|
grayish skin color
|
15 - 30 %
|
cyanosis and chocolate
brown blood
|
30 – 50 %
|
dyspnea, headache,
fatigue, dizziness, syncope, with oxygen saturation as low as 80 %, as seen
in our case
|
50 – 70 %
|
tachypnea, metabolic
acidosis, cardiac arrhythmias, seizures, CNS depression and coma [2]
|
Organs
with high oxygen demands i.e. central nervous system and cardiovascular system
are usually the first to manifest toxicity. Main symptoms include central cyanosis not
responding to oxygen, and in severe cases altered mental status, convulsions
and coma leading to death when level rises to 70%.
Most
common complications during pregnancy include anemia, threatened abortion,
preterm labor, pregnancy induced hypertension, IUGR, and placental abruption. [4]
These changes may be a result of hypoxia, excessive production of free radicals,
resultant oxidative damage to cellular membranes and DNA. Monitoring of methemoglobin concentrations in
maternal blood is a reliable indicator of effects of free radicals and
oxidative states. Our patient presented with pregnancy induced hypertension and
placental abruption for which emergency LSCS was performed. Environmental
toxins like nitrogen oxides, sulphur dioxide and their metabolites over longer
periods, cause maternal vascular endothelial dysfunction from early pregnancy. There is no definitive
treatment for hereditary methemoglobinemia which is a chronic and mild
condition. Treatment depends upon symptoms and level of methemoglobin. Chronic
mild forms are given ascorbic acid (which acts as reducing agent), riboflavin
and N-acetylcystine to reduce oxidative damage.
Primary emergency
treatment includes administration of intravenous methylene blue in
symptomatic cases. It is a thiazine dye with dose-dependent antiseptic
and oxidizing properties. Methylene blue
activates NADPH methemoglobin reductase, resulting in
reduction of methylene blue to
methylene leucoblue, which transforms methemoglobin into normal hemoglobin by a
non-enzymatic mechanism. Methylene blue restores the iron in
hemoglobin to its normal oxygen-carrying state by providing an artificial
electron acceptor for NADPH methemoglobin reductase. Methemoglobin level falls
significantly 30 to 60 minutes after the first dose; in our case we commenced
LSCS within 30 minutes of methylene blue. [2] Rapid intravenous
administration or higher doses can cause thoracic pain, dyspnoea, hypertension,
diaphoresis and haemolysis. It should be administered carefully in patients
with renal failure; it is slowly excreted by the kidneys and the urine has a
bluish tint.
Exchange
transfusion or hyperbaric oxygen is suggested treatment options in resistant
cases and in G6PD deficient individuals in whom methylene blue is
contraindicated. Combined efforts of hematologist, obstetrician and anesthetist
contributed towards effective management of this case.
References
1. Palaniappan S, Aan GJ, Ken
CC. Case
report in congenital methemoglobinemia in pregnancy Research
Updates in Medical Sciences (RUMeS) 2013; 1:30-32. The internet journal of obstetrics and gynecology.
Available from: http://rumesjournal.com/sites/default/files/articles/pdf%20choo%20%282%29.pdf
2. Nascimento TS, Pereira
3.
Pepper
G, Weinstein HG, and Heller P. Congenital methemoglobinemia in pregnancy. The
journal of American medical association. 1961; 177(5):328-330. Available from: http://jama.jamanetwork.com/article.aspx?articleid=331509
4. Mohorovic L. The role
of methemoglobinemia in early and late complicated pregnancy. Medical hypothesis.
2007;68(5):1114-1119.
Available from: www.mdpi.com
Citation