A CASE TOXIN INDUCED METHEMOGLOBINEMIA CAUSED BY ANTI TERMITE

1. A CASE OF TOXIN INDUCED
CYANOSIS
IMCU & TOXICOLOGY UNIT
IIM
DR.B.MIDHUN KUMAR
I ST YEAR POST GRADUATE

3. INTRODUCTION
 We present a case of a patient who developed
methemoglobinemia after consuming cell oil (anti
termite oil) for suicidal intention.
 Methemoglobinemia is an uncommon , but
potentially fatal hemoglobinopathy.
 It leads to rapid oxygen desaturation, and
therefore requires prompt recognition and
treatment.

4. HISTORY
 A 45 year old male pt was brought on
19/07/2012 at 3 PM to our toxicology ward in an
unconscious state,
 With Alleged history of consumption of around 1
bottle (100 ml) of anti termite oil(CORAL) in his
house at Perambur at 1 p.m.

6.  Pt did not have any seizures or vomiting or frothing
from the mouth after he was seen by his relative at
1.30 PM who brought him here
 No h/o any tremors/ fasciculations/ other abnormal
movements noted by the attenders
 No h/o increased urination or defecation
 No h/o any injuries

7.  No h/o other co-morbidities
 No previous h/o poisoning/ suicidal attempts
 Known alcoholic for the past 20 years – frequent
binge drinking for last 1 week

8. EXAMINATION
 Pt was unconscious, Not responding to deep pain
 GCS-E1V1M1
 He was Afebrile,
 Dyspnoeic,
 Tachypneic ( RR-30/min)

10.  He was pale, peripheries cold
 CYANOSIS +,FINGERS,TOES,LIPS AND
TONGUE
 Not Icteric,No Clubbing,No pedal edema
 His spontaneous respiratory effort was poor
 Smell of cell oil (Anti-Termite oil) was present

11.  VITAL SIGNS:
 PR: 96/min,Small volume, Felt in all peripheral
vessels
 BP: 90/60 mm Hg
 RR: 30 / min , irregular, accessory muscles acting
 Temp: 98.8 F
 SpO2: 70 % in room air,75 % with O2 6l/min
 CBG- 148 mg/dl

12. SYSTEMIC EXAMINATION
 CVS: S1S2+, No murmurs or added sounds
 RS : B/L NVBS+, No added sounds
 P/A: Soft ,No Organomegaly, BS +
 CNS:
Pupils : B/L 4 mm RTL sluggishly
No neck rigidity
No fasciculations
Plantar reflex: B/L No response

13.  An intravenous (IV) line was inserted
 Blood taken from the patient was dark brown
in colour and sent for complete blood
count,serum electrolytes, blood urea nitrogen
(BUN), glucose, ABG and serum methemoglobin
levels

15. Initial investigations
 CBC
TC-16,400
DC-P95/L2/ E3
ESR-20
HB-11.9G/dl
PCV-34
PLT-2 LAKHS

16.  RFT
UREA-75
CREATININE-1.7
SODIUM-142
POTASSIUM-2.8
CALCIUM- 9.3 mg/dl.

17.  LFT
TB- 1
DB- 0.4
SAP-84
TP-6.9
ALB-3.7

18.  ABG- SEVERE METABOLIC ACIDOSIS
 URINE R/E- 1+ ALBUMINURIA
 SERUM LDH-196 U/L
 SERUM METHEMOGLOBIN> 3%
 URINE Hb , MYOGLOBIN - NEGATIVE

19. TREATMENT
 Pt was Intubated and started on Assisted
ventilation
 Stomach wash and Activated charcoal was given
 Pt started on IV fluids at the rate of 200ml/hr

20.  Inj. Methylene blue 100mg(2mg/kg/dose) in 100ml
of 5% Dextrose IV Infusion given over 10 mins,
2nd dose repeated after 1 hr(2mg/kg/dose).
Cyanosis improved.
 Pt started on Inotropic support as BP did not improve
with IV fluids
 Inj.Vitamin C started at a dose of 500 mg IV TDS
 IV antibiotics

21. COURSE
 Cyanosis showed little improvement and hence pt
was started on exchange transfusion and 7
cycles were done
 Pt’s SpO2 continued to be around 75% even with
ventilatory support
 Pt’s respiratory effort and sensorium improved
and hence he was connected to T piece
ventilation with O2 after weaning gradually on
Day 2

22.  Pt was Extubated on Day 3 and put on O2 mask
as he became totally conscious
 His saturation was 80% with O2 6l/min
.

23.  His RFT values started rising and his creatinine
became 3.7mg/dl on Day 5 .
 He also developed Myoglobinuria and
Albuminuria
 His LFT also started showing increasing Bilirubin
levels

24.  Forced alkaline diuresis was started
 Patient improved and on 7 th day of admission
he was completely normal.
 His cyanosis disappeared and his saturation went
up to 95% on room air, sr. methemoglobin levels
came below 3%.

27. THE COMPOUND
 The compound which the patient consumed was
cell oil (CORAL ,HYPOL-SLM) which is an anti
termite oil used for varnishing the furniture,
 Its ingredients are
 pine tar
 Nitro toluene compounds
 Chlorobenzene compounds
 Of these ,nitro toluene and chlorobenzene are
powerful oxidizing agents which are implicated in
causing methemoglobinemia,

28. METHEMOGLOBIN
 Oxidized form of normal hemoglobin, in which the
iron atom in hemoglobin loses 1 electron to an
oxidant, and the ferrous (Fe2+) state of iron is
transformed into the ferric (Fe3+) state .
 Methemoglobin not only decreases the available
oxygen-carrying capacity, but also increases the
affinity of the unaltered hemoglobin for oxygen.
 This shifts the oxygen hemoglobin dissociation curve
to the left, which further impairs oxygen delivery
, leading to tissue hypoxia.

30. FELIX HOPPE SEYLER
 Methemoglobin was
first described by Felix
Hoppe-Seyler in 1842.
 German physiologist
and chemist.
 He also discovered
the functions of
hemoglobin.

31.  Methemoglobinemia may produce symptoms of
cellular hypoxia and should be considered in the
differential diagnosis of the cyanotic patient who
has no apparent cardiovascular cause.
 In the cases of methemoglobinemia and
sulfhemoglobinemia, cyanosis is not caused by
deoxyhemoglobin but rather by the color imparted
to the skin as a result of oxidized hemoglobin

32.  Because of the spontaneous and toxins induced
oxidation of hemoglobin, the erythrocyte has
developed multiple mechanisms to maintain the
normal level of methemoglobin at <1%.
 All of these systems donate an electron to the
oxidized iron atom.
 The half-life of methemoglobin acutely formed as
a result of exposure to oxidants is between 1 and
3 hours.
 With continuous exposure to the oxidant, the half-
life of methemoglobin appears prolonged.

33.  The most important reductive system requires
nicotinamide adenine di nucleotide (NADH), which is
generated in the Embden-Meyerhof glycolytic
pathway
 NADH serves as an electron donor, and along with
the enzyme NADH methemoglobin reductase,
reduces the oxidized ferric (Fe3+) iron to the more
functionally favourable ferrous (Fe2+) iron state
 Individuals who are subjected to oxidant stresses like
the toxin in cell oil cannot exclusively be dependent
on the system

34.  Within the red cell is another enzyme system for
reducing oxidized iron that is dependent on the
nicotinamide adenine dinucleotide phosphate
(NADPH) generated in the hexose
monophosphate shunt pathway
 NADPH reduces only a small percentage of
methemoglobin under normal circumstances

35. METHYLENE BLUE
 When the NADPH methemoglobin reductase
system is provided with an exogenous electron
carrier such as methylene blue, this system is
accelerated and can assist in the reduction of
oxidized hemoglobin
 This is the basis of using methylene blue in the
treatment of methemoglobin.

37. Ascorbic acid
 Oxidized iron can also be reduced
nonenzymatically using ascorbic acid and
reduced glutathione as electron donors
 But this method is much quantitatively less
important under normal circumstances

38. Etiologies of
Methemoglobinemia
 Hereditary
Hemoglobin M(Hb IWATE, Hb MILWAUKEE, Hb
BOSTON)
Cytochrome b5 reductase deficiency
(homozygote and heterozygote)

39.  Acquired
 Medications
Amyl nitrite
Benzocaine
Dapsone
Lidocaine
Nitric oxide
Nitroglycerin
Nitroprusside
Phenacetin
Phenazopyridine
Prilocaine (local anesthetic)
Quinones (chloroquine, primaquine)
Sulfonamides
(sulfanilamide, sulfathiazide, sulfapyridine, sulfamethoxa
zole)

40.  Other xenobiotics
Aniline dye derivatives (shoe dyes, marking inks)
Butyl nitrite
Chlorobenzene
Fires (heat-induced denaturation)
Food adulterated with nitrites
Food high in nitrates
Isobutyl nitrite
Naphthalene
Nitrates
Nitrites
Nitrophenol
Nitrous gases (seen in arc welders)
Silver nitrate
Trinitrotoluene
Well water (nitrates)

41. Methemoglobin symptoms
levels

42. DIAGNOSIS
 Cooximetry is generally the preferred laboratory
technique for diagnosis of methemoglobinemia .
 co-oximetry is a simplified spectophotometer that
measure light absorbency at four different
wavelengths and these wavelengths correspond
to specific absorbency characteristics of
deoxyhemoglobin, oxyhemoglobin, carboxyhemo
globin, and hemoglobin.

44.  Pulse oximetry is unreliable in the presence
of methemoglobinemia because methemoglobin
(MetHb) absorbs light equally well at wavelengths
(typically 660 and 940 nm) used to determine
oxygen saturation
 Arterial blood-gas analysis can also be
misleading in methemoglobinemia because it will
show normal Po2, even in the presence of high
MetHb concentration and inaccurate oxygen
saturation if values were calculated from the pH
and arterial Po2.

45. EVELYN MALLOY METHOD
 Met hb assay Quantitative test is by EVELYN
MALLOY method
 Take 2 aliquots of blood 1 & 2 ;
 1) Absorbance measured at 630nm (A1);add
pot.cyanide; measure again absorbance(A2) ; if
any met hb + the cyanide will abolish the
absorbance peak
 2)add pot.ferricyanide; allHb converted to metHb;
now measure absorbance before(A3) and after
adding cyanide(A4)
 % of met Hb = ( A1-A2)×100 / (A3-A4)

46. ANCILLARY INVESTIGATIONS
 CBC
 RFT
 LFT
 SERUM METHEMOGLOBIN
 URINE HEMOGLOBIN
 SERUM CPK, LDH
 PERIPHERAL SMEAR
 BLOOD GROUPING
 G 6 PD ASSAY
 X RAY
 ECG

47. MANAGEMENT
 The most widely accepted treatment of
methemoglobinemia due to drugs or toxin
exposure is administration of methylene blue
1to2 mg/kg body weight infused intravenously
over 5 minutes
 Clinical improvement should be noted within 1
hour of methylene blue administration if an
elevated methemoglobin level is etiologic.

48.  If cyanosis does not disappear within 1 hour of
the infusion, a second dose should be given while
other factors are considered
 Its action depends on the availability of reduced
nicotinamide adenine nucleotide phosphate
(NADPH) within the red blood cells
 After an acute exposure to an oxidizing agent,
treatment should be considered when the
methemoglobin is 30% in an asymptomatic
patient and 20% in a symptomatic patient.

49.  Patients with anemia or cardiorespiratory
problems should be treated at lower levels of
methemoglobin.
 Methemoglobinemia due to hemoglobin M does
not respond to ascorbic acid or methylene blue.
 Dextrose should be given because the major
source of NADH in the red blood cells is the
catabolism of sugar through glycolysis.
 Dextrose is also necessary to form NADPH
through the hexose monophosphate shunt, which
is necessary for methylene blue to be effective.

50.  Methylene blue is an oxidant; its metabolic
product leukomethylene blue is the reducing
agent.
 Therefore, large doses of methylene blue may
result in higher levels of methylene blue rather
than the leukomethylene blue, which will result in
hemolysis .
 It may, paradoxically causes
methemoglobinemia in patients with glucose-6-
phosphate dehydrogenase (G6PD) deficiency.

51.  Use of methylene blue in patients with G6PD
deficiency is controversial. G6PD-deficient
patients have been excluded from most treatment
protocols because methylene blue is a mild
oxidant and case reports suggest methylene blue
toxicity
 However, because of the lack of immediate
availability of the test for G6PD deficiency, most
patients who need treatment
receive methylene blue therapy before their
G6PD status is known

52.  N-Acetylcysteine, cimetidine, and ketoconazole
are experimental therapies in the treatment of
methemoglobinemia that have shown some
promising results.
 Exchange transfusion is reserved for patients in
whom methylene blue therapy is ineffective.

53. Review of literature
 Rodriguez LP, Smolik LM, Zbehlik AJ:
Benzocaine-induced methemoglobinemia: report
of a severe reaction and review of the literature.
 Tingle MD, Coleman MD, Park BK dapsone-
induced methaemoglobinaemia .
 Severe methemoglobinemia from topical
anesthetic spray: Riyad B. Abu-Laban, Peter J.
Zed,