IMCU & TOXICOLOGY UNIT

IIM

DR.B.MIDHUN KUMAR

I ST YEAR POST GRADUATE

A CASE OF TOXIN INDUCED

CYANOSIS

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.

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.

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

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

EXAMINATION

Pt was unconscious, Not responding to deep pain

GCS-E1V1M1

He was Afebrile,

Dyspnoeic,

Tachypneic ( RR-30/min)

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

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

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

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

Initial investigations

CBC

TC-16,400

DC-P95/L2/ E3

ESR-20

HB-11.9G/dl

PCV-34

PLT-2 LAKHS

RFT

UREA-75

CREATININE-1.7

SODIUM-142

POTASSIUM-2.8

CALCIUM- 9.3 mg/dl.

LFT

TB- 1

DB- 0.4

SAP-84

TP-6.9

ALB-3.7

ABG- SEVERE METABOLIC ACIDOSIS

URINE R/E- 1+ ALBUMINURIA

SERUM LDH-196 U/L

SERUM METHEMOGLOBIN> 3%

URINE Hb , MYOGLOBIN - NEGATIVE

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

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

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

Pt was Extubated on Day 3 and put on O2 mask

as he became totally conscious

His saturation was 80% with O2 6l/min

.

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

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%.

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,

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.

FELIX HOPPE SEYLER

Methemoglobin was

first described by Felix

Hoppe-Seyler in 1842.

German physiologist

and chemist.

He also discovered

the functions of

hemoglobin.

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

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.

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

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

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.

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

Etiologies of

Methemoglobinemia

Hereditary

Hemoglobin M(Hb IWATE, Hb MILWAUKEE, Hb

BOSTON)

Cytochrome b5 reductase deficiency

(homozygote and heterozygote)

Acquired

MedicationsAmyl nitriteBenzocaineDapsoneLidocaineNitric oxideNitroglycerinNitroprussidePhenacetinPhenazopyridinePrilocaine (local anesthetic)Quinones (chloroquine, primaquine)Sulfonamides(sulfanilamide, sulfathiazide, sulfapyridine, sulfamethoxazole)

Other xenobiotics

Aniline dye derivatives (shoe dyes, marking inks)Butyl nitriteChlorobenzeneFires (heat-induced denaturation)Food adulterated with nitritesFood high in nitratesIsobutyl nitriteNaphthaleneNitratesNitritesNitrophenolNitrous gases (seen in arc welders)Silver nitrateTrinitrotolueneWell water (nitrates)

Methemoglobin symptoms

levels

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.

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.

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)

ANCILLARY INVESTIGATIONS CBC

RFT

LFT

SERUM METHEMOGLOBIN

URINE HEMOGLOBIN

SERUM CPK, LDH

PERIPHERAL SMEAR

BLOOD GROUPING

G 6 PD ASSAY

X RAY

ECG

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.

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.

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.

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.

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

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.

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,