Rationale for the use of Sodium Thiosulphate as an Antidoe in the Treatment of the Victims of the Bhopal Gas Disaster - A Review
Item
- Title
- Rationale for the use of Sodium Thiosulphate as an Antidoe in the Treatment of the Victims of the Bhopal Gas Disaster - A Review
- Date
- 1986
- extracted text
-
!• •.
"RATIONALE
AS
AN
OF
THE
FOR
USE
OF
SODIUM
THIOSULPHATE
OF
A
ANTIDOTE IN THE TREATMENT
THE BHOPAL GAS DISASTER
THE VICTIMS
REVIEW"
June 7, 1985
b y
Thelma Narayan,
C. Sathyamala,
Mira Sadgopal*
326 V Main
Members, Medico Friend Circle,
Bangalore 560 034
I Block, Koramangala,
and
Vijaya Shankar Varma
Department of Physics, Delhi University, Delhi 110 007
Consultant, Technical Cell, Zahreeli Gas Kand Sangharsh
Morcha.
Summary
Multisystemic involvement, persist:nee of
symptoms, continued alteration of blood gas
percentages indicative of poor oxygen carry
ing capacity of blood with resultant tissue
anoxia, suggest that some toxin still exists
in the body (the cyanogenic pool) and needs
to be eliminated*
Significant symptomatic relief, increased
excretion of urinary thiocyanates and improve
ment in the blood gas picture after administ
ration of sodium thiosulphate indicates that
it is an effective antidote in the; treatment
of the victims of the Bhopal gas disaster*
*Contact address: Gandhi Bhavan, near Polytechnic College,
Shyamala Hills, Bhopal 462 002.
\
.... I
I
CONTENTS
Part - I
1.
Introduction
2.
Clinical picture in the sub-acute phase
3,
A flashback -
Autopsy findings
Haemoglobin Examination
Urine thiocyanates
The initial double blind study with thiosulphate
and subsequent developments
Blood gas analysis
Animal experiments
Cyanogenic pool
Guidelines for the use of sodium t'liosulphate (ICMR)
4e
Conclusion
5.
References
6.
Appendix
I
-
proforma for the clinical monitoring
of patients on .thiosulphate therapy.
Part
II
Review of literature on cyanide poisoning
1.
Symptoms
2.
Lethal dosage
3.
Toxic action
4.
Detoxification
Antidotes
a) Sodium nitrite
b) Sodium thiosulphate
c) Oxygen
d) Hydroxo cobalamin
e) Cobalt edetate
5.
Fate of cyanide ion in the body
6.
References
*
par t -__I
1.
Introduction
- ■»
w— ■— I
•*
Since the gas disaster in December, 1984, at Bhopal which
killed thousands of people and left approximately 70,000
seriously injured and 45,000 with mild to moderate disability,
controversy has surrounded the issue of an effective form
of therapy for the affected population. This has led to
the withholding of sodium thiosulphate (NaTS - an antidote,
recommended by ICMR in February, 1985) and hence to the
prolonged and unnecessary suffering of people.
After months of uncertainty the Madhya Pradesh Government
Health Services officially sanctioned the use of sodium
thiosulphate in April, 1985, and it reached the peripheral
dispensaries and health centres only in May.
To cover the
affected population, at the rate set by the M.P. Government,
iae. 13 centres giving approximately 300 injections a day,
complete detoxification will take years, by which time it
may just be too late.
If the majority of victims are to receive this specific
therapy in time it is essential to pressurize the government
to tackle the problem on a war footing, There is a need
to utilize all available resources in as efficient a manner
as possible, Dispensaries and health centres run by non
governmental agencies too, need to be involved.
To undertake this task, medical personnel from the govem-
ment and voluntary sector need to understand the rationale
behind the use of sodium thiosulphate as one of the specific
therapies for the gas affected victims.
This paper is intended to sort out some of the confusion
that has
arisen from the controversy regarding the use
of sodium thiosulphate and hopefully to clarify some of
the questions.
2.
Clinical picture in _the sub-acute jehasa
2.1 A common picture has emerged from observations by
three independent studies, viz.
a) “Health effects of exposure to toxic gas at
Bhopal. An update on ICMR sponsored researches",
10th March, 1985.1
b) "Medical survey on Bhopal gas victims" (March 1985),
conducted by Nagrik Rahat aur Punarvas Committee,
Bhopal, in collaboration with Voluntary Health,
Association of India, Delhi and Bhopal Relief Trust,
Bombay .2
J
2
c)
:!The Bhopal disaster aftermath - a socio-medical
and epidemiological survey1’ (March, 1985) Medico Friend Circle.3 (unpublished data)
2.2 In the affected areas, most persons had more than one
These have been grouped
according to the body systems they belong to, with
some inevitable overlap. 3
symptom or group of symptoms.
Breathlessness on rest and
on accustomed exertion, dry cough, cough with
expectoration, pain/tightness in the chest.
a) Respiratory sysecern
*
-•
Persistent tachypnoea is a common feature.
Rales and rhonchi are present in 9.1%.3 In
some patients symptoms were out of proportion to
the physical and radiological observations.
40% of those who complained of respiratory symp
toms had ventilatory impairment, 12% had restr
ictive lung disease, 6% obstructive airway
disease, 22% obstructive-cum-rescrictive defect.
Ventilatory defects were not observed in patients
with mild exposure to toxic gas.1
Blood gas analysis in 35 patients indicates
abnormality in the oxygen carrying capacity of
haemoglobin. 23 patients with severe exposure
had Pa02 60 mm Hg. Arterial CO2 tension 35 mm
Hg. was observed in 12.1
b) Gclstropintes_tinal system - Loss of appetite,
nausea, vomiting, abdominal pain ai'.d burning,
flatulence, diarrhoea.
Endoscopic examination has revealed superficial
gastritis and oesophagitis.c) Eye - Blurring of vision, irritation and burning
of eyes, redness, difficulty in sec: ng bright
lighto 80%^of people within \ km bad ophthalmic
symptoms, as did 60% of those at 2
and 40% of
those at 8 km distance.^
d) Reproductive system g Women - Frequent menstrual
periods, polymenorrhoea, abnormalities of menstr
ual flow - scanty or heavy, blackish in colour,
excessive vaginal discharge, suppression of lacta
tion .
Men
loss of libido.
e) Neuromuscular - Muscle weakness, sensation of
pins and needles, tingling and numbness.
f) Mental - Headache, anxiety, apprehension,
confusion, irritability, forgetfulness, grief,
guilt or apathy, disturbed sleep, depression.
2.3 The picture which emerges is one of multisystemic
involvement.
2.4 Present explanations for the cause of the above
i
• picture are ?
;s
a) after-effects of lung damage.
b) increase in the cyanogenic pool in the body.
c) psychosomatic manifestations as a result of the
severe trauma experienced.
2.5 In each individual there is possibly an overlap and
interplay of the three causative factors which result
from variations in parameters such as distance from
disaster site, type of house, action taken at the time
of disaster, degree of breavement, etc. The percent
ages of patients with symptoms predominantly due to any
one of the above factors is not known.
3.
A Flashback
3.1 Autopsy Findings
To begin with, there was a great deal of uncertainty
as to the nature and composition of the gas that
escaped. Initial autopsy findings showed a cyanidelike poisoning as the cause of death. Instead of the
normal postmortem lividity and cyanosis, there was
a pinkish discolouration of the organs. The arterial
and venous blood and the organs had a characteristic
bright "cherry-red3 colour. Lung weight was 2.5 to
3 times the normal, heavily water-logged by oedema.
There was also a varying degree of oedema of the
brain. Autopsy findings even up to the 21st of
December, 1984, remained similar.
3.2 Haemoglobin Examination
Spectroscopic and spectrophotometric studies of haemo
globin were carried out from the 14th to 21st of
December. Control blood samples, samples of blood
preserved in the deep freeze and fresh samples from
subsequent autopsies were analysed. The samples did
not show any evidence of the presence of carboxyhaemo1
globin or cyanomethaemoglobin.
Further, samples from
the victims showed the presence of the characteristic
twin bands of oxyhaemoglobin.
This ruled out carbon
monoxide poisoning which is also characterised by a
cherry red appearance of the blood. ArterializatioYi
of venous blood as seen here is a characteristic of
2 S
4
S 2
Later, experimental studies
in all animal species carried out so far have shown
that MIC also produces a cherry-red appearance of the
cyanide poisoning also.
blood. A recent study also indicates a 26-60% reduc
tion of the free amino groups in the haemoglobin of
persons exposed to the toxic gas.
On estimating 2-3 DPG (diphosphoglycerate) in blood,
levels were found to be raised in the gcs-exposed
population —- thereby indicating anoxia Haemoglobin percentage was found to be significantly
higher among the affected population in Anna Hagar
indicating compensatory polycythemia (to anoxia). 3
3.3 Urinary Thigcyan ates ■-
Thiocyanaces arc normally
present in urine and smokers show levels 50% higher
than non-smokers.
The presence of increased levels of urinary thiocyanates
(the form in which cyanide is excreted) ..n the affected
victims also seemed to indicate a cyanic'c, like poisoning. Taking 20 Delhi-based urine sampL s as a control,
a base-line of 0.5 rng/lCO ml of t.iiccyanute in urine
was set as the upper limit of normal. In persons who
were exposed to the toxic gas the urinary thiocyanate
levels estimated were, always greater then 2 rng/100 ml.
In a study at Bhopal, it was observed txt over 6,5% of
the samples from the gas affected population and 70% of
samples from hospital workers (indirect exposure) showed
urinary thiocyanate levels greater than 1 mg/100 ml,
while only 33% of samples from the non-exposed popula
tion had similar levels. After administration of NaTS,
the level of thiocyanate in urine increased several
folds initially and then showed a dip. On the basis
of the experiments it is felt that urine thiocyanate
level is a reasonably good indicator that will corro
borate the other clinic al manifestations of the toxic
exposure and in such cases, administration of NaTS
will produce significant increase in the the thiocyaz!
nate excretion in urine. ’
n
f
s;
3.4
5
The initial Double Blind Study with Thiosulphate
Thirty patients were selected.
They were given two
injections of either sodium thiosulphate or glucose.
Urinary thiocyanate levels were determined at 3 and
5 hour intervals and compared to the baseline level
before the injection. In patients given sodium thio
sulphate there was an 8-10 fold increase in excretion
of thiocyanate in a significantly large number (10 out
of 15). Only one of 15 receiving the-glucose injection
1
;
’
showed such increase.
Subsequently 230 cases were treated with NaTS with over
lz000 injections. Of these complete records are avail
able for 167 (87 men, 69 women and 11 children). The
symptomatology at the time of inclusion of therapy was
weakness and breathlessness. This was present at rest
in 29 cases and in another 132 cases moderate exercise ,
elicited the symptoms. Following NaTS administration/
there was no effect in 9 cases. The remaining 158
persons showed varying grades of improvement for variable
Adverse reactions
were: 5 cases of feverishness, 1 case each of transient
loss of memory, exaggerated reflexes, sense of ’heat’
4
over the body, skin rash and transient venospasm.
periods of time.
There were no deaths.
In another study various clinical symptoms were scored
on an arbitrary scale so that in the worst case the
score totalled 100. Of the 100 patients given NaTS
therapyt 60 showed a decrease in score. 19 showed an
increase/ while 21 showed no change.
/The worse the
initial symptoms the smaller the improvement after the
rapy. Of another 10 patients given intravenous glucose
8 showed reduction in score, but nocchange in their
lung function. Another 10 were given intravenous amino
phylline, all of whom claimed they felt better with
their FVC, FEV^, MEFR all showing improvement. However,
the scoring system adopted needs improvement as differ
ent symptoms should not be given equal weightage nor
should the scores be just added linearly. The question
also arises as to why the results of lung function tests
on the persons given NaTS were not reported. The find4
ings of this study are, therefore, not conclusive.'
i
zz
3.5
6
zz
Blood gas analysis
In the initial study, blood gas was analyzed in 20
patients, using ABL gas analyzer and an oxymeter.
PaO2 was lower than normal with a range of 47.3 to
85.6 mm Hg. Those showing higher values had a history
of treatment with sodium thiosulphate. 8 out of 14
untreated patients had arterial PaC02 of 35 mm Hg or
less, which is below normal. The venous sample showed
a normal or low PvO2 value bub an elevated PvC02 in 9
of 13 cases. The level of PvC02 after treatment with
sodium thiosulphate was increased markedly in comparison
to pre-treatment levels. The increase in PvC02 was pro
portional to improvement in clinical symptoms. The
inference from the above is that oxygen transport was
found to be affected leading to tissue anoxia which
eventually produced less carbon dioxide in the peripheral
veins.
On.treatment with NaTS, the increase in PvCO
2
occurred with predictable reproducibility. It was
thought that owing to the inability of haemoglobin to
take up carbon dioxide it was carried in solution in
the blood with the partial pressure going up to 70 mm Hg.
On cardiac catheterisation the difference in levels of
PvC02 between central and peripheral venous samples was
negligible. Serial data showed that after administration
of NaTS-, PvC02 in both central and peripheral veins
showed .-a significant rise indicating better uptake and
utilisation of oxygen by the tissues„ Studies have
shown'that pure MIC had no effect on cytochrome oxidase,
but its degradation products did
4. n
uptake.
3.6
thus■affecting oxygen
4
Animal Experiments ■
MIC has an LD 50 dose of 85 mg in mice, but with thio
sulphate therapy it is shifted to 195 mg. For rats,
the figures are 270 and 344 respectively, Normal rabbit
lungs weighed 6 gms, with MIC they weighed 29 gms and
had a large number of haemorrhagic patches. When given
NaTS immediately after MIC, lungs weighed 24 gms and
appearance was near normal. Generally longer the dura
tion after exposure, greater was the lung oedema observed. Salbutamol had no blocking effect on the action
4
of* MIC. Haematocrit increased to a high level.
I
I
y anogeixa-c 1 ool
The continued presence of the cyanide radical in the
body of the gas affected victims increases the cyano
genic pool in the body,
multisystemic symptoms.
This was responsible for the
An improvement in symptoms
could occur only if the cyanogenic pool was depleted.
(Refer to Part-II for greater details).
i
t
ICMR studies show that NaTS therapy gives significant
symptomatic relief to people suffering after-effects of
exposure to toxic gas. This relief can be objectively
quantified by appropriate investigations. In general
NaTS therapy has also been found to be harmless, although
allergic reactions may occur in 1 out of 1,000 or 10,00.0
cases arising from imprities in the NaTS. Hence it has
been recommended for use, besides other therapeutic
measures, in selected patients.
4
Guidelines for the use of sodium thiosulphate (ICMR)
Criteria for selection of Patients -
1. Patients suffering from acute and/or chronic symptoms
relating to the respiratory, gastro-intestinal and
neuromuscular systems presumably related to possible
exposure to MIC gas.
2. Patients presenting with recurrence of symptoms after
having obtained some measure of relief from the acute
phase.
3. Recorded cases of acute pulmonary oedema and/or coma
occuring immediately following the episode and those
who are currently symptomatic.
Contradictions
1. Pregnancy - routine use not advised, decision depends
on severity of symptoms.
2. Renal disease.
Procedure
1. Record name, address.
2. Detailed record of symptoms and clinical findings
should be made with special reference to a tendency
8
S 2
for early fatigue, exhaustion, respiratory signs
and symptoms. This information should be recorded
before and after treatment.
(Refer Appendix-I for a sample proforma)
3. Check urine for albumin.
4. Dose :
a) Adults - 1 gm (10 cc of 10% NaTS or 4 cc of
25% NaTS) given intravenously, daily for a
maximum of 5-6 days,
b) Children - less than 2 years s 3; cc of 10% NaTS.
2-8 years
s 5 cc of 10% NaTS.
more than 8 years 2 Adult dose.
5. Disposable syringes and needles are to be used for
this purpose.
6. Alkaline mixture diuretic
with sodium chloride should
be administered to the patients to facilitate increased
excretion of thiocyanate for the duration of therapy.
7. The patient should be kept under observation for at
least one hour after the injection.
8. Pulse rate, respiratory rate, response to exercise
and level of physical activity should be recorded
during therapy and afterwards in order to assess
the progress/improvement.
Side-ef fee ts/P recautions
1. It is a safe drug.
Minor side-effects - feverishness,
bodyache etc. respond to symptomatic treatment and
antihistaminics.
2. Adverse reactions, if any, should be brought to the
notice of local senior physicians for prompt manage
ment, and also to the health authorities.
3. Routine precautionary measures to manage anaphylactic
reactions which are kept as stand-by’s when giving
any I.V. injections should be available in the dis
pensary, eg. I.V. fluids, steroids and antihistamine
inj ections.
4. If extravascation of the drug occurs, the patient
will have intense burning locally which is transitory
> and needs reassurance,
,
t
: o
Drug Interactions
9
Nil.
Availability
1. The following are available with Dr. Tandon, Medical
Superintendent, JP Hospital, 1250, South TT Nagar,
Bhopal
(Timings 2 9 am - 1 pm and 4 pm - 6 pm) 2
a) Inj. Sodium Thiosulphate.
b) Disposable syringes and needles.
c) Alkaline mixture.
d) Printed forms for recording and.monitoring
patients* symptoms and signs.
e) Cotton, spirit, steroids, antihistaminies etc*
2. Presently NaTS stocks have been given to peripheral
government dispensaries and polyclinics, Red Cross
and a couple of voluntary agencies.
3. There is an urgent need for government and voluntary
agencies to work in a coordinated manner and cover
the affected population within 3-6 months.
4. OXFAM has also made an offer to help voluntary agenc
ies interested in using thiosulphate for the affected
population. Contact Nagpur office - Field Director,
OXFAM (India) Trust, P.O. Box 71, Nagpur 440 001*
4*
Conclusions
Scientific investigations show the continued presence of an
increase in the cyanogenic pool in persons exposed to the
toxic gas, even months after the disaster.
This is one of the factors responsible for continued morbidity
The other known causative
factors are structural lung damage and manifestations follow
ing severe psychic trauma.
among the affected population.
Many areas, even regarding existing theories, are yet unknown
—and there is an urgent need for further study.
When on the basis of experiments and investigations therapeutic
interventions are suggested it is essential that the logic
for such measures is made open for scientific scrutiny• This
information should also be made available to the treating
medical personnel since it is irrational to expect physicians
to prescribe drugs without being aware of the rationale for
their use.
I ■
2;
10
s:
This is perhaps one of the many reasons why NaTS is at
present being given half-heartedly at the cost of much ill-
health, suffering and econoraic loss for thousands of helpless
victims•
After the draft of this paper was ready, we came across a
report of the Pollution Control Board giving the chemical
analysis of samples of air collected on the 5th and 6th
Despite the fact that these samples had been
collected in the open air 3 to 4 days after the gas leak,
December, 1984.
these measurements show that the air near the MIC storage
tank of the Union Carbide factory contained cyanide at a con-
centration of 4,533 mg/m'
(4W5 ppm).
This is nearly half the
Maximal Allowed Concentration (MAC) and about l/50th of the
Lethal Concentration (LC) set for hydrogen cyanide. The
cyanide level reduced to half this value 50 metres away from
the tank and cyanide was not detected in samples collected
from three other localities further away from the factory the clear inference being that cyanide was still leaking from
the MIC storage tank even on the 5th and 6th of December.
The most probable origin of the cyanide must, have been the
thermal decomposition of the MIC stored in the ill-fated tank.
When one ties up the above mentioned evidence with the reports
that cyanide was detected by the Gorman toxicologist Dr. Max
Daunderer in the blood of the gas victims and also by the
Cbi team in the ambient air using chemical spot tests, a few
days after the tragedy, the case of NaTS therapy for the
surviving gas-affected population becomes almost irrefutable.
I
11
ss
5.
References for Part-I
1.
“Health effects of exposure to toxic gas at Bhopal”,
An update on ICMR sponsored researches, 10th March,
1985.
2.
“Medical survey on Bhopal gas victims'’’, conducted by
Nagrik Rah at aur Punarvas Committee, Bhopal, in
collaboration with Voluntary Health Association of
India, Delhi and Bhopal Relief Trust, Bombay,
March, 1985.
3.
"The Bhopal disaster aftermath - a sociomedical and
epidemiological survey”, Medico Friend Circle,
March, 1985.(unpublished)
4.
Minutes of the third meeting of the Working Group
on Thiosulphate Therapy of the MIC exposed population,
4th April, 1985.
/
Appendix - I
PROFORMA FOR THE CLINICAL MONITORING. OF SODIUM THIOSULPHATE
ADMINISTRATION
PEOPLE'S
HEALTH
PROGRAMME
Date of Registration
Sl.No.
Name
Age
Sex
Smoking : Yes/fto
Tobacco chewing s Yes/No
What work do/did do
Present
Employment
Past
Employment
Exposure to Gas
Monthly Income
X
I
X___________________ X
X
X
X
X
X
X
Heavy
X
Moderate
X
x /
y
J
X
X
Mild
Where were you when the Gas leaked
Where did you run and how
Were you admitted to Hospital?
If yes, which hospital?
Did any family member die?
Treatment
Government
Private
Fees
Expenses
Drug
Others
Compens ation
What have you heard about proper treatmerit for the gas?
What have you heard about sodium thiosulphate?
X
4
SUMMARY TREATMENT AND INVESTIGATION
Yes
Previous Complaints
No
What
Nervous System
Eyes
Nose and Throat
Chest
G.I.T,
Skin
Genito Urinary
Musculo-skeletal
4
Treatment
Date
Details
Investigation
Date
Details
{
I
I
I.
Nervous System
HE AD ACHE/HE AVIN ES S
s
DIZZINESS
ANXIETY
POOR MEMORY
LOSS OF SLEEP
TINGLING AND NUMBNESS
r
II. Eyes
BURNING OF EYES
s
WATERING OF EYES
DIMNESS/BLURRING OF VISION:
III. Nose -and Throat
RUNNING NOSE/SNEEZING
s
SORE THROAT
IV. Chest and Cardiovascular system
PALPITATION
BREATHLESSNESS
CHEST PAIN
DRY COUGH
COUGH WITH EXPECTORATION
HAEMOPTYSIS
V. Gastrointestinal System
ULCERS IN MOUTH
LOSS OF APPETITE
NAUSEA
DISTENSION OF ABDOMEN
PAIN ABDOMEN
DIARRHOEA
CONSTIPATION
HAEMATEMESIS
VI. Skin
•ITCHING
s
VII.
Urogenital Syston
BURNING ON PASSING URINE
LEUCORRHOEA
IMPOTENCE
PAIN ON INTERCOURSE
VIII.
SCANTY/HEAVY BLEEDING
s
SHORTEN ED/LENGTHEN ED
CYCLES
IX.
Musculoskeletal System
TIREDNESS/WEAKNESS
FEVER
PAIN IN THE CALF MUSCLES
BACK PAIN/BODYACHE
PAIN IN THE EXTREMITES
X.
Any others
V
PRESENT SIGNS-CHECK LIST
ANAEMIA
PULSE RATE
RE5- JURATORY RATE
CYANOSIS
CORNEA AND CONJUNCTIVA
ACUITY OF VISION
SKIN INFECTION
SKIN RASH
SHIFT OF MEDIASTINUM
NATURE AND CHARACTER
OF BREATH SOUND
ADDED SOUNDS
s
y
t
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