Antidotes for Poisoning by Cyanide

IPCS/CEC EVALUATION OF ANTIDOTES SERIES

VOLUME 2

ANTIDOTES FOR POISONING BY CYANIDE

IPCS/CEC Evaluation of Antidotes Series

IPCS International Programme on Chemical Safety
CEC Commission of the European Communities

Volume 1 Naloxone, flumazenil and dantrolene as antidotes
Volume 2 Antidotes for poisoning by cyanide

This important new series will provide definitive and authoritative
guidance on the use of antidotes to treat poisoning. The
International Programme on Chemical Safety (IPCS) and the Commission
of the European Communities (CEC) (ILO/UNEP/WHO) have jointly
undertaken a major programme to evaluate antidotes used clinically
in the treatment of poisoning. The aim of this programme has been
to identify and evaluate for the first time in a scientific and
rigorous way the efficacy and use of a wide range of antidotes.
This series will therefore summarise and assess, on an antidote by
antidote basis, their clinical use, mode of action and efficacy. The
aim has been to provide an authoritative consensus statement which
will greatly assist in the selection and administration of an
appropriate antidote. This scientific assessment is complemented by
detailed clinical information on routes of administration,
contraindications, precautions and so on. The series will therefore
collate a wealth of useful information which will be of immense
practical use to clinical toxicologists and all those involved in the
treatment and management of poisoining.

Scientific Editors

T.J. MEREDITH
Department of Health, London, United Kingdom

D. JACOBSEN
Ulleval University Hospital, Oslo, Norway

J.A. HAINES
International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland

J-C. BERGER
Health and Safety Directorate,
Commission of the European Communities, Luxembourg

Guest Editor

A.N.P. van HEIJST
Formerly of the Dutch National Poison Control Centre,
Utrecht, The Netherlands

EUR 14280 EN

Published by Cambridge University Press on behalf of the World Health
Organization and of the Commission of the European Communities

CAMBRIDGE UNIVERSITY PRESS

The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar
nature that are not mentioned.

Neither the Commission of the European Communities nor any person
acting on behalf of the Commission is responsible for the use which
might be made of the information contained in this report.

^(c) World Health Organization, Geneva, 1993 and
ECSC-EEC-EAEC, Brussels-Luxembourg, 1993

First published 1993

Publication No. EUR 14280 EN of the Commission of the European
Communities, Dissemination of Scientific and Technical Knowledge
Unit, Directorate-General Information Technologies and Industries,
and Telecommunications, Luxembourg

ISBN 0 521 45458 1 hardback

CONTENTS

PREFACE
ABBREVIATIONS
1. OVERVIEW
1.1. Historical review
1.2. Potential sources of cyanide
1.2.1. Industrial sources
1.2.2. Non-industrial sources
1.2.3. Natural sources
1.2.4. Iatrogenic sources
1.3. Toxicity of cyanide in man
1.3.1. Acute poisoning
1.3.2. Chronic poisoning
1.4. Mechanism of toxicity
1.5. Clinical features
1.6. Laboratory findings
1.6.1. Lactic acidosis
1.6.2. Hyperglycaemia
1.6.3. Cyanide concentration in blood and plasma
1.7. Biological detoxification of cyanide
1.7.1. Thiocyanate toxicity
1.8. Protective measures for occupational exposure
1.9. Treatment
1.9.1. Supportive treatment
1.9.2. Antidotal treatment
1.9.2.1 Oxygen
1.9.2.2 Sodium thiosulfate
1.9.2.3 Amyl nitrite
1.9.2.4 Sodium nitrite
1.9.2.5 4-Dimethylaminophenol
1.9.2.6 Hydroxocobalamin
1.9.2.7 Dicobalt edetate
1.9.2.8 Antidotes to methaemoglobin-forming
agents
1.10. Summary of treatment recommendations
1.10.1. First aid and treatment measures at the site of
the incident
1.10.2. Hospital treatment
1.10.2.1 Severe poisoning
1.10.2.2 Moderately severe poisoning
1.10.2.3 Mild Poisoning
1.11. Summary of analytical aspects
1.12. Proposed areas for research
1.13. New developments in cyanide antidotes
1.13.1. Nonspecific agents
1.13.2. Sodium pyruvate
1.13.3. Ifenprodil
1.13.4. Rhodanese
1.13.5. Alpha-ketoglutaric acid

1.13.6. Stroma-free methaemoglobin solution
1.14. References

2. OXYGEN
2.1. Introduction
2.2. Name and chemical formula of antidote
2.3. Physico-chemical properties of molecular oxygen
2.4. Synthesis
2.5. Analytical methods
2.5.1. Quality control procedures
2.5.1.1 Tests
2.5.1.2 Assay for oxygen
2.5.2. Methods for identification
2.5.3. Methods for analysis of the antidote in
biological samples
2.5.3.1 In the gas phase
2.5.3.2 In solution
2.5.4. The saturation of haemoglobin by oxygen
2.6. Storage conditions
2.7. General properties
2.8. Animal studies
2.8.1. Pharmacokinetics
2.8.2. Pharmacodynamics
2.8.3. Toxicology
2.8.3.1 Mechanism of injury
2.9. Volunteer studies of pulmonary oxygen toxicity
2.10. Clinical studies of oxygen toxicity
2.10.1. Eyes
2.10.2. Central nervous system
2.11. Clinical studies - case reports
2.11.1. Patients treated alone with supportive therapy
and who survived
2.11.2. Hyperbaric oxygen therapy in cyanide poisoning
2.11.3. Cyanide poisoning due to smoke inhalation
2.12. Summary of evaluation
2.13. Model information sheet
2.13.1. Uses
2.13.2. Dosage and route
2.13.3. Precautions/contraindications
2.13.4. Adverse effects
2.13.5. Use in pregnancy and lactation
2.13.6. Storage
2.14. References

3. SODIUM THIOSULFATE
3.1. Introduction
3.1.1. Indications
3.1.2. Rationale for the choice of the antidote
3.1.3. Risk groups
3.2. Name and chemical formula of antidote
3.3. Physico-chemical properties

3.3.1. Melting point, boiling point
3.3.2. Solubility in vehicle for administration
3.3.3. Optical properties
3.3.4. Acidity
3.3.5. pKa
3.3.6. Stability
3.3.7. Refractive index, specific gravity
3.3.8. Loss of weight on drying
3.3.9. Excipients
3.3.10. Incompatibility
3.3.11. Other information
3.4. Synthesis
3.5. Analytical methods
3.5.1. Quality control procedures for sodium thiosulfate
3.5.2. Methods for identifying sodium thiosulfate
3.5.3. Assay
3.5.4. Methods for analysis of sodium thiosulfate in
biological samples
3.6. Shelf-life
3.7. General properties
3.7.1. Mechanism of antidotal activity
3.7.2. Other biochemical/pharmacological profiles
3.8. Animal studies
3.8.1. Pharmacokinetics
3.8.2. Pharmacodynamics
3.8.3. Toxicology
3.9. Volunteer studies
3.10. Clinical studies
3.11. Clinical studies - case reports
3.12. Summary of evaluation
3.12.1. Indications
3.12.2. Route of administration
3.12.3. Dose
3.12.4. Other consequential or supportive therapy
3.13. Model information sheet
3.13.1. Uses
3.13.2. Dosage and route of administration
3.13.3. Precautions and contraindications
3.13.4. Adverse effects
3.13.5. Use in pregnancy/lactation
3.13.6. Storage
3.14. References

4. HYDROXOCOBALAMIN
4.1. Introduction
4.2. Name and chemical formula of antidote
4.3. Physico-chemical properties
4.3.1. Characteristics
4.3.2. Melting-point
4.3.3. Solubility in vehicles for administration
4.3.4. Optical properties

4.3.5. Acidity
4.3.6. Stability in light
4.3.7. Thermal stability
4.3.8. Interference with other compounds
4.4. Synthesis
4.5. Analytical methods
4.5.1. Identification of hydroxocobalamin
4.5.1.1 UV spectroscopy
4.5.1.2 Colorimetric method
4.5.2. Quality controls
4.5.3. Raw materials
4.5.4. Finished galenic form
4.5.5. Measurement
4.5.5.1 In raw materials and in finished form
4.5.5.2 In biological samples
4.6. Shelf-life
4.7. General properties
4.8. Animal studies
4.8.1. Pharmacokinetics
4.8.2. Pharmacodynamics in the presence of the toxin
4.8.3. Toxicology
4.8.3.1 Acute toxicity
4.8.3.2 Sub-acute and chronic toxicity
4.9. Volunteer studies
4.10. Clinical studies
4.11. Clinical studies - case reports
4.12. Summary of evaluation
4.12.1. Indications
4.12.2. Advised route and dosage
4.12.3. Practical advice
4.12.4. Side effects
4.13. Model information sheet
4.13.1. Uses
4.13.2. Dosage and route
4.13.3. Precautions/contraindications
4.13.4. Adverse effects
4.13.5. Use in pregnancy and lactation
4.13.6. Storage
4.14. References

5. DICOBALT EDETATE
5.1. Introduction
5.2. Name and chemical formula
5.3. Physico-chemical properties
5.4. Synthesis
5.4.1. Source of materials
5.4.1.1 Cobalt carbonate
5.4.1.2 Ethylenediaminetetraacetic acid
5.4.1.3 Glucose

5.5. Analytical methods
5.5.1. Free cobalt
5.5.2. Dicobalt edetate
5.5.3. Analysis in biological fluids
5.6. Stability and shelf-life
5.7. General properties
5.8. Animal studies
5.8.1. Pharmacokinetics
5.8.2. Pharmacodynamics
5.8.2.1 Efficacy in animals
5.8.2.2 Comparison of dicobalt edetate with
other compounds
5.8.2.3 Interactions with other drugs
5.8.3. Toxicology
5.8.3.1 In vitro studies
5.8.3.2 Acute toxicity studies
5.8.3.3 Repeated dose toxicity
5.8.3.4 Circulatory effects in dogs
5.8.3.5 Other toxicity studies
5.9. Volunteer studies
5.10. Clinical trials
5.11. Clinical studies - case reports
5.11.1. Successful use
5.11.2. Use in pregnant women and children
5.11.3. Adverse effects
5.11.4. Use in combination with other antidotes
5.12. Summary of evaluation
5.12.1. Indications
5.12.2. Administration
5.12.3. Other consequential or supportive therapy
5.12.4. Contraindications
5.12.5. Comparison with other antidotes
5.13. Model information sheet
5.13.1. Uses
5.13.2. Dosage and route
5.13.3. Precautions/contraindications
5.13.4. Adverse effects
5.13.5. Use in pregnancy and lactation
5.13.6. Storage
5.14. References

6. AMYL NITRITE
6.1. Introduction
6.2. Name and chemical formula
6.3. Physico-chemical properties
6.4. Synthesis
6.5. Analytical methods
6.5.1. Identification
6.5.2. Purity
6.5.2.1 Acidity
6.5.2.2 Non-volatile residue

6.5.2.3 Assay for total nitrites
6.6. Shelf-life
6.7. General properties
6.8. Animal studies
6.8.1. Pharmacokinetics
6.8.2. Pharmacodynamics
6.8.3. Toxicology
6.9. Volunteer studies
6.10. Clinical studies
6.11. Clinical studies - case reports
6.12. Summary of evaluation
6.12.1. Indications
6.12.2. Advised routes and dose
6.12.3. Other consequential or supportive therapy
6.13. Model information sheet
6.13.1. Uses
6.13.2. Dosage and route
6.13.3. Precautions/contraindications
6.13.4. Storage
6.14. References

7. SODIUM NITRITE
7.1. Introduction
7.2. Name and chemical formula
7.3. Physico-chemical properties
7.4. Synthesis
7.5. Analytical methods
7.5.1. Quality control
7.5.1.1 Solid sodium nitrite
7.5.1.2 Sodium nitrite injection
7.5.1.3 Preparation of volumetric solutions
7.5.2. Identification
7.5.2.1 Sodium
7.5.2.2 Nitrite
7.5.3. Impurities
7.5.3.1 Preparation of sodium nitrite to test
7.5.3.2 Preparation of special reagents
7.5.3.3 Preparation of standard
7.5.3.4 Preparation of test
7.5.3.5 Preparation of monitor
7.5.3.6 Preparation of hydrogen sulfide test
solution
7.5.3.7 Test procedure
7.6. Shelf-life
7.7. General properties
7.7.1. Mode of action
7.7.2. Other relevant properties
7.8. Animal studies
7.8.1. Pharmacokinetics
7.8.2. Pharmacodynamics
7.8.3. Toxicology

7.9. Volunteer studies
7.9.1. Pharmacokinetics
7.9.2. Sodium nitrite poisoning
7.10. Clinical studies
7.11. Clinical studies - case reports
7.12. Summary of evaluation
7.12.1. Indications
7.12.2. Contraindications
7.12.3. Advised route and dosage
7.12.4. Other consequential or supportive therapy
7.13. Model information sheet
7.13.1. Uses
7.13.2. Dosage and route
7.13.3. Precautions/contraindications
7.13.4. Adverse effects
7.13.5. Use in pregnancy and lactation
7.13.6. Storage
7.14. References

8. 4-DIMETHYLAMINOPHENOL
8.1. Introduction
8.2. Name and chemical formula
8.3. Physico-chemical properties
8.4. Synthesis
8.5. Analytical methods
8.5.1. Identity
8.5.2. Quantification
8.5.3. Purity
8.5.4. Methods for analysis of 4-DMAP in biological
samples
8.6. Shelf-life
8.7. General properties
8.8. Animal studies
8.8.1. In vitro studies
8.8.1.1 Metabolism of 4-DMAP in the liver
8.8.1.2 Red cell metabolism of 4-DMAP
8.8.1.3 Toxic effects of 4-DMAP on
erythrocytes
8.8.1.4 Toxic effects of 4-DMAP on isolated
rat kidney tubules
8.8.1.5 Oxygen saturation and methaemoglobin
formation
8.8.2. Pharmacokinetics
8.8.3. Pharmacodynamics
8.8.4. Toxicology
8.8.4.1 Nephrotoxicity
8.8.4.2 Mutagenicity
8.9. Volunteer studies
8.9.1. Metabolism of 4-DMAP in the liver
8.9.2. Metabolism of 4-DMAP in erythrocytes

8.9.3. Adverse effects
8.10. Clinical studies
8.11. Clinical studies - case reports
8.12. Summary of evaluation
8.12.1. Indications
8.12.2. Recommended routes and dosage
8.12.3. Other consequential or supportive therapy
8.12.4. Areas of use where there is insufficient
information to make recommendations
8.13. Model information sheet
8.13.1. Uses
8.13.2. Dosage and route
8.13.3. Precautions/contraindications
8.13.4. Adverse effects
8.13.5. Use in pregnancy and lactation
8.13.6. Storage
8.14. References

9. METHYLENE BLUE AND TOLUIDINE BLUE
9.1. Methylene blue
9.1.1. Introduction
9.1.2. Name and chemical formula of antidote
9.1.3. Physico-chemical properties
9.1.4. Synthesis
9.1.5. Analytical methods
9.1.6. Shelf-life
9.1.7. General properties
9.1.8. Animal studies
9.1.9. Volunteer studies
9.1.10. Clinical studies
9.1.11. Clinical studies - case reports
9.1.12. Summary of evaluation
9.1.12.1 Indications
9.1.12.2 Advised route and dosage
9.1.12.3 Precautions and contraindications
9.1.12.4 Adverse effects
9.1.12.5 Other consequential or supportive
theory
9.1.13. Model information sheet
9.1.13.1 Uses
9.1.13.2 Dosage and route of administration
9.1.13.3 Precautions and contraindications
9.1.13.4 Adverse effects
9.1.13.5 Use in pregnancy/lactation
9.1.13.6 Storage
9.1.14. References
9.2. Toluidine blue
9.2.1. Introduction
9.2.2. Name and chemical formula of antidote
9.2.3. Physico-chemical properties
9.2.4. Synthesis

9.2.5. Analysis
9.2.5.1 Analysis of methaemoglobin
9.2.6. Stability
9.2.7. General properties
9.2.8. Animal studies
9.2.8.1 Pharmacokinetics
9.2.8.2 Pharmacodynamics
9.2.8.3 Toxicology
9.2.9. Volunteer studies
9.2.10. Clinical studies
9.2.11. Clinical studies - case reports
9.2.12. Summary of evaluations
9.2.13. Model information sheet
9.2.13.1 Indications
9.2.13.2 Side effects
9.2.13.3 Advised route and dose
9.2.13.4 Use in pregnancy and children
9.2.13.5 Storage
9.2.14. References

10. ANALYTICAL METHODS FOR CYANIDE ALONE AND IN
COMBINATION WITH CYANIDE ANTIDOTES IN BLOOD

10.1. Qualitative methods
10.1.1. Detection in blood with a detector tube
10.1.1.1 Principle
10.1.1.2 Materials
10.1.1.3 Procedure
10.1.1.4 Specificity
10.1.2. Spot test
10.1.2.1 Principle
10.1.2.2 Equipment
10.1.2.3 Chemicals
10.1.2.4 Reagents
10.1.2.5 Specimen collection
10.1.2.6 Procedure
10.1.2.7 Specificity
10.2. Quantitative methods
10.2.1. Gas chromatographic head space technique
10.2.1.1 Principle
10.2.1.2 Equipment
10.2.1.3 Chemicals
10.2.1.4 Solutions
10.2.1.5 Calibration standards
10.2.1.6 Specimen collection and sample
preparation
10.2.1.7 Operational parameters for gas
chromatography
10.2.1.8 Analytical determination
10.2.1.9 Calibration
10.2.1.10 Calculation of the analytical result

10.2.1.11 Reliability of the method
10.2.1.12 Detection limit
10.2.1.13 Specificity
10.2.2. Microdiffusion technique
10.2.2.1 Principle
10.2.2.2 Equipment
10.2.2.3 Chemicals
10.2.2.4 Solvents and reagents
10.2.2.5 Calibration standards
10.2.2.6 Specimen
10.2.2.7 Procedure
10.2.2.8 Reliability of the method
10.2.2.9 Detection limit
10.2.2.10 Specificity
10.3. References

WORKING GROUP ON ANTIDOTES TO POISONING BY CYANIDE

Members

Professor C. Bismuth, Hôpital Fernand Widal, Clinique Toxicologique,
Paris, France

Professor M. von Clarmann, Poisons Centre, Toxicology Department, 11
Med. Klinikrechts der Isar der Tecknischer Universität, Munich,
Germany

Dr A. van Dijk, Apotheek, Academisch Ziekenhuis, Utrecht, The
Netherlands

Professor M. Geldmacher von Mallinckrodt, Institut für
Rechtsmedizia, Erlangen, Germany

Dr A. Hall, Rocky Mountain Poison and Drug Center, Denver, Colorado,
USA

Professor A.N.P. van Heijst, Bosch en Duin, The Netherlands

Dr T.C. Marrs, Department of Health, London, United Kingdom

Dr T.J. Meredith, Department of Health, London, United Kingdom
(Rapporteur)

Dr A.C.G.M. Parren, Te Heerlen, The Netherlands

Dr H. Persson, Poison Information Centre, Karolinska Sjukhuset,
Stockholm, Sweden

Dr U. Taitelman, Rambam Medical Center, Haifa, Israel

Observers

Dr J. Aubrun, Rhone-Poulenc, Courbevoie, France

Dr A. Heath, Poisons Therapy Group, Department of Anaesthesia and
Intensive Care, Sahlgren's Hospital, Gothenburg, Sweden

Dr J. Henry, Poisons Unit, New Cross Hospital, London, United
Kingdom

Dr J.A. Vale, West Midlands Poisons Unit, Dudley Road Hospital,
Birmingham, United Kingdom

Secretariat

Dr J.-C. Berger, Health and Safety Directorate, Commission of the
European Communities, Luxembourg

Dr J.A. Haines, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland (Chairman)

Dr M. ten Ham, Pharmaceuticals Programme, World Health Organization,
Geneva, Switzerland

Dr M.-Th. van der Venne, Health and Safety Directorate, Commission
of the European Communities, Luxembourg

PREFACE

At a joint meeting of the World Federation of Associations of
Clinical Toxicology and Poison Control Centres, the International
Programme on Chemical Safety (IPCS), and the Commission of the
European Communities (CEC), held at the headquarters of the World
Health Organization in October 1985, the evaluation of antidotes
used in the treatment of poisonings was identified as a priority
area for international collaboration. During 1986, the IPCS and CEC
undertook the preparatory phase of a joint project on this subject.
For the purpose of the project an antidote was defined as a
therapeutic substance used to counteract the toxic action(s) of a
specified xenobiotic. Antidotes, as well as other agents used to
prevent the absorption of poisons, to enhance their elimination and
to treat their effects on body functions, were listed and
preliminarily classified according to the urgency of treatment and
efficacy in practice. With respect to efficacy in practice, they
were classified as: (1) those generally accepted as useful; (2)
those widely used and considered promising but not yet universally
accepted as useful and requiring further research concerning their
efficacy and/or their indications for use; and (3) those of
questionable usefulness. Additionally, certain antidotes or agents
used for specific purposes were considered to correspond to the WHO
criteria for essential drugs (see Criteria for the Selection of
Essential Drugs, WHO Technical Report Series 722, Geneva, 1985).

A methodology for the principles of evaluating antidotes and
agents used in the treatment of poisonings and a proforma for
preparing monographs on antidotes for specific toxins were drafted.
These were included in volume 1 of this series.

Monographs are being prepared, using the proforma, for those
antidotes and agents provisionally classified in category 1 as
regards efficacy in practice. For those classified in categories 2
and 3, where there are insufficient data or controversy regarding
efficacy in practice, it was agreed that further study was
necessary. Accordingly, several were selected for initial review
and evaluation, among which were antidotes used in the treatment of
poisoning by cyanide.

The review and evaluation of antidotes used in the treatment of
poisoning by cyanide was initiated at a joint meeting of the
European Association of Poison Control Centres and Clinical
Toxicologists (EAPCCT; formerly known as the European Association of
Poison Control Centres), the IPCS, and the CEC, organized by the
National Poison Information Centre of the Netherlands National
Institute of Public Health and Environmental Hygiene and held at the
University Hospital AZU, Utrecht, The Netherlands, 13-15 May 1987.
In preparation for this meeting, documents were drafted, using the
proforma, on oxygen by Dr U. Taitelman, sodium thiosulfate by Dr H.
Persson, hydroxocobalamin by Professor C. Bismuth, dicobalt edetate

by Dr T.C. Marrs, sodium nitrite by Dr A. Hall, and
4-dimethylaminophenol by Professor M. von Clarmann. Also in
preparation for the meeting, documents were drafted by Professor M.
Geldmacher von Mallinckrodt on the analytical assessment of cyanide
poisoning, by Dr A. van Dijk on the pharmaceutical aspects of
cyanide antidotes, and by Professor A.N.P. van Heijst (formerly
Director, Dutch National Poison Control Centre, Utrecht, the
Netherlands) on the clinical aspects of cyanide antidotes. The
documents presented by each author were discussed at the meeting and
participants gave their own experience and views. Experience of
industrial aspects of cyanide poisoning was presented by Dr A.C.G.M.
Parren.

The main meeting was followed by that of an IPCS/CEC working
group, consisting of the authors of documents, the meeting
rapporteur and a number of observers, at which a review was made of
the comments on the documents and of the additional material
presented at the main meeting. Based on the available material, an
evaluation was made of the different approaches to treatment of
cyanide poisoning depending on the type of cyanide exposure
(hydrogen cyanide, either alone or with carbon monoxide, cyanide
salts or cyanogenic glycosides), the state of intoxication and
number of patients, the location of the patient with respect to
treatment facilities, and special situations (e.g., inherited
metabolic and haemoglobin abnormalities). The group concentrated on
acute poisoning by cyanide, considering that there were insufficient
data for evaluating approaches to treatment of chronic cyanide
toxicity. Nevertheless, it was considered that a review of chronic
poisoning by cyanide, particularly in relation to cyanide ingestion
from food, was needed. It was agreed that traditional means of
treatment of cyanide poisoning would have to be revised, and that
any evaluation of approaches to treatment must also include
antidotes for methaemoglobin-forming agents. Concerning the
analytical aspects, it was noted that there was particular
difficulty in measuring the concentration of cyanide in blood if an
antidote had already been administered, a problem that is being
studied by a group of experts established under the auspices of the
German Research Association Commission on Clinical Analytical
Toxicology. A number of new cyanide antidotes in various stages of
research and development were discussed. An editorial group
consisting of Professor A.N.P. van Heijst (chairman of the meeting),
Dr T.J. Meredith (rapporteur), Dr J.A. Haines (IPCS, chairman of the
working group) and Dr J.-C. Berger (CEC) was established in order to
prepare a consolidated monograph on cyanide antidotes.

Draft documents were revised by their authors. Those on
methylene blue and toluidine blue were prepared by Dr Christina
Alonzo (CIAT, Montevideo, Uruguay) and Dr T.C. Marrs, respectively.
Subsequently Dr J.A. Vick (Food and Drug Administration, USA), who
was invited to the meeting but was unable to attend, prepared a
draft document on experience with the use of amyl nitrite in

treating cyanide poisoning in animals. Professor C. Bismuth and
Dr A. Hall drafted material on new antidotes under development for
clinical trials, and Dr A.C.G.M. Parren drafted material on
protective measures.

The editorial group met twice in Utrecht on 22-23 October 1987
and 20-22 July 1988. Material was checked and rearranged,
additional material was prepared for a number of the chapters and
the overview chapter was drafted. The efforts of all who helped in
the preparation and finalization of this monograph are gratefully
acknowledged.

ABBREVIATIONS

ATA atmosphere absolute
BE base excess
CNS central nervous system
CT computer tomography
4-DMAP 4-dimethylaminophenol
EDTA ethylenediaminetetraacetic acid
G6PD glucose-6-phosphate dehydrogenase
Hb haemoglobin
HMPS hexose monophosphate shunt
INN international non-proprietary name
LDLo lowest published lethal dose
MLD minimal lethal dose
NADH reduced nicotinamide adenine dinucleotide
NADPH reduced nicotinamide adenine dinucleotide phosphate
OHB₁₂ hydroxocobalamin
LD₅₀ Lethal Dose 50
USP United States Pharmacopoeia
B₁₂ Vitamin B₁₂
HbO₂ Oxyhaemoglobin
AV atrioventricular
SNP sodium nitroprusside
VS volumetric solution

1. Overview

1.1 Historical Review

The recognition of cyanide as a poison in bitter almonds,
cherry laurel leaves, and cassava goes back to antiquity. An
inscription on an Egyptian papyrus in the Louvre Museum, Paris,
refers to the "penalty of the peach," and Dioscorides in the first
century A.D. was aware of the poisonous properties of bitter almonds
(Sykes, 1981).

The first description of cyanide poisoning was by Wepfer in
1679 and dealt with the effects of the administration of extract of
bitter almonds (Sykes, 1981). Two fatal cases of poisoning in
Ireland caused by drinking cherry laurel water, used as a flavouring
agent in cooking and to dilute brandy, led to the experiments of
Madden (1731). He showed that cherry laurel water contains a
poison; given orally, into the rectum, or by injection, it rapidly
killed dogs. It was not until 1786 that isolation of pure hydrogen
cyanide (HCN) from the dye Prussian blue was achieved by Scheele
(1786). The mechanism of toxicity of cyanide was explored by
Fontana (1795). Cyanide was obtained from bitter almonds by
Schrader (1802). The introduction of cyanide as a medicament to
treat coughs and lung diseases was suggested by Magendie (1817).
Indeed, it was not until 1948 that cherry laurel water was removed
from the British Pharmacopoeia! Attempts to antagonize the toxic
effects of cyanide were reported by Blake (1839 and 1840).
Hoppe-Seyler (1876) reported that cyanide inhibits tissue oxidation
reactions.

Antagonism between amyl nitrite and prussic acid was mentioned
by Pedigo (1888), and, as early as 1894, cobalt compounds were
advocated by Antal (1894) as cyanide antagonists. Sodium nitrite
was used as an antidote in experimental cyanide poisoning by
Mladoveanu & Gheorghiu (1929).

A biochemical mechanism for cyanide antagonism was described by
Chen et al. (1933, 1934). They suggested using a combination of
amyl nitrite, sodium nitrite and sodium thiosulfate, the latter
compound serving as a sulfur donor for rhodanese (thiosulfate sulfur
transferase). Rhodanese accelerates cyanide detoxification by
forming the metabolite thiocyanate. This represented the
development of one of the first antidotes based on scientific
toxicological reasoning. This combination of antidotes has stood
the test of time, and still represents one of the most efficacious
antidotal combinations for the treatment of cyanide intoxication.

Interest in cobalt compounds was renewed by Mushett et al.
(1952), who demonstrated in 1952 that hydroxocobalamin (vitamin
B_12a) combined with cyanide to form cyanocobalamin (vitamin
B₁₂).

Paulet (1960) subsequently reported that cobalt EDTA was more
effective as a cyanide antidote than the classic nitrite-thiosulfate
combination.

1.2 Potential Sources of Cyanide

1.2.1 Industrial sources

Hydrogen cyanide is used in the fumigation of ships, large
buildings, flour mills, private dwellings, freight cars, and
aeroplanes that have been infested by rodents or insects. It is
bound to a carrier, commonly diatomaceous earth, and blended with an
odorous or irritating product as a warning marker.

Cyanide salts are utilized in metal cleaning, hardening,
ore-extracting processes, and electroplating.

Halogenated cyanides (chloro-, bromo- and iodocyanide) in
contact with water produce the non-toxic cyanic acid. As a result
of contact with strong acids, hydrogen cyanide is liberated.

Nitriles are cyano-derivatives of organic compounds. Acetonitrile
is used as a solvent and is less toxic (LD₅₀ = 120 mg/kg) than
hydrogen cyanide (LD₅₀= 0.5 mg/kg), but often contains toxic
admixtures due to metabolism to inorganic cyanide. While aliphatic nitriles
metabolise to inorganic cyanide, the aromatic nitrile bond is stable
in vivo. Acrylonitrile is the raw material used for the
manufacture of plastics and synthetic fibres. Contact with skin
causes bullae formation. Pyrolysis generates hydrogen cyanide.
Acrylonitrile and propionitrile are less toxic (LD₅₀ = 35 mg/kg)
than butyronitrile (LD₅₀ = 10 mg/kg). Trichloroacetonitrile
(LD₅₀ = 200 mg/kg) is used as an insecticide. The aromatic
nitriles, bromoxynil (LD₅₀= 190 mg/kg) and ioxynil (LD₅₀= 110
mg/kg), are used as herbicides.

Cyanamide, cyanoacetic acid, ferricyanide and ferrocyanide do
not release cyanide. They are therefore less toxic (LD₅₀=
1000-2000 mg/kg) than the cyanogenic compounds above, though they
may cause toxicity by other means, e.g. cyanide in combination with
alcohol.

1.2.2 Non-industrial sources

Fires and automobile pollution-control devices with
malfunctioning catalytic converters (Voorhoeve et al., 1975)
generate cyanide. Natural substances, such as wool, silk, horse
hair, and tobacco, as well as modern synthetic materials, such as
polyurethane and polyacrylonitriles, release cyanide during
combustion (Levine et al., 1978; Birky et al., 1979; Anderson &
Harland, 1982; Clark et al., 1983; Alarie, 1985; Lowry et al., 1985)
(Table 1).

Table 1. Hydrogen cyanide generated by pyrolysis

µg HCN per
Material g material

paper 1100
cotton 130
wool 6300
nylon 780
polyurethane foam 1200

From: Montgomery et al. (1975)

1.2.3 Natural sources

Cyanide is found in foodstuffs such as cabbage, spinach, and
almonds, and as amygdalin in apple pips, peach, plum, cherry, and
almond kernels. In the kernels themselves, amygdalin seems to be
completely harmless as long as it is relatively dry. However, the
seeds contain an enzyme that is capable of catalysing the following
hydrolytic reaction when the seeds are crushed and moistened:

C₂₀H₂₇NO₁₁ + 2H₂O --> 2C₆H₁₂O₆ + C₆H₅CHO + HCN

amygdalin glucose benzaldehyde hydrogen
cyanide

The reaction is slow in acid but rapid in alkaline solution.

Natural oil of bitter almonds contains 4% HCN. American white
lima beans contain 10 mg cyanide/100 g bean. The dried root of
cassava (tapioca) may contain 245 mg cyanide/100 g root. The
cyanide content in 100 g of cultivated apricot seeds has been found
to be about 9 mg and that in wild apricot seeds more than 200 mg.

1.2.4 Iatrogenic sources

Cyanide is also formed during nitroprusside therapy, especially
when it is prolonged, because tachyphylaxis sometimes requires the
use of higher doses than the recommended maximum of 10 µg/kg per min
(Smith & Kruszyna, 1974; MacRae & Owen, 1974; Piper, 1975; Atkins,
1977; Anon, 1978). Cyanide metabolises to thiocyanate. Thiocyanates
were used some years ago as
antihypertensive agents and they saw wide use because they were very
effective. However, a variety of subacute toxic effects, including
anorexia, fatigue, and gastrointestinal tract and CNS disturbances,
led to their disfavour.

Laetrile, amygdalin derived from apricot kernels, has been used
as an anticancer agent, but it is now obsolete because a therapeutic
effect could not be demonstrated in either retrospective or
prospective studies. Laetrile has caused fatal cyanide poisoning
(Sadoff et al., 1978).

1.3 Toxicity of Cyanide in Man

1.3.1 Acute poisoning

It is generally accepted that inhalation of approximately 50 ml
(at 1.85 mmol/l) of hydrogen cyanide gas is fatal within minutes.
Poisoning from hydrogen cyanide is more frequently
accidental than suicidal. Thus accidental cyanide poisoning may
occur in fumigators and chemists who use hydrogen cyanide during the
course of their work (Chen et al., 1944). In fires, a combination
of HCN and carbon monoxide (CO) toxicity, as a result of inhalation of
combustion products, may cause fatalities.

Suicidal ingestion of cyanide salts most commonly occurs in
personnel with occupational access to cyanide. The ingestion of as
little as 250 mg of an inorganic cyanide salt may be fatal (Peters
et al., 1982). However, death may be delayed for several hours
following the ingestion of cyanide on a full stomach; a first-pass
effect in the liver may also delay the onset of toxicity
(Naughton, 1974).

1.3.2 Chronic poisoning

Chronic low-dose neurotoxicity have been suggested by
epidemiological studies of populations ingesting naturally occurring
plant glycosides (Blanc et al, 1985). These glycosides are present
in a wide variety of plant species, most notably the cassava plant,
a major tropical foodstuff (Conn, 1973; Cook & Coursey, 1981;
Ministry of Health, Mozambique, 1984). Cassava has been associated
with tropical ataxic neuropathy (Cook & Coursey, 1981). Epidemic
spastic paraparesis has been associated with a combination of a high
cyanide and a low sulfur intake from diets dominated by
insufficiently processed cassava and lacking protein supplementary
food (Rosling, 1989). A neurotoxicological role for cyanide has
also been suggested in tobacco-associated amblyopia (Grant, 1980)
and in amygdalin-associated peripheral neuropathy (Kalyanaraman et
al., 1983). Long-term cyanide intoxication has been shown to be
associated both with thyroid gland enlargement and dysfunction in
case reports and in cohort studies of individuals exposed
occupationally (Blanc et al., 1985), through dietary intake (Cook &
Coursey, 1981), and experimentally (El Ghawabi et al., 1975).

1.4 Mechanism of Toxicity

Cyanide has a special affinity for the ferric ions that occur
in cytochrome oxidase, the terminal oxidative respiratory enzyme in
mitochondria. This enzyme is an essential catalyst for tissue
utilization of oxygen. When cytochrome oxidase is inhibited by
cyanide, histotoxic anoxia occurs as aerobic metabolism becomes
inhibited. In massive cyanide poisoning, the mechanism of toxicity
is more complex. It is possible that autonomic shock from the
release of biogenic amines may play a role by causing cardiac
failure (Burrows & Way, 1976). Cyanide could cause both pulmonary
arteriolar and/or coronary arterial vasoconstriction, which would
result, either directly or indirectly, in pump failure and a
decrease in cardiac output. This theory is supported by the sharp
increase in central venous pressure that was observed by Vick &
Froelich (1985) at a time when the arterial blood pressure fell
after the intravenous administration of sodium cyanide to dogs. The
observation that phenoxybenzamine, an alpha-adrenergic blocking
drug, partially prevented these early changes (Vick & Froelich,
1985) supports the concept of an early shock-like state not related
to inhibition of the cytochrome oxidase system. Inhalation of amyl
nitrite, a potent arteriolar vasodilating agent, resulted in the
survival of dogs in these experimental circumstances. This could
have been due to reversal of early cyanide-induced vasoconstriction
with restoration of normal cardiac function (Vick & Froelich, 1985).

1.5 Clinical Features

The smell of bitter almonds in expired air is an important sign
in cyanide poisoning. However, many people are unable to perceive
the odour of hydrocyanic acid (Kalmus & Hubbard, 1960). The
incidence of "non-smellers" is reported to be 18% among males and 5%
among females (Kirk & Stenhouse, 1953; Fukumoto et al., 1957).

Immediately after swallowing cyanide, very early symptoms, such
as irritation of the tongue and mucous membranes, may be
experienced. A blood-stained aspirate may be observed if gastric
lavage is performed. Early symptoms and signs that occur after
inhalation of HCN or the ingestion of cyanide salts include anxiety,
headache, vertigo, confusion, and hyperpnoea, followed by dyspnoea,
cyanosis, hypotension, bradycardia, and sinus or AV nodal
arrythmias.

In the secondary stage of poisoning, impaired consciousness,
coma and convulsions occur and the skin becomes cold, clammy, and
moist. The pulse becomes weaker and more rapid. Opisthotonos and
trismus may be observed. Late signs of cyanide toxicity include
hypotension, complex arrythmias, cardiovascular collapse, pulmonary
oedema, and death.

It should be emphasized that the bright-red coloration of the
skin or absence of cyanosis mentioned in textbooks (Gosselin et al.,
1984; Goldfrank et al., 1984) is seldom described in case reports of
cyanide poisonings. Theoretically this sign could be explained by
the high concentration of oxyhaemoglobin in the venous return, but,
especially in massive poisoning, cardiovascular collapse will
prevent this from occurring. Sometimes, cyanosis can be observed
initially, while later the patient may become bright pink (Hilmann
et al., 1974).

The pathogenesis of pulmonary oedema could be due to several
different mechanisms: (1) an intracellular metabolic process that
could injure the alveolar and capillary epithelium directly,
producing a capillary leak syndrome; (2) neurogenic pulmonary oedema
or, (3) most likely, a direct effect on the myocardium leading to
left ventricular failure and increased pulmonary venous pressure.

The brain is obviously the key organ involved in cyanide
poisoning and it has been shown that cyanide significantly increases
brain lactate and decreases brain ATP concentrations (Olsen & Klein,
1947).

1.6 Laboratory Findings

1.6.1 Lactic acidosis

Since oxidative phosphorylation is blocked, the rate of
glycolysis is markedly increased, which in turn leads to lactic
acidosis. The degree of lactic acidosis can be correlated with the
severity of cyanide poisoning (Trapp, 1970; Naughton, 1974).

1.6.2 Hyperglycaemia

A reversible toxic effect occurs on the pancreatic beta-cells,
which may occasionally give rise to an erroneous diagnosis of
hyperglycaemic diabetic coma.

1.6.3 Cyanide concentration in blood and plasma

Before intravenous treatment with antidotes is commenced, it is
necessary to collect a heparinized (not fluoride) blood sample for
determination of cyanide concentration. Results from samples
collected after treatment are totally unreliable. A quantitative
test employing a detector tube (see chapter 10) can be used if the
diagnosis is in doubt. The blood can also be used for a
quantitative test (see chapter 10), so that the severity of
poisoning can be evaluated. Therapeutic measures after antidotal
treatment should be based on the clinical condition of the patient
rather than on blood cyanide concentrations (Berlin, 1971; Vogel et
al., 1981; Peters et al., 1982). Since blood concentrations of up
to 0.005-0.04 mg/l have been recorded in healthy non-smokers, and

0.01-0.09 mg/l in smokers, only concentrations above these values
were previously considered to be toxic (Vogel et al., 1981; Peters
et al., 1982). Lundquist et al., (1985) reported even lower
concentration: non-smokers 3.4 µg/l (whole blood), 0.5 µg/l
(plasma), 6.0 µg/l (erythrocytes); smokers 8.6 µg/l (whole blood),
0.8 µg/l (plasma), 17.7 µg/l (erythrocytes).

Fatal cyanide poisoning has been reported with whole blood
concentrations of >3 mg/l and severe poisoning with 2 mg/l (Graham
et al., 1977). However, when cyanide enters the bloodstream, up to
98% quickly enters the red blood cells where it becomes tightly
bound. A plasma-to-blood ratio as high as 1:10 has been reported
and, as a consequence, the whole blood cyanide concentration may not
accurately reflect tissue concentrations of cyanide. Plasma levels
of cyanide may be of greater significance because severe toxicity
occurs in the presence of only modest concentrations (Vesey et al.,
1976). However, a serious drawback to the use of plasma cyanide
determinations in the assessment of poisoning is the pronounced
instability of cyanide in plasma (Lundquist et al., 1985).

1.7 Biological Detoxification of Cyanide

The major pathway of endogenous detoxification is conversion,
by means of thiosulfate, to thiocyanate. Minor routes of elimination
are excretion of hydrogen cyanide through the lungs and binding
to cysteine or hydroxocobalamin.

.Metabolic Detoxification of Cyanide;V02ANnew.BMP

The detoxification of cyanide occurs slowly at the rate of
0.017 mg/kg per min (McNamara, 1976). A sulfurtransferase
enzyme is needed to catalyse the transfer of a sulfur atom
from the donor thiosulfate to cyanide. The classical theory
indicating that mitochondrial thiosulfate sulfurtransferase
is the most important enzyme in this reaction is now in
doubt because thiosulfate penetrates lipid membranes slowly
and would, therefore, not be readily available as a
source of sulfur in cyanide poisoning. The modern concept assumes a
greater role for the serum albumin-sulfane complex, which is the
primary cyanide detoxification buffer operating in normal metabolism
(Sylvester et al., 1983). A further enzyme, beta-mercaptopyruvate
sulfurtransferase, also converts cyanide to thiocyanate (Vesey et
al., 1974). This enzyme is found in the erythrocytes, but in human
cells its activity is low.

1.7.1 Thiocyanate toxicity

The detoxification product of cyanide, thiocyanate, is excreted
in the urine. Thiocyanate concentrations are normally between
1-4 mg/l in the plasma of non-smokers and 3-12 mg/l in smokers. The
plasma half-life of thiocyanate in patients with normal renal
function is 4 h (Blaschle & Melmon, 1980), but in those with renal

insufficiency it is markedly prolonged and these patients are
therefore at increased risk of toxicity (Schulz et al., 1978).
Thiocyanate levels exceeding 100 mg/l are thought to be associated
with toxicity. Thiocyanate toxicity is characterized by weakness,
muscle spasm, nausea, disorientation, psychosis, hyper-reflexia, and
stupor (Smith, 1973; Michenfelder & Tinker, 1977). Lethal poisoning
at concentrations greater than 180 mg/l has been reported (Healy,
1931; Garvin, 1939; Russel & Stahl, 1942; Kessler & Hines, 1948;
Domalski et al., 1953). Haemodialysis is recommended as an
effective means of removing thiocyanate (Marbury et al., 1982).
Dialysance values of 82.8 ml/min ( in vivo) and 102.3 ml/min
( in vitro) have been recorded (Pahl & Vaziri, 1982). Little is
known about the protein-binding characteristics of thiocyanate, and
haemoperfusion may be more effective than haemodialysis.

1.8 Protective Measures for Occupational Exposure

Accidental exposure to cyanide, as either hydrogen cyanide or
cyanide salts, will occur primarily in the occupational context, and
appropriate preventive and protective measures need to be taken
wherever cyanides are manufactured or used. Many industrial accidents
occur as a result of mixing cyanide salts and acids, and care
should be taken when both are present on industrial premises.
As hydrogen cyanide may be generated during combustion of organic
substances, fire fighters may also be exposed occupationally.

The public may be affected in the case of a major industrial
emergency, or of a transport accident, involving the release of
cyanides. It is essential for local authorities in areas where
cyanides are used to have contingency plans that will enable them to
respond effectively. Adequate hospital facilities for treatment of
casualties must be available.

Proper maintenance of plant, good operating practice, and
industrial hygiene are essential for the prevention of cyanide
poisoning. Areas in the workplace where cyanides are used and
containers for storage and transport of cyanide should be clearly
marked. Work schedules should ensure that there are at least two
people in zones where cyanide could be released accidentally. There
should be showers and first-aid kits in these areas. Personnel
without proper training should not be allowed in the plant. Normal
industrial and laboratory hygiene measures for personnel handling
toxic materials, such as dirty and clean locker facilities and
showers, should be provided. Eating, drinking, and smoking should
not be allowed in the work area where cyanides are used but in
places specially reserved for these purposes.

Each employee working at a plant or laboratory that handles
cyanides, should receive instruction on the dangers of cyanides and
be trained in appropriate first-aid measures, as should
emergency-service personnel. They should be aware of the hazards
and informed about the possible routes of exposure (inhalation, skin
absorption, ingestion). Training should involve recognition of the
symptoms and signs of cyanide poisoning and how to achieve safe

removal of victims from the source of intoxication. Personnel
should also be able to guide a rescue or fire-fighting team to a
trapped intoxicated person. Rescue personnel should be able to put
on protective clothing quickly in an emergency. There should be
regular instruction sessions covering procedures for handling
cyanides and for rescue in case of accidents, as well as random
alarm exercises. First-aid training should include the essential
measures to be taken before medical help arrives, which may need to
be undertaken at the same time as removal of contaminated clothing
and decontamination of exposed skin and eyes. It should be realized
that further uptake of cyanide into the blood may occur after
showering because of continued skin absorption.

Each plant handling cyanide should have its own medical staff
trained in the emergency treatment of cyanide poisonings. The
atmospheric concentrations of hydrogen cyanide should be monitored
in plants where the gas is used or may be generated. Warning
devices are available for this purpose and should be installed. In
certain circumstances in which cyanide is used, it is possible to
add a warning gas, e.g., cyanogen chloride and chloropicrin have
been added to hydrogen cyanide used as a fumigant (Cousineau & Legg,
1935; Polson & Tattersall, 1969).

Filter respirators should be carried at all times by employees
working in zones where hydrogen cyanide may be released. At high
hydrogen cyanide concentrations, absorption occurs through the skin
and impermeable butyl rubber protective clothing is required.
Oxygen breathing apparatus may be needed.

In the case of an accident involving hydrogen cyanide there
should be both an acoustic and a visual alarm for the plant, which
may be activated by workers in zones where the gas is used. Each
worker should be aware of the emergency procedures to be followed
and the protective clothing and equipment to be used. If a large
number of victims is involved or if there is a danger to the public,
local authorities need to be warned, so that contingency plans are
put into effect and hospitals alerted.

For accidents at plants in remote areas where a qualified
physician is not readily available and there are no hospital
intensive care facilities, attending paramedical personnel should
have the authority and training to perform the special resuscitation
measures involved in treating cyanide poisonings, including rapid
endotracheal intubation and techniques for obtaining intravenous
access.

1.9 Treatment

1.9.1 Supportive treatment

Although effective antidotes are available, general supportive
measures should not be ignored and may be life-saving.

According to Jacobs (1984), who reported his personal
experience of 104 industrial poisoning cases, the use of specific
antidotes was indicated only in cases of severe intoxication with
deep coma, wide non-reactive pupils, and respiratory insufficiency
in combination with circulatory insufficiency. In patients with
moderately severe poisoning, who had suffered only a brief period of
unconsciousness, convulsions, vomiting, and cyanosis, therapy
consisted of intensive care and intravenous sodium thiosulfate. In
cases of mild intoxication with dizziness, nausea, and drowsiness,
rest and oxygen alone were used.

Peden et al. (1986) described nine patients poisoned by
hydrogen cyanide released by a leak from a valve. Three of them
were briefly unconscious but recovered rapidly after being moved
from the area where they had been working. The arterial whole-blood
cyanide concentrations on admission were 3.5, 3.1 and 2.8 mg/l,
respectively. The cyanide concentrations in the other cases ranged
between 2.6 and 0.93 mg/l. All recovered with supportive therapy
alone.

Between 1970 and 1984, three other men were treated similarly;
two were transiently unconscious, and in these cases the cyanide
concentrations 30 min after exposure were 7.7 and 4.7 mg/l. The
concentration in the other patient was 1.6 mg/l. All three patients
recovered without the use of cyanide antidotes. Small numbers of
comatose patients with potentially lethal blood concentrations on
admission, and who recovered without cyanide antidotes, have been
reported by Graham et al. (1977), Edwards & Thomas (1978), and Vogel
et al. (1981).

Even if a patient is unconscious, an antidote does not
necessarily have to be administered immediately unless vital signs
deteriorate.

A patient exposed to hydrogen cyanide who reaches hospital
fully conscious is only likely to require observation and
reassurance.

1.9.2 Antidotal treatment

1.9.2.1 Oxygen

It is difficult to understand how oxygen has a favourable
effect in cyanide poisoning, because inhibition of cytochrome
oxidase is non-competitive. However, oxygen has always been
regarded as an important first-aid measure in cyanide poisoning, and
there is now experimental evidence that oxygen has specific
antidotal activity. Oxygen accelerates the reactivation of
cytochrome oxidase and protects against cytochrome oxidase
inhibition by cyanide (Takano et al., 1980). Nevertheless, there
are other possible modes of action and those that are clinically
important have yet to be determined.

Hyperbaric oxygen is recommended for smoke inhalation victims
suffering from combined carbon monoxide and cyanide poisoning, since
these two agents are synergistically toxic. The use of hyperbaric
oxygen in pure cyanide poisoning remains controversial.

1.9.2.2 Sodium thiosulfate

The major route of cyanide detoxification in the body is
conversion to thiocyanate by rhodanese, although other
sulfurtransferases, such as beta-mercaptopyruvate sulfurtransferase,
may also be involved. This reaction requires a source of sulfane
sulfur, but endogenous supplies of this substance are limited.
Cyanide poisoning is an intramitochondrial process and an
intravenous supply of sulfur will only penetrate mitochondria
slowly. While sodium thiosulfate may be sufficient alone in mild to
moderately severe cases, it should be administered with other
antidotes in cases of severe poisoning. It is also the antidote of
choice when the diagnosis of cyanide intoxication is not certain,
for example in cases of smoke inhalation. Sodium thiosulfate is
assumed to be intrinsically nontoxic but the detoxification product
formed from cyanide, thiocyanate, may cause toxicity in patients
with renal insufficiency (see section 1.7).

1.9.2.3 Amyl nitrite

The administration of amyl nitrite by inhalation has been used
for many years as a simple first-aid measure that generates
methaemoglobin and which can be employed by lay personnel. Its use
was abandoned because the methaemoglobin concentration obtained with
amyl nitrite is no more than 7% and it is thought that at least 15%
is required to bind a potentially lethal dose of cyanide. However,
recent studies suggest that methaemoglobin formation plays only a
small role in the therapeutic effect of amyl nitrite, and
vasodilatation may be the most important mechanism of antidotal
action. Artificial respiration with amyl nitrite ampoules broken
into an Ambu bag proved to be life-saving in dogs severely poisoned

with cyanide. Amyl nitrite may therefore be reintroduced as a
first-aid measure.

1.9.2.4 Sodium nitrite

Nitrites generate methaemoglobin, which combines with cyanide
to form the nontoxic substance cyanmethaemoglobin. Methaemoglobin
does not have a higher affinity for cyanide than does cytochrome
oxidase, but there is a much larger potential source of
methaemoglobin than there is of cytochrome oxidase. The efficacy of
methaemoglobin is therefore primarily the result of mass action. A
drawback of methaemoglobin generation is the resultant impairment of
oxygen transport to cells and, ideally, the total amount of free
haemoglobin should be monitored to ensure aerobic metabolism of the
cells. Methaemoglobin can be measured very quickly, but this in
itself will not provide an accurate guide to the amount of
haemoglobin available for oxygen transport because the
cyanmethaemoglobin concentration is not taken into account.
Individuals deficient in glucose-6-phosphate dehydrogenase (G6PD)
are at great risk from sodium nitrite therapy because of the
likelihood of severe haemolysis, but the risk from amyl nitrite is
likely to be less because only low plasma concentrations are
achieved. Excess methaemoglobinaemia may be corrected with either
methylene or toluidine blue (see Chapter 9) or, preferably, where
feasible, by exchange transfusion.

1.9.2.5 4-Dimethylaminophenol (4-DMAP)

4-DMAP generates a methaemoglobin concentration of 30-50%
within a few minutes (Weger, 1968) and, theoretically, it should
therefore be valuable as a first-aid measure. However, the problems
associated with methaemoglobin formation, as described above for
nitrites, apply to 4-DMAP to an even greater extent. Furthermore,
it has very poor dose-response curve reproducibility. Haemolysis as
a result of 4-DMAP therapy has been observed in overdose as well as
following a correct therapeutic dose. Treatment with 4-DMAP is
contraindicated in patients with G6PD deficiency. Excess
methaemoglobinaemia may be corrected with either methylene or
toluidine blue (see section 1.9.2.8).

1.9.2.6 Hydroxocobalamin (vitamin B_l2a)

This antidote binds cyanide strongly to form cyanocobalamin
(vitamin B₁₂) and, compared to nitrite and 4-DMAP therapy, it has
the great advantage of not interfering with tissue oxygenation. The
disadvantage of hydroxocobalamin as a cyanide antidote is the large
dose required for it to be effective. Detoxification of 1 mmol
cyanide (corresponding to 65 mg KCN) needs 1406 mg hydroxocobalamin.
In most countries it is only commercially available in formulations
of 1-2 mg per ampoule. In some countries, e.g., France, a
formulation is available that contains 4 g hydroxocobalamin powder

that has to be reconstituted with 80 ml of a 10% sodium thiosulfate
solution prior to use and administered intravenously in a minimum of
220 ml of 5% dextrose. Recorded side effects are anaphylactoid
reactions and acne. Some authors have reported a reduced antidotal
effect as a result of mixing hydroxocobalamin and sodium thiosulfate
in the same solution (Evans, 1964; Friedberg & Shukla, 1975).
Histological changes in the liver, myocardium, and kidney apparently
induced by hydroxocobalamin have been reported in animal
experiments (Hoebel et al., 1980), but their relevance to man has
not yet been established. Transient pink discoloration of mucous
membranes and urine is an unimportant and nontoxic side-effect.

1.9.2.7 Dicobalt edetate

This agent has been shown to be effective in the treatment of
cyanide poisoning in man, and in the United Kingdom it is the
current treatment of choice provided that cyanide toxicity is
definitely present. This is a strict criterion, because as a result
of the manufacturing process some free cobalt ions are always
present in solutions of dicobalt edetate. Cobalt ions are toxic and
the use of dicobalt edetate, in the absence of cyanide, will lead to
serious cobalt toxicity. There is evidence from animal experiments
that glucose protects against cobalt toxicity and it is recommended
that this be given at the same time as dicobalt edetate. Serious
adverse effects recorded include vomiting, urticaria, anaphylactic
shock, hypotension, and ventricular arrhythmias (Hilmann et al.,
1974; Naughton, 1974).

1.9.2.8 Antidotes to methaemoglobin-forming agents

Accurate determination of methaemoglobin and free haemoglobin
concentrations in the presence of cyanide is difficult.
Nevertheless, excess methaemoglobinaemia does undoubtedly occur on
occasions following the use of nitrites and 4-DMAP. Excess
methaemoglobin concentrations may be reduced by methylene or
toluidine blue. However, regeneration of haemoglobin will release
cyanide back into the circulation, leading to a recurrence of
toxicity.

1.10 Summary of Treatment Recommendations

The management of cyanide poisoning is determined by (i) the
nature of exposure, i.e. hydrogen cyanide (with or without carbon
monoxide), cyanide salts, aliphatic nitriles, cyanogenic glycosides;
(ii) the severity of poisoning; (iii) the number of patients
involved; (iv) the proximity of hospital facilities; (v) the
presence of risk factors, e.g., G6PD deficiency. Urgent specific
antidotal therapy is not indicated unless the patient is in a deep
coma, with dilated non-reactive pupils and deteriorating
cardio-respiratory function. A patient exposed to hydrogen cyanide

confwho reaches hospital fully conscious requires observation and
reassurance only.

In order to assess the severity of cyanide poisoning, it is
necessary to take a blood sample before the administration of
antidotes. Analytical results are otherwise unreliable.

1.10.1 First aid and treatment measures at the site of the incident

The doses given are for adults. Model Information Sheets
should be consulted for the pediatric dose and for the use of
antidotes in special-risk groups, e.g., G6PD-deficient patients.

The following should be undertaken:

(a) Trained personnel (wearing appropriate protective clothing
and breathing apparatus if hydrogen cyanide or liquid
cyanide preparations are involved) should

* terminate further exposure
* commence artificial ventilation with 100% oxygen^a
* administer 0.2-0.4 ml amyl nitrite via Ambu bag

(b) A physician (if immediately present on the scene) should

* terminate further exposure
* artificial ventilation with 100% oxygen^a
* administer 0.2-0.4 ml amyl nitrite via Ambu bag

In cases of unequivocal moderate to severe poisoning, the above
procedure should be followed by

50 ml of 25% sodium thiosulfate solution
(12.5 g) i.v. for 10 minutes

and either 20 ml of 1.5% dicobalt edetate solution
(300 mg) i.v. for 1 minute

or 10 ml of 40% hydroxocobalamin solution (4 g)
i.v. for 20 minutes

or 10 ml of 3% sodium nitrite solution (300 mg)
i.v. for 5-20 minutes

or 5 ml of 5% 4-DMAP solution (250 mg or
3-4 mg/kg) i.v. for 1 minute

^a Oxygen should be administered using a mask and a bag with a
"non-return" valve to prevent inspiration of exhaled gases.

1.10.2 Hospital treatment^a

The doses given are for adults. Model Information Sheets
should be consulted for the pediatric doses and for the use of
antidotes in special-risk groups, e.g., G6PD-deficient patients.

1.10.2.1 Severe poisoning

Patients in deep coma with dilated non-reactive pupils and
deteriorating cardio-respiratory function (blood cyanide
concentrations 3 to 4 mg/l) should be given

* artificial ventilation with 100% oxygen^b

* cardio-respiratory support

This should be followed by

50 ml of 25% sodium thiosulfate solution
(12.5 g) i.v. over 10 min

and either 20 ml of 1.5% dicobalt edetate solution
(300 mg) i.v. over 1 min

or 10 ml of 40% hydroxocobalamin solution (4 g)
i.v. over 20 min

or 10 ml of 3% sodium nitrite solution (300 mg)
i.v. over 5-20 min

or 5 ml of 5% 4-DMAP solution (250 mg or
3-4 mg/kg) i.v. over 1 min

^a Hospital physicians must establish whether specific antidotal
therapy was administered at the time of the incident before
further doses are administered, especially in the case of
methaemoglobin-forming agents.

^b Oxygen should be administered using a mask and a bag with a
"non-return" valve to prevent inspiration of exhaled gases.

1.10.2.2 Moderately severe poisoning

Patients who have suffered a short-lived period of
unconsciousness, convulsions, vomiting, and/or cyanosis (blood
cyanide concentrations 2-3 mg/l) should be given

* 100% oxygen, but for no longer than 12-24 h
* 50 ml of 25% sodium thiosulfate solution (12.5 g)
i.v. over 10 min
* observation in an intensive-care area

1.10.2.3 Mild poisoning

Patients with nausea, dizziness, drowsiness only (blood cyanide
concentrations < 2 mg/l) should be given

* oxygen
* reassurance
* bed rest

It should be noted that severely poisoned patients may
occasionally fail to respond to the initial dose of a specific
antidote. Whilst repeat doses of hydroxocobalamin and/or sodium
thiosulfate are unlikely to be associated with toxicity, expert
advice should be sought before a repeat dose of any other specific
antidote is administered. Intensive supportive therapy is of
paramount importance in these circumstances.

1.11 Summary of Analytical Aspects

There are many reliable methods for the detection and
qualitative determination of cyanide in biological material in cases
of suspected intoxication (see Chapter 10). They can be used as
"bedside methods" as well as for qualitative determination in cases
of acute poisoning but only before antidotes are administered.
Interference results from the presence of thiosulfate,
methaemoglobin, thiocyanates, and chelating agents during the course
of whole-blood cyanide analysis. For this reason, it may be more
appropriate to measure plasma rather than whole-blood cyanide
concentrations. However, the pronounced instability of cyanide in
plasma is a serious drawback (Lundquist et al., 1985).

Quantitative analysis of cyanide in blood or serum before the
administration of antidotes is a useful means of evaluating the
severity of poisoning. Evaluation of the efficacy of different
antidotes will not be possible before accurate methods of analysis
free from interference are developed.

When methaemoglobin-generating agents (nitrites or 4-DMAP) are
administered as antidotes in cyanide poisoning, it is necessary to
maintain an adequate concentration of free haemoglobin in order to
guarantee sufficient oxygen transport to allow aerobic tissue
metabolism.

Special instruments for rapid analysis of methaemoglobin in
hospitals do not provide information about the amount of haemoglobin
available for oxygen transport, because the multicomponent analysis
is invalidated by the presence of a haemoglobin derivate
(cyanmethaemoglobin). Since there is no satisfactory means of
quantifying cyanmethaemoglobin under these circumstances, therapy
with methaemoglobin-generating agents cannot be monitored at present
by laboratory methods.

1.12 Proposed Areas for Research

There are two areas of research where further work is needed as
a matter of urgency:

(a) Analytical techniques currently available for the
measurement of methaemoglobin do not permit accurate
estimation of the amount of free haemoglobin available for
oxygen transport, because cyanmethaemoglobin cannot be
quantified. A rapid and accurate technique for measuring
methaemoglobin and cyanmethaemoglobin concentrations in
conjunction is therefore needed to monitor the use of
methaemoglobin-generating cyanide antidotes.

(b) Reliable quantitative analytical methods for cyanide in
whole blood in the presence of one or more antidotes are
needed.

(c) Determination of cyanide concentration in plasma or serum
may be the best reflection of the tissue concentration of
cyanide, since cyanide trapped in erythrocytes will not
affect tissue utilization of oxygen. However, cyanide has
been shown to be very unstable in these body fluids. A
method to prevent this phenomenon is urgently needed.

(d) The intravenous injection of DMAP generates high
concentrations of methaemoglobin within minutes. However,
the absorption kinetics of DMAP administered
intramuscularly are not known with certainty, particularly
in patients who are shocked with poor muscle perfusion.
The efficacy of intramuscular DMAP as a first-aid measure
in cases of severe cyanide poisoning needs further
evaluation.

(e) Hydroxocobalamin has recently been reported to cause
histological changes in the liver, kidney, and myocardium
of animals. The relevance of these findings to man is not
known and further investigation is required.

(f) Enzyme systems other than cytochrome oxidase may be
inhibited. This may be the cause for the symptomatology
in acute severe cyanide poisoning.

1.13 New Developments in Cyanide Antidotes

Currently available cyanide antidotes have potentially
undesirable adverse effects, and none has been successful in all
cases of acute, severe cyanide poisoning. Various agents for the
treatment of cyanide poisoning are at the experimental stage of
development. However, these antidotes are not currently recommended
for administration in cases of human poisoning.

1.13.1 Nonspecific agents

Based on animal studies, certain nonspecific agents, such as
naloxone in huge doses (equivalent to 700 mg in a 70 kg human adult
compared with a usual therapeutic dose of 0.4 to 10 mg) (Leung et
al., 1986) or alpha-adrenergic blocking agents such as
chlorpromazine (which has no beneficial effect when administered
alone but variably enhances sodium nitrite and/or sodium thiosulfate
efficacy) (Kong et al., 1983; Petterson & Cohen, 1985), have been
suggested as adjunctive therapy. However, at the moment, there is
no accepted place for the use of these agents in human poisoning.

1.13.2 Sodium pyruvate

This agent re-establishes cellular respiration in tumour
tissues inactivated by cyanide and has some efficacy in experimental
animal poisoning. It may promote cyanide detoxification through
combination of the cyanide anion with a carbonyl radical, producing
cyanohydrin (Pronczuk de Garbino & Bismuth, 1981). Sodium pyruvate
acts rapidly and is well distributed to tissues, but clinical trials
in human cyanide poisoning have not been undertaken.

1.13.3 Ifenprodil

Ifenprodil is a 2-piperidine allonal derivative, which, in
experimental poisoning, affords some protection including decreased
respiratory distress, improved blood pressure, normalization of
cardiac rhythm, and lessened electroencephalographic abnormalities.
The mechanism of action is thought to be a direct stimulation of
mitochondrial respiratory function. At present, ifenprodil is in
the investigational stage and no human clinical trials have been
proposed (Pronczuk de Garbino & Bismuth, 1981).

1.13.4 Rhodanese

Rhodanese (thiosulfate-cyanide sulfurtransferase) is the
naturally-occurring cyanide-detoxifying enzyme (see section 1.7).
Although the availability of sulfane sulfur is the rate-limiting
factor, studies in dogs have indicated that there is enough
rhodanese present in the normal liver and muscle tissue to detoxify
about 500 grams of cyanide. When derived from hepatic tissue, the
enzyme is unstable and requires an optimal pH for cyanide

detoxification. Bacterial enzyme, derived from cultures of
Thiobacillus denitrificans, is more stable and has been studied
in experimental animals. It is efficacious in experimental cyanide
poisoning, but no human clinical applications have yet been proposed
(Pronczuk de Garbino & Bismuth, 1981).

1.13.5 Alpha-ketoglutaric acid

The cyanide ion can react with carbonyl groups to form
cyanohydrins, and this could represent an important detoxification
reaction. In rodents poisoned with cyanide and pretreated with
various antidotes, alpha-ketoglutaric acid was more effective than
either sodium nitrite or sodium thiosulfate, and nearly as effective
as sodium nitrite and sodium thiosulfate in combination (Moore et
al., 1986). The combination of alpha-ketoglutaric acid with sodium
nitrite plus sodium thiosulfate increased the cyanide LD₅₀ from a
mean of 6.7 mg/kg in control animals to 119.4 mg/kg, whereas the
sodium nitrite/thiosulfate combination alone increased the mean
LD₅₀ to only 35.0 mg/kg (alpha-ketoglutaric acid alone increased
the mean LD₅₀ to 33.3 mg/kg). No methaemoglobin induction was
observed with alpha-ketoglutaric acid administration. Some tremors
were noted when this agent was administered alone. Tremors did not
occur when sodium thiosulfate was added to the treatment regimen,
and the LD₅₀ value was increased to 101.3 mg/kg with this
combination (very close to the 19.4 mg/kg LD₅₀ observed with
addition of both sodium nitrite and sodium thiosulfate to
alpha-ketoglutaric acid). While these studies demonstrated only
protective activity with prophylactic alpha-ketoglutaric acid
administration, they raise the possibility of another potentially
efficacious and safe antidote combination with sodium thiosulfate
(Moore et al., 1986). Alpha-ketoglutaric acid, especially in
combination with sodium thiosulfate, deserves further study.

1.13.6 Stroma-free methaemoglobin solution

Stroma-free methaemoglobin solution is prepared from outdated
red blood cells by the removal of all cellular membranes (stroma)
and induction of methaemoglobinaemia equivalent to 90% of the total
haemoglobin with potassium ferricyanide. Any excess potassium
ferricyanide is then removed by dialysis against saline. The
resultant preparation does not contain the antigenic components that
have been previously reported to cause renal failure and
coagulopathies. No rats given stroma-free methaemoglobin solution
alone died or had any adverse reactions. Concentrated stroma-free
methaemoglobin solution (200-300 g/l) was an effective experimental
antidote when administered 30 seconds after doses of cyanide up to 6
times the LD₉₀. More dilute solutions were effective 90% of the
time following cyanide administration up to 4 times the LD₉₀.
None of the animals in these studies were given any supportive
therapy. In animals administered an amount of stroma-free
methaemoglobin solution thought to be equivalent to the conversion

of 1.5% of the endogenous haemoglobin, a 90% survival rate was noted
when a cyanide LD₁₀₀ was administered. Spectroscopic examination
of urine revealed cyanmethaemoglobin excretion (Ten Eyck et al.,
1984, 1985, 1986).

These studies suggest that methaemoglobin prepared exogenously
may be an effective cyanide antidote. Exogenously administered
methaemoglobin would not be expected to interfere with oxygen
transport and, unlike methaemoglobin-generating agents (Moore et
al., 1987), could even be used in smoke-inhalation victims with
elevated carboxyhaemoglobin levels. Since no adverse effects have
been noted, this agent may be a safe alternative to currently
available cyanide antidotes. However, no human studies have been
undertaken and extensive animal toxicology experiments have not yet
been reported.

1.14 References

Alarie Y (1985) The toxicity of smoke from polymeric materials
during thermal decomposition. Am Rev Pharmacol Toxicol, 25: 325-347.

Anderson RA & Harland WA (1982) Fire deaths in the Glasgow area.
III. The role of hydrogen cyanide. Med Sci Law, 22: 35-37.

Anon (1978) Controlled intravascular sodium nitroprusside treatment.
Br Med J, 6140: 784-785.

Antal J (1894) [Experimental studies on the treatment of cyanide
poisoning.] Ung Arch Med, 3:117-128 (in German).

Atkins D (1977) Cyanide toxicity following nitroprusside-induced
hypotension. Can Anaesth Soc J, 24: 651-660.

Berlin AM (1971) The treatment of cyanide poisoning in children.
Pediatrics, 46: 793.

Birky MM, Halpin BM, Caplan YH, Fisher RS, McAllister JM, & Dixon AM
(1979) Fire fatality study. Fire Mater, 3: 211-217.

Blake G (1839) Observations on the physiological effects of various
agents introduced into the circulation, as indicated by the
hemodynamometer. Edinburgh Med Surg J, 53: 35-49.

Blake G (1840) Observations and experiments in the mode in which
various poisonous agents act on the animal body. Edin Med Surg J 53:
35-49.

Blanc P, Hogan M, Malin K, Hryhorczuk D, Hessl S, & Bernard B (1985)
Cyanide intoxication among silver reclaiming workers. J Am Med
Assoc, 253: 367-371.

Blaschle TE & Melmon KL (1980) Antihypertensive agents and the drug
therapy of hypertension. In: Goodman LS & Gilma A ed. The
pharmacological basis of therapeutics. New York, MacMillan
Publishing Co., vol 6, pp 807-808.

Burrows GE & Way JL (1976) Antagonism of cyanide toxicity by
phenoxybenzamine. Fed Proc, 35: 533.

Chen KK, Rose CL, & Clowes GHA (1933) Methylene blue, nitrites and
sodium thiosulfate against cyanide poisoning. Proc Soc Exp Biol Med,
31: 250-252.

Chen KK, Rose CL, & Clowes GHA (1934) Comparative values of several
antidotes in cyanide poisoning. Am J Med Sci, 188: 767.

Chen KK, Rose CL, & Clowes GHA (1944) The modem treatment of cyanide
poisoning. J Indiana Med Assoc, 37: 344-350.

Clark CJ, Campbell D, & Reid WH (1983) Blood carboxyhaemoglobin and
cyanide levels in fire survivors. Lancet, 1: 1332-1335.

Conn EE (1973) Cyanogenic glucosides (Committee on Food Protection,
Food and Nutrition Board, National Research Council). In: Toxicants
occurring naturally in foods, 2nd ed. Washington, DC, National
Academy of Sciences, pp 299-308.

Cook RD & Coursey DB (1981) Cassava: a major cyanide-containing food
crop. In: Vennesland B, Conn E, Knowles CJ, Westley J, & Wissing F
ed. Cyanide in biology. New York, London, Academic Press, pp 11-28.

Cousineau A & Legg FG (1935) Hydrocyanic acid gas and other toxic
gases in commercial fumigation. Am J Public Health, 25: 277-294.

Domalski CA, Kolb LC, & Hines EA (1953) Deleterious reactions
secondary to thiocyanate therapy of hypertension. Proc Mayo Clin,
28: 272-280.

Edwards AC & Thomas IC (1978) Cyanide poisoning. Lancet, 1: 92.

El Ghawabi SH, Gaafar MA, El Saharti AA, Ahmed SH, Malash KK, & Fares
R (1975) Chronic cyanide exposure, a clinical, radio isotope and
laboratory study. Br J Ind Med, 32: 215-219.

Evans CL (1964) Cobalt compounds as antidotes for hydrocyanic acid.
Br J Pharmacol Chemother, 23: 455-475.

Fontana F (1795) Treatise on the venom of viper; on the American
poisons; and on the Cherry Laurel and some other vegetable poisons.
J Skinner (trans), London.

Friedberg KD & Shukla UR (1975) The efficiency of aquocobalamin as
an antidote in cyanide poisoning when given alone or combined with
sodium thiosulfate. Arch Toxicol, 33: 103-113.

Fukumoto Y, Nakajimo H, Uetake M, Matusyama A, & Yoshida T (1957) A
study on the sense of smell with respect to potassium cyanide solution
and its hereditary transmission. Jpn J Hum Genet, 2: 7-16.

Garvin CF (1939) The fatal toxic manifestations of the thiocyanates.
J Am Med Assoc, 112: 1125-1127.

Goldfrank L, Bresnitz EA, Weisman RS, & Lewin NA (1984) The inhaled
agents and other disorders of oxygen transport. In: Hanson W Jr ed.
Toxic emergencies. New York, Churchill Livingstone, pp 204-211.

Gosselin RE, Smith RP, & Hodge HC (1984) Cyanide. In: Clinical
toxicology of commercial products. Baltimore, London, Williams &
Wilkins Co., pp 123-130.

Graham DL, Laman D, Theodore J, & Robin ED (1977) Acute cyanide
poisoning complicated by lactic acidosis and pulmonary edema. Arch
Intern Med, 137: 1051.

Grant WM (1980) The peripheral visual system as a target. In: Spencer
PS & Schaumberg HH ed. Experimental and clinical neurotoxicology.
Baltimore, London, Williams & Wilkins Co., pp 77-91.

Healy JC (1931) Therapeutics and toxicology of sulfocyanates. New Engl
J Med, 205: 5481-5583.

Hilmann B, Bardham, KD, & Bain JTB (1974) The use of dicobalt edetate
(Kelocyanor) in cyanide poisoning. Postgrad Med J, 50: 171-174.

Hoebel M, Engeser P, Nemeth L, & Pill J (1980) The antidote effect of
thiosulfate and hydroxocobalamine in formation of nitroprusside
intoxication of rabbits. Arch Toxicol, 46: 207-13.

Hoppe-Seyler F (1876) [On fermentation processes and their
relationship to the life of organisms.] PfQgers Arch gesamte Physiol
Menschen Tieren, 12: 1-17 (in German).

Jacobs K (1984) [Report on experience with the administration of
4-DMAP in severe prussic acid poisoning. Consequences for medical
practice.] Zentralbl Arbeitsmed, 34: 274-277 (in German).

Kalmus H & Hubbard DJ (1960) The chemical senses in health and
disease. Springfield, Illinois, Charles C. Thomas.

Kalyanaraman UP, Kalyanaraman K, & Cullinan SA (1983) Neuropathy of
cyanide intoxication due to "laetrile" (amygdalin). Cancer, 51:
2126-2133.

Kessler DL & Hines LE (1948) Hazards of thiocyanate therapy in
hypertension. J Am Med Assoc, 138: 549-551.

Kirk RI & Stenhouse NS (1953) Ability to smell solutions of
potassium cyanide. Nature (Lond), 171: 698-699.

Kong A, Shen A, Burrows G, Sylvester D, Ison GE, & Way JL (1983)
Effect of chlorpromazine on cyanide intoxication. Toxicol Appl
Pharmacol, 71: 407-413.

Leung P, Sylvester DM, Chiou F, Way LI, Way EL, & Way JL (1986)
Stereospecific effect of naloxone hydrochloride on cyanide
intoxication. Toxicol Appl Pharmacol, 83: 525-530.

Levine MS, Radford MPH, & Radford EP (1978) Occupational exposures
to cyanide in Baltimore fire fighters. J Occup Med, 20: 53-56.

Lowry WT, Juarez L, Petty CS, & Roberts B (1985) Studies of toxic
gas production during actual structural fires in the Dallas area. J
Forensic Sci, 30: 59-72.

Lundquist P, Rosling H, & Sorbo B (1985) Determination of cyanide in
whole blood, erythrocytes and plasma. Clin Ther, 31: 591-595.

McNamara BP (1976) Estimation of the toxicity of hydrocyanid acid
vapors in man. (Edgewood Arsenal Technical Report No. EB-TR-76023)
(Army Department).

MacRae WR & Owen M (1974) Severe metabolic acidosis following
hypotension induced with sodium nitroprusside. Br J Anaesth, 46:
795-797.

Madden T (1731) Poisoning by laurel leaves. Philos Trans R Soc Lond
Biol Sci, 37: 84-99.

Magendie F (1817) Sur l'emploi de l'acide prussique dans le
traitement de plusieurs maladies de poitrine, et particulièrement
dans la phtisie pulmonaire. Ann Chim Phys, 6: 347-360.

Marbury TC, Sheppard JE, Gibbons K, & Lee CC (1982) Combined antidotal
and hemodialysis treatments for nitroprusside-induced cyanide
toxicity. J Toxicol Clin Toxicol, 19: 475-482.

Michenfelder JD & Tinker JH (1977) Cyanide toxicity and thiosulfate
protection during chronic administration of sodium nitroprusside in
the dogs: correlation with a human case. Anesthesiology, 47:
441-448.

Ministry of Health, Mozambique (1984) Mantakassa: an epidemic of
plastic paraparesis associated with chronic cyanid intoxication in a
cassava staple area of Mozambique. I.

Epidemiology and clinical and laboratory findings in patients. Bull
World Health Organ, 62: 477-488.

Mladoveanu C & Gheorghiu P (1929) Le nitrite de soude comme antidote
de l'empoisonnement experimental par le cyanure de potassium. C R
Soc Biol (Paris), 102: 164-166.

Montgomery R, Reinhart CF, & Terril JB (1975) Comments on fire
toxicity. Comb Toxicol, 2: 179-212.

Moore SJ, Norris JC, Ing KH, & Hume AS (1986) The efficacy of
alpha-ketoglutaric acid in the antagonism of cyanide intoxication.
Toxicol Appl Pharmacol, 81: 265-273.

Moore SJ, Norris JC, Walsh DA, & Hume AS (1987) The antidotal use of
methemoglobin-forming cyanide antagonists in concurrent carbon
monoxide/cyanide intoxication. J Pharmacol Exp Ther, 242: 70-73.

Mushett CW, Kelly KL, Boxer GE, & Rickards JC (1952) Antidotal
efficacy of vitamin B_12a (hydroxocobalamin) in experimental
cyanide poisoning. Proc Soc Exp Biol Med, 81: 234-237.

Naughton M (1974) Acute cyanide poisoning. Anesth Intensive Care, 4:
351-356.

Olsen NS & Klein RJ (1947) Effect of cyanide on the concentration of
lactate and phosphates in brain. J Biol Chem, 167: 739.

Pahl MV & Vaziri ND (1982) In vivo and in vitro hemodialysis studies
of thiocyanate. J Toxicol Clin Toxicol, 19: 965-974.

Paulet G (1960) Les chelatés de cobalt dans le traitement de
l'intoxication cyanhydrique. Pathol Biol, 8: 255-266.

Peden NR, Taha A, McSofiey PD, Bryden GT, Murdoch IB, & Anderson JM
(1986) Industrial exposure to hydrogen cyanide: implications for
treatment. Br Med J, 293: 538.

Pedigo LG (1888) Antagonism between amyl nitrite and prussic acid.
Trans Med Soc Virginia, 19: 124-131.

Peters CG, Mundy JVB, & Rayner PR (1982) Acute cyanide poisoning.
Anaesthesia, 37: 582-586.

Petterson JC & Cohen SD (1985) Antagonism of cyanide poisoning by
chloro-promazine and sodium thiosulfate. Toxicol Appl Pharmacol, 81:
265-273.

Piper J (1975) Use and toxicity of nitroprusside. New Engl J Med,
292: 1081-1082.

Polson CJ & Tattersall RN (1969) Clinical toxicology. London,
Pitman, pp 128-159.

Pronczuk de Garbino J & Bismuth C (1981) Propositions thérapeutiques
actuelles en cas d'intoxication par les cyanures. Toxicol Eur Res,
III(2): 69-76.

Rosling H (1989) Cassava associated neurotoxicity in Africa. In:
Proceedings of the 5th International Congress of Toxicology. Volans
GN, Sims J, Sullivan FM, & Turner P ed. Brighton, Taylor & Francis, pp
605-614.

Russel WO & Stahl WC (1942) Fatal poisoning from potassium
thiocyanate treatment of hypertension. J Am Med Assoc, 119:
1177-1181.

Sadoff L, Fuchs J, & Hollander J (1978) Rapid death associated with
laetrile ingestion. J Am Med Assoc, 239: 1532.

Scheele CW (1786) Chemical essays. Beddves T (trans) Reprint 1966,
London, Dawson.

Schrader JCC (1802) Des expériences de M. Schrader sur l'acide
prussique continu dans les plantes. J Phys Chim Hist Nat Arts, 56:
224-226.

Schulz V, Dohring W, & Rathsac (1978) [Thiocyanate poisoning in
antihypertensive therapy with sodium nitroprusside.] Klin
Wochenschr, 56: 355-361 (in German).

Smith RP (1973) Cyanate and thiocyanate: Acute toxicity. Proc Soc
Exp Biol Med, 142: 1041-1044.

Smith RP & Kruszyna H (1974) Nitroprusside produces cyanide
poisoning via a reaction with hemoglobin. J Chem Exp Ther, 191:
557-563.

Sykes AH (1981) Early studies on the toxicology of cyanide. In:
Vennesland B, Conn EE, Knowles CJ, Westley J, & Wissing F ed.
Cyanide in biology. New York, London, Academic Press, pp 1-9.

Sylvester DM, Hayton WL, Morgan RL, & Way JL (1983) Effects of
thiosulfate on cyanide pharmacokinetics in dogs. Toxicol Appl
Pharmacol, 69: 265.

Takano T, Miyzaki Y, Nashimoto I, & Kobayashi K (1980) Effect of
hyperbaric oxygen on cyanide intoxication: in situ, changes in
intracellular oxidation reduction. Undersea Biomed Res, 7: 191-197.

Ten Eyck RP, Schaerdel AD, Lynett JE, Marks DH, Patrissi GA,
Ottinger WE, & Stansell MJ (1984) Stroma-free methemoglobin solution
as an antidote for cyanide poisoning: a preliminary study. Clin
Toxicol, 21: 343-358.

Ten Eyck RP, Schaerdel AD, & Ottinger WE (1985) Stroma-free
methemoglobin solution: an effective antidote for acute cyanide
poisoning. Am J Emergency Med, 3: 519-523.

Ten Eyck RP, Schaerdel AD, & Ottinger WE (1986) Comparison of
nitrite treatment and stroma-free methemoglobin solution as
antidotes for cyanide poisoning in a rat model. Clin Toxicol, 23:
477-487.

Trapp WG (1970) Massive cyanide poisoning with recovery. Can Med
Assoc J, 102: 3517.

Vesey CJ, Cole PV, Linnell JC, & Wilson J (1974) Some metabolic
effects of sodium nitroprusside in man. Br Med J, 2: 140-142.

Vesey CJ, Cole PV, & Simpson PJ (1976) Cyanide and thiocyanate
concentration following sodium nitroprusside infusion in man, Br J
Anaesth, 48: 651-659.

Vick JA & Froelich HL (1985) Studies on cyanide poisoning. Arch Int
Pharmacodyn, 273: 314-322.

Vogel SN, Sultan TR, & Ten Eyck RP (1981) Cyanide poisoning. Clin
Toxicol, 18: 367-383.

Voorhoeve RJH, Patel CKW, Trimble LE, & Kerl RJ (1975) Automobile
pollution control devices with malfunctional catalytic converters.
Science, 190: 149-151.

Weger N (1968) [Aminophenols as antidotes to prussic acid.] Arch
Toxikol, 24: 49-50 (in German).

2. OXYGEN

2.1 Introduction

Oxygen consumption is indispensable for human life. All organs
of the body will undergo successive dysfunction, permanent damage,
and then death if oxygen consumption falls below that necessary for
metabolic needs. A decrease in oxygen consumption may be due to
inadequate oxygen delivery to the cells or to an inability of the
cells to utilize oxygen.

The ambient atmospheric pressure at sea level is defined as one
atmosphere absolute (1 ATA), equivalent to an air pressure of
1.03 kg per sq. cm., i.e., 101 kPa or 760 mm of mercury. Molecular
oxygen constitutes about 21% of atmospheric air. Hence the partial
pressure of oxygen at sea level is 0.21 ATA.

Hyperoxia is the artificial elevation of the partial pressure
of oxygen in the body and can be produced by increasing the partial
pressure of oxygen from 0.21 to 1 ATA (normobaric oxygen therapy) or
above 1 ATA (hyperbaric oxygenation). Normobaric oxygenation is
commonly used in many conditions associated with decreased delivery
of oxygen to tissues, such as cardiac and pulmonary failure and
cardiopulmonary resuscitation.

Both normobaric and hyperbaric oxygen therapy have an antidotal
effect on carbon monoxide (CO), hydrogen sulfide (H₂S), and
cyanide (CN) poisoning. However, hyperoxia may induce oxygen
toxicity related to the length of exposure and the partial pressure
of oxygen employed. The use of oxygen therapy is therefore limited
by oxygen toxicity.

2.2 Name and Chemical Formula of Antidote

Molecular oxygen is a diatomic molecule and is properly named
dioxygen (formula O₂, relative molecular mass 16). More than
99.9% of atmospheric oxygen consists of molecules containing the
¹⁶O isotope. Trace quantities of ¹⁷O and ¹⁸O exist in
atmospheric air.

2.3 Physico-chemical Properties of Molecular Oxygen
Critical temperature 154.575 K
Critical density 0.4361 g/cm³
Critical pressure 50.14 ATA
Boiling point 90.188 K
Melting point 54.361 K
Solubility
in water, 25 °C 2.8%
in ethanol 22.6%
in plasma approx 3.0%
in whole blood 20.0%

2.4 Synthesis

Oxygen is obtained on a large scale by the liquefaction of air.
Modern manufacturing processes produce the gas at a concentration
much higher than 99.0% (v/v) of oxygen, this being the lowest
permissible concentration in medical oxygen allowed in the European
Pharmacopoeia. Contamination with carbon monoxide or carbon dioxide
is therefore very slight.

2.5 Analytical Methods

2.5.1 Quality control procedures

2.5.1.1 Tests

For the tests, deliver the sample to be examined at a rate of
4 l/h.

Carbon monoxide Carry out the test using 7.5 l of the
substance to be examined and 7.5 l of argon R for the blank. The
difference between the volumes of sodium thiosulfate (2 mmol/l) used
in the titrations should not be more than 0.4 ml (5 ppm v/v).

For the following three tests, pass the sample to be examined
through the appropriate reagent contained in a hermetically closed
flat-bottomed glass cylinder (with dimensions such that 50 ml of
liquid occupies a height of 12 cm to 14 cm) fitted with: (a) a
delivery tube terminated by a capillary 1 mm in internal diameter
and reaching to within 2 mm of the bottom of the cylinder; (b) an
outlet tube. Prepare the reference solutions in identical
cylinders.

Acidity or alkalinity

Test solution Pass 2.0 litres of the sample to be examined
through a mixture of 0.1 ml of hydrochloric acid (0.01 mol/l) and
50 ml of CO₂-free water R.

Reference solution (a) 50 ml of CO₂-free water R.

Reference solution (b) To 50 ml of CO₂-free water R add
0.2 ml of hydrochloric acid (0.01 mol/l).

To each solution add 0.1 ml of a 0.02% m/v solution of methyl
red R in alcohol (70% v/v). The intensity of the colour of the test
solution should be between those of reference solutions (a) and (b).

Carbon dioxide Pass 1.0 litre through 50 ml of barium
hydroxide solution R (the solution to be used must be clear). Any
turbidity in the solution after passage of the gas should not be
more intense than that in a reference solution prepared by adding

1 ml of a 0.11% m/v solution of sodium hydrogen carbonate R in
CO₂-free water R to 50 ml of barium hydroxide solution R
(300 ppm v/v).

Oxidizing substances Place in each of two cylinders 50 ml
of freshly prepared potassium iodide and starch solution R, and add
0.2 ml of glacial acetic acid R. Protect the cylinders from light.
Pass 5.0 l of the substance to be examined into one of the
cylinders. The test solution should remain colourless when compared
with the blank.

2.5.1.2 Assay for oxygen

Use a gas burette (see Fig. 1) of 25 ml capacity in the form of
a chamber having at its upper end a tube graduated in 0.2% divisions
between 95 and 100, and isolated at each end by a tap with a conical
barrel. The lower tap is joined to a tube with an olive-shaped
nozzle and is used to introduce the gas into the apparatus. A
cylindrical funnel above the upper tap is used to introduce the
absorbent solution. Wash the burette with water and dry. Open the
two taps. Connect the nozzle to the source of the sample to be
examined and set the flow rate to 1 l/min. Flush the burette by
passing the substance to be examined through it for 1 min. Close
the upper tap of the burette and immediately afterwards the lower
tap. Rapidly disconnect the burette from the source of the sample
to be examined and give a half turn to the upper tap to eliminate
any excess pressure in the burette. Keeping the burette vertical,
fill the funnel with a limited amount of freshly prepared mixture of
21 ml of a 56% m/v solution of potassium hydroxide R and 130 ml of a
20% m/v solution of sodium dithionite R. Open the upper tap slowly.
The solution absorbs the oxygen and enters the burette. Allow to
stand for 10 min without shaking. Read the level of the liquid
meniscus on the graduated part of the burette. This figure
represents the percentage v/v of oxygen.

2.5.2 Methods for identification

(a) Place a glowing splint of wood in the substance to be
examined. The splint bursts into flame.

(b) Shake with alkaline pyrogallol solution R. The sample to
be examined is absorbed and the solution becomes dark
brown.

2.5.3 Methods for analysis of the antidote in biological samples

2.5.3.1 In the gas phase

(a) Chemical volumetric methods based on absorption of oxygen
by chemical reagents (such as alkaline pyrogallol) are
still in use. The skill of the operator is a major factor
in the accuracy of the results.

(b) Methods based on physical properties of oxygen:

* paramagnetic susceptibility;
* thermomagnetic (magnetic wind);
* differential pressure (Quincke);
* magnetic auto-balance (Faraday);
* electron capture;
* ultraviolet absorption;
* mass spectrometry.

2.5.3.2 In solution

Polarographic measurement is a sensitive method for measuring
the partial pressure of oxygen in solution. The Clark electrode is
commonly used for biological samples. This has a cathode made of a
platinum wire, while the anode is Ag/AgCl in phosphate buffer with
added KCl.

2.5.4 The saturation of haemoglobin by oxygen

The degree of saturation of haemoglobin by oxygen (HbO₂ %)
can be measured by photometric procedures. This method is
particularly useful for the non-invasive monitoring of patients
(oximeters, pulse oximeters).

2.6 Storage Conditions

Oxygen should be stored under pressure in a suitable metal
container of a type permitted by the safety regulations of the
national authority. Valves and taps should not be lubricated with
oil or grease.

The containers for medical oxygen are coded with a white colour
at the top according to ISO-32-19 (Fig 2) and carry the indication
"Medical Oxygen" carved in the iron material of the container. To
prevent connection with other medical gases, the containers are
provided with an international standardized "Pin Index Safety
System" ISO-407. This system is the same for medical and for
industrial oxygen so that in emergencies industrial oxygen can also
be used.

Regular control of gas pressure is necessary to prevent
shortage of oxygen in emergency situations.

Although the duration of storage will not alter the quality, it
is recommended that the gas should not be stored for more than six
months.

2.7 General Properties

In most circumstances, supplemental oxygen is indicated if
tissue hypoxia is imminent. In the case of cyanide poisoning,
however, cytochrome oxidase activity is inhibited and tissue
utilization of oxygen prevented. Even so, animal experiments
(Takano et al., 1980) suggest that inhibition of cytochrome oxidase
activity by cyanide is prevented, and recovery accelerated, in the
presence of oxygen.

2.8 Animal Studies

2.8.1 Pharmacokinetics

The bioavailability of oxygen depends on the following factors:

(a) the thickness of the alveolar membrane; as a result of
oedema fluid in the interstitial spaces of the membrane
oxygen cannot readily diffuse into the blood;

(b) haemoglobin configuration:

(i) oxygen transport by the blood to the tissues can be
disturbed by methaemoglobin-forming antidotes, e.g.,
sodium nitrite or 4-dimethylaminophenol, often used
in the treatment of cyanide poisoning;

(ii) oxygen transport is also hampered in carbon monoxide
poisoning, which occurs in combination with cyanide
poisoning following smoke inhalation.

2.8.2 Pharmacodynamics

Isom & Way (1982) studied the reduction of cytochrome oxidase
prepared from brains and livers of mice poisoned with potassium
cyanide. They examined several groups of animals and compared
exposure to air and to oxygen at 0.95 ATA, both with and without
sodium nitrite and sodium thiosulfate treatment. Cytochrome oxidase
was inhibited by 75% within 2 min of the injection of 5 KCN mg/kg.
The inhibition of cytochrome oxidase was similar whether the animals
inhaled air or 0.95 ATA O₂, but the reactivation phase of
cytochrome oxidase was faster in oxygen-breathing animals. They
also found that, at a lower dose (4 KCN mg/kg), enzyme activity was
increased from 22% to 66% by increasing the partial pressure of
oxygen from 0.11 to 0.95 ATA O₂. Oxygen shifted the dose-response
curve of brain cytochrome oxidase inhibition by KCN to the right:
the dose of KCN producing 50% inhibition was 24 mg/kg in
air-breathing animals and 55 mg/kg in animals breathing oxygen. The
authors also found that liver rhodanese activity was 15 times higher
than brain rhodanese activity and that treatment with sodium nitrite
and sodium thiosulfate protected liver, but not brain, cytochrome
oxidase at high doses of KCN.

Way et al. (1972) found that oxygen alone antagonized cyanide
toxicity. However, they found no significant benefit in increasing
the partial pressure of oxygen from 1 to 4 ATA O₂. The authors
demonstrated that oxygen potentiates the effect of thiosulfate and
that the