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    VOLUME 2


    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

    Department of Health, London, United Kingdom

    Ulleval University Hospital, Oslo, Norway

    International Programme on Chemical Safety,
    World Health Organization, Geneva, Switzerland

    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


    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


         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
                 Sodium thiosulfate
                 Amyl nitrite
                 Sodium nitrite
                 Dicobalt edetate
                 Antidotes to methaemoglobin-forming
         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
                Severe poisoning
                Moderately severe poisoning
                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
                 Assay for oxygen
               2.5.2. Methods for identification
               2.5.3. Methods for analysis of the antidote in
                       biological samples
                 In the gas phase
                 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
                 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

         3.1. 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

         4.1. 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
                 UV spectroscopy
                 Colorimetric method
               4.5.2. Quality controls
               4.5.3. Raw materials
               4.5.4. Finished galenic form
               4.5.5. Measurement
                 In raw materials and in finished form
                 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
                 Acute toxicity
                 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

         5.1. Introduction
         5.2. Name and chemical formula
         5.3. Physico-chemical properties
         5.4. Synthesis
               5.4.1. Source of materials
                 Cobalt carbonate
                 Ethylenediaminetetraacetic acid

         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
                 Efficacy in animals
                 Comparison of dicobalt edetate with
                                  other compounds
                 Interactions with other drugs
               5.8.3. Toxicology
                  In vitro studies
                 Acute toxicity studies
                 Repeated dose toxicity
                 Circulatory effects in dogs
                 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

         6.1. 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
                 Non-volatile residue

                 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

         7.1. Introduction
         7.2. Name and chemical formula
         7.3. Physico-chemical properties
         7.4. Synthesis
         7.5. Analytical methods
               7.5.1. Quality control
                 Solid sodium nitrite
                 Sodium nitrite injection
                 Preparation of volumetric solutions
               7.5.2. Identification
               7.5.3. Impurities
                 Preparation of sodium nitrite to test
                 Preparation of special reagents
                 Preparation of standard
                 Preparation of test
                 Preparation of monitor
                 Preparation of hydrogen sulfide test
                 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

         8.1. 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
         8.6. Shelf-life
         8.7. General properties
         8.8. Animal studies
               8.8.1.  In vitro studies
                 Metabolism of 4-DMAP in the liver
                 Red cell metabolism of 4-DMAP
                 Toxic effects of 4-DMAP on
                 Toxic effects of 4-DMAP on isolated
                                  rat kidney tubules
                 Oxygen saturation and methaemoglobin
               8.8.2. Pharmacokinetics
               8.8.3. Pharmacodynamics
               8.8.4. Toxicology
         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

         9.1. 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
                Advised route and dosage
                Precautions and contraindications
                Adverse effects
                Other consequential or supportive
               9.1.13. Model information sheet
                Dosage and route of administration
                Precautions and contraindications
                Adverse effects
                Use in pregnancy/lactation
               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
                 Analysis of methaemoglobin
               9.2.6. Stability
               9.2.7. General properties
               9.2.8. Animal studies
               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
                Side effects
                Advised route and dose
                Use in pregnancy and children
               9.2.14. References


         10.1. Qualitative methods
               10.1.1. Detection in blood with a detector tube
               10.1.2. Spot test
                Specimen collection
         10.2. Quantitative methods
               10.2.1. Gas chromatographic head space technique
                Calibration standards
                Specimen collection and sample
                Operational parameters for gas
                Analytical determination
               Calculation of the analytical result

               Reliability of the method
               Detection limit
               10.2.2. Microdiffusion technique
                Solvents and reagents
                Calibration standards
                Reliability of the method
                Detection limit
         10.3. References



    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,

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

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

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

    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

    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


    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

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


    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


         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.

         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


    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

         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
    B12a) combined with cyanide to form cyanocobalamin (vitamin

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

    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

    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

         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

         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,

    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

    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

         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

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

    1.9.2  Antidotal treatment  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.  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).  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.  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.  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  Hydroxocobalamin (vitamin Bl2a)

         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.  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).  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

    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% oxygena
              *    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% oxygena
              *    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 treatmenta

         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.  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% oxygenb

              *    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.						
	  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  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

         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

         (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

         (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.

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    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
                   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  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

         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.  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

    FIGURE 01

    2.5.3  Methods for analysis of the antidote in biological samples  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.  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.

    FIGURE 02

         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

    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.

         (c)  Oxygen utilization by tissues is prevented by the
              inhibition of cytochrome oxidase activity in cyanide

    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