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Nitrous oxide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
   3.4 Other characteristics
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES
    CHEMICAL SUBSTANCES
    1. NAME
     1.1 Substance
       Nitrous oxide
     1.2 Group
       Inhalation anaesthetic
     1.3 Synonyms
       azoto protossido (Budavari, 1989; Reynolds, 1989)
       d'azote
       Dinitrogen monoxide
       dinitrogen oxide
       distickstoffmonoxid
       hyponitrous acid anhydride
       laughing gas
       nitrogen monoxide
       nitrogenii monoxidium
       nitrogenii oxidium
       nitrogenium oxydulatum
       oxyde nitreux
       oxydum nitrosum
       protoxyde
       stickoxydul
     1.4 Identification numbers
       1.4.1 CAS number
             10024-97-2 
       1.4.2 Other numbers
     1.5 Brand names, Trade names
       To be completed by each centre
     1.6 Manufacturers, Importers
       To be completed by each centre
    2. SUMMARY
     2.1 Main risks and target organs
       The main complication following inhalation of nitrous oxide is 
       varying  degrees of hypoxia,  affecting the functions of the 
       heart and the brain.  Chronic exposure can cause neurological 
       and haematological changes.
     2.2 Summary of clinical effects
       Nitrous oxide poisoning mainly causes varying degrees of 
       hypoxia. This  may be associated with hypotension, fatal 
       cardiac arrhythmias, headache,  dizziness, anoxic brain damage,
        cerebral oedema and permanent mental  deficit. Chronic 
       exposure can cause megaloblastic erythropoiesis and  
       neurological features similar to subacute combined 
       degeneration of the
       spinal cord.
     2.3 Diagnosis
       Symptoms of poisoning include hypotension, fatal cardiac 
       arrhythmias,  headache, dizziness, anoxic brain damage, 
       cerebral oedema and permanent  mental deficit
       
       Measurement of nitrous oxide levels in blood is of no 
       therapeutic value. In  cases of acute toxicity, arterial blood 
       gas analysis may be helpful. Full  blood counts are useful in 
       chronic exposure.
     2.4 First-aid measures and management principles
       Remove the patient from the source of exposure.

       
       Establish and maintain adequate airway by removing secretions 
       from mouth and trachea.
       
       Administer oxygen.
       
       Maintain respiration. Respiratory depression should be treated 
       with assisted  respiration.
       
       Maintain blood pressure.
       
       Maintain body warmth.
                 
       Treat cerebral oedema.
       
       Symptomatic and supportive therapy.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Nitrous oxide is a synthetic substance.
            
       It can be prepared by the following methods:
       
       A.   Decomposition of ammonium nitrate by heat
       
                 NH4NO3 = N2O + H2O
                      
       B.   Decomposing an equimolecular mixture of ammonium  
            sulphate and sodium nitrate at 240C.
       
       C.   A number of methods have been described for the 
       preparation of nitrous oxide by reduction of nitric acid or 
       nitrates.  The chemicals used are stannous chloride, anhydrous 
       formic acid and  oxalic acid. 
       
                      2HNO3 + SnCl2 + 8HCl = 4SnCl4 + 5H2O + N2O
                      2KNO3 + 6H.COOH = N2O + 4CO2 + 2H.COOK          
                              +
         5H2O
                      2KNO3 + H2SO4 + 4 (COOH)2 = N2O + 8CO2 +        
                                        
       K2SO4 + 5H2O
       
       D.   Nitric acid when reduced with hydrazine or hydroxylamine 
       yields  nitrous oxide.
       
                      HNO2 + N2H4 = N2O + NH3 + H2O
       
                      HNO2 + NH2OH = N2O + 2H2O
       
       E.   It is also possible to isolate nitrous oxide produced 
       directly  by the union of its elements in the nitrogen-oxygen 
       flame.
     3.2 Chemical structure
       Molecular weight:   44.02
       
       As the nitrous oxide molecule is linear  it must have either 

       two  double links or a single and a triple.  There are two 
       possible structures.
       
                 N <-- N = O+ and N+ = N --> O (Sidgwick, 1962)
     3.3 Physical properties
       A stable, non-irritating colourless gas with slightly 
       sweetish odour  and taste (Reynolds, 1989; Budavari, 
       1989).
       
       Solubility - freely soluble in alcohol and chloroform 
       and also soluble in  ether and oils (Reynolds, 1989; 
       Budavari, 1989).
       
       The solubility of nitrous oxide in aqueous salt 
       solutions and in solutions  of aqueous glycerol are 
       lower than those in water (Prideaux and Lambourne,  
       1928).
       
       Solubility in water - 1 litre of gas in 1.5 litre of 
       water at 20C and 2 atm.
       
       Boiling point: -88.46C (at atmospheric pressure)
       
       Melting point: -90.81C (at atmospheric pressure)
       
       Density as a gas: 1.997 mg/cm3 at 0C at atmospheric 
       pressure
       (Budavari, 1989).
       
       Vapour pressure: 4.93 pascals (at 20C)
       
       Relative molecular mass: 44.02
       
       Viscosity: 1488.99 poise (at 27C)
       
       Specific gravity: 1.529 at 0C,  at atmospheric 
       pressure.
     3.4 Other characteristics
    4. USES/CIRCUMSTANCES OF POISONING
     4.1 Uses
       Nitrous oxide is used for induction and maintenance of 
       anaesthesia and,  in sub-anaesthetic concentrations, for 
       analgesia in a variety of situations.   For anaesthesia, 
       it is commonly used in a concentration of 50-70% in 
       oxygen  as part of a balanced technique in association 
       with other inhalation or  intravenous agents.
       
       A mixture of nitrous oxide and oxygen containing 50% of 
       each gas (Entonox)  is used to produce analgesia without 
       loss of consciousness.   Self-administration, using a 
       demand valve, is popular and may be appropriate  in 
       obstetric practice, for changing painful dressings, as 
       an aid to  post-operative
       physiotherapy, and in emergency ambulances (Prasad, 
       1988).
     4.2 High risk circumstance of poisoning

       4.2.1 Adults
       
       Using a suitable anaesthetic apparatus, a mixture with 20-30% 
       oxygen for induction and maintenance of light anaesthesia.  
       For analgesia, as a mixture  with 50% oxygen, according to the 
       patient's needs.
       
       4.2.2 Children
       
       No data 
     4.3 Occupationally exposed populations
       Nitrous oxide is not recommended for anaesthesia and analgesia 
       in  patients with head injuries, impaired consciousness, 
       facial injuries, the  very young and the very old, 
       pneumothorax, decompression sickness and heavy  sedation 
       including the effects of alcohol (Johnson, 1979; Reynolds, 
       1989).
       
       Nitrous oxide diffuses into gas-filled body cavities and care 
       is essential  when using it in at-risk patients (eg. gaseous 
       abdominal distension,  pneumothorax, or similar cavities in 
       pericardium or peritoneum) (Reynolds,  1989).
       
       Nitrous oxide should not be administered for more than 24 
       hours because of  the risk of bone marrow depression (Reynolds,
        1989).
       
       Anaesthesia may be obtained, with some sub-oxygenation, with 
       alveolar  concentrations of 85-90% (625-650 mm/Hg). These 
       concentrations are not safe  and nitrous oxide is therefore 
       unsuitable as a sole agent for surgical  anaesthesia (Adriani, 
       1983).
    5. ROUTES OF ENTRY
     5.1 Oral
       Unknown.
     5.2 Inhalation
       The main route of exposure is through inhalation.
     5.3 Dermal
       Unknown.
     5.4 Eye
       Unknown.
     5.5 Parenteral
       Unknown.
     5.6 Others
       Unknown.
    6. KINETICS
     6.1 Absorption by route of exposure
       Nitrous oxide is rapidly absorbed on inhalation (Reynolds, 
       1989).
     6.2 Distribution by route of exposure
       As a result of lower tissue/blood partition coefficients, the  
       equilibration of nitrous oxide in most tissues occurs rapidly.
     6.3 Biological half-life by route of exposure
       Not known.
     6.4 Metabolism
       Nitrous oxide is not metabolized in the body.          

     6.5 Elimination by route of exposure
       The blood/gas partition coefficient is low and most of the 
       inhaled  nitrous oxide is rapidly eliminated through the lungs,
        though small amounts  diffuse through the skin (Reynolds, 
       1989).
    7. TOXICOLOGY
     7.1 Mode of Action
       Toxicodynamics
       
       Nitrous oxide is 35 times more soluble than nitrogen.  The gas 
       exchanges with nitrogen and diffuses into hollow viscera and 
       body spaces  potentially containing air such as pneumothorax, 
       paranasal sinuses and  pneumoperitoneum or into the cerebral 
       ventricles following  pneumoencephalography. This expands the 
       body of trapped air and increases  the pressure within such 
       closed spaces.  When administration is discontinued,  nitrous 
       oxide is released into the alveoli, diluting the alveolar 
       gases.  A  reduction in alveolar oxygen tension may result.  
       This is referred to as  diffusion anoxia (Adriani, 1983).
       
       Because of the high concentration of nitrous oxide required to 
       produce and maintain anaesthesia, hypoxia is an unavoidable 
       accompaniment to its use.  During induction with high 
       concentrations of  nitrous oxide, the oxygen in the lungs is 
       rapidly used up and the anoxia  with increased respiratory 
       effort causes rapid depletion of carbon dioxide  in the 
       tissues.  
       
       Absence of carbon dioxide and depression of the medullary 
       centres by the anaesthetic quickly lead to respiratory failure,
        and rarely, the patient's  cerebral function fails to recover 
       from cerebral damage caused by the  prolonged anoxia.  The 
       brain suffers anoxia from the very beginning of the  
       administration of the gas, and not from just the moment of 
       cessation of  respiratory movements.  Thus, the period of 
       anoxia may be five minutes or more, sufficient to cause 
       permanent brain  damage in the susceptible individual.  The 
       arbitrary "safe period" of eight  minutes may be too long for 
       some patients (Thienes and Haley, 1972).
       
       Pharmacodynamics
       
       Nitrous oxide induces inconsistent changes in the basal levels 
       of the  thalamic nuclei.  The  mechanism of analgesia is 
       believed to involve a  direct intraspinal anti-nociceptive 
       action rather than depression of limbic  function.  In the 
       brain stem, responses evoked by pain stimulation are  
       depressed, although the extent of depression may be variable.
       
       Nitrous oxide in anaesthetic doses increases cerebral blood 
       flow and  intracranial pressure (Frost, 1985).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Nitrous oxide is harmless and non-irritating to  
                     the respiratory tract, but concentrations over 

                     50 ppm  reduce dexterity, cognition and motor 
                     and audiovisual  skills (Adriani, 1983;
                     Ellenhorn and Barceloux, 1988).
                     
                     Neurological manifestations similar to subacute 
                     combined degeneration of the spinal cord were 
                     reported following  prolonged heavy exposure to 
                     nitrous oxide in 15 patients
                     (Layzer, 1978).
                     
                     Poisoning manifested by symptoms such as 
                     cyanosis,  hypotension and methaemoglobinaemia 
                     occurred in two  patients anaesthetized with 
                     nitrous oxide contaminated  with nitric oxide 
                     (Reynolds, 1982).
                     
                     Psychological dependency on nitrous oxide may 
                     occur  (Adriani, 1983).
                     
                     Prolonged as well as intermittent repeated 
                     exposure to  nitrous oxide may cause 
                     megaloblastic haemopoiesis  (Amess  et al, 
                     1978; Nunn et al, 1982).
             7.2.1.2 Children
                     Malignant hyperpyrexia induced by nitrous oxide  
                     anaesthesia was reported in an eleven year-old 
                     girl (Ellis  et al 1974).
       7.2.2 Relevant animal data
             Exposure of pregnant rats to nitrous oxide has caused 
             foetal  death, skeletal malformations and various 
             macroscopic lesions  (Reynolds, 1989).
             
             Physical dependency and withdrawal have been 
             demonstrated in mice  (Adriani, 1983).
       7.2.3 Relevant in vitro data
              Not available.
       7.2.4 Workplace standards
       7.2.5 Acceptable daily intake (ADI) and other guideline levels
     7.3 Carcinogenicity
       In the USA, the FDA considered that there was sufficient 
       evidence to  cause concern about the carcinogenic and 
       teratogenic potential of nitrous  oxide (Reynolds, 1982).  
       However, no convincing evidence of carcinogenicity  in
       man has been shown by epidemiological studies (Baden, 1985).
     7.4 Teratogenicity
       The incidence of spontaneous abortion is increased among women 
       exposed  to nitrous oxide.  It has been suggested, but not 
       proven, that there is an  increased incidence of congenital 
       anomalies in the offspring of women  exposed during pregnancy 
       and of spontaneous abortion in the wives of exposed  men 
       (Baden, 1985). No adverse effects were found in a etrospective 
       study of  175 pregnancies during which nitrous oxide was 
       administered. However, all anaesthesias were of short duration 
       (20 to 30  minutes ) and 97% were administered during the 
       second trimester (Aldridge  and Tunstall, 1986).
     7.5 Mutagenicity

       Nitrous oxide is not mutagenic (Baden, 1985).
     7.6 Interactions
       There are conflicting reports that nitrous oxide can reduce or 
       enhance therapeutic effects of methotrexate (Reynolds, 1989).
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Unknown.
       9.1.2 Inhalation
             As the main complications are those due to varying 

             degrees  of hypoxia, administration of nitrous oxide 
             without adequate oxygen  can cause hypotension, cardiac 
             arrhythmias and anoxic brain damage  with headache, 
             cerebral oedema, and permanent mental deficit.
       9.1.3 Skin exposure
             Unknown.
       9.1.4 Eye contact
             Unknown.
       9.1.5 Parenteral exposure
             Unknown.
       9.1.6 Other
             Unknown.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Unknown.
       9.2.2 Inhalation
             Chronic exposure to nitrous oxide may have adverse 
             effects  on rapidly dividing cells such as those of the 
             bone marrow, germ  plasma and foetal tissues.  A 
             transient leukopenia may follow  prolonged use (24 hours 
             or more).  Chronic exposure affects vitamin B12  
             metabolism, resulting in bone marrow and neurological 
             changes.   Neurological changes in dentists have been 
             reported that are  strongly suggestive of combined 
             degeneration of the spinal cord similar to that 
             occurring in pernicious anaemia (Adriani, 1983).
       9.2.3 Skin exposure
             Unknown.
       9.2.4 Eye contact
             Unknown
       9.2.5 Parenteral exposure
             Unknown
       9.2.6 Other
             No data
     9.3 Course, prognosis, cause of death
       Recovery from respiratory depression is usually complete.
       
       Deaths have been reported from use for non-medical purposes or 
       for "entertainment".  These have been ascribed to asphyxia 
       from inadequate ventilation of areas in which high 
       concentrations may develop from  inhalation of mixtures with 
       insufficient oxygen or from suicide (Adriani, 1983; Suruda and 
       McGlothin, 1990). The cause of death may be cardiac
       arrhythmia (Ellenhorn and Barceloux, 1988).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Recovery from respiratory depression is usually 
             complete.
             
             Deaths have been reported from use for non-medical 
             purposes or for  "entertainment".  These have been 
             ascribed to asphyxia from  inadequate ventilation of 
             areas in which high concentrations may  develop from
             inhalation of mixtures with insufficient oxygen or from 
             suicide  (Adriani, 1983; Suruda and McGlothin, 1990). 
             The cause of death may  be cardiac arrhythmia (Ellenhorn 

             and Barceloux, 1988).
       9.4.2 Respiratory
             During anaesthesia, nitrous oxide decreases tidal volume,
               increases respiratory rate and minute ventilation, and 
              pCO2 is  normally unchanged.  It depresses ventilatory 
             response to hypoxia  and
             tracheal mucociliary flow.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Exposure to nitrous oxide can cause headache,  
                     dizziness, euphoria, excitation, depression and 
                     raised  intracranial pressure as a result of 
                     hypoxia.
                          
                     Six patients experienced psychotic sensations of 
                     varying  severity during anaesthesia with 
                     nitrous oxide and oxygen  for caesarean section 
                     (Reynolds, 1982).
             9.4.3.2 Peripheral nervous system
                     Severe neurological symptoms in 15 patients (all 
                      but one of whom were dentists) following 
                     prolonged heavy  exposure to nitrous oxide 
                     associated with professional use,  self-
                     administration, or both, have been reported.  
                     Initial  symptoms were usually numbness or 
                     tingling in the hands or  legs.  Later symptoms 
                     included: Lhermitte sign (12 patients), numbness 
                      of trunk (10 patients), impairment of 
                     equilibrium or gait  (12 patients), inability to 
                     walk unassisted (7 patients),  impotence (7 
                     patients), sphincter impairment (4 patients),  
                     mental changes (7 patients), dysarthria (2 
                     patients), and  impairment of smell or taste.  
                     Ten patients were forced to  stop work.  
                     Symptoms resembled those of subacute 
                     combineddegeneration of the spinal cord, and it 
                     was considered  possible that nitrous oxide 
                     interfered with the action of  vitamin B12 on 
                     the nervous system.  All improved on  stopping 
                     exposure to nitrous oxide and regained the 
                     ability to walk  unaided, but 6 patients had a 
                     relapsing course associated  with re-exposure to 
                     nitrous oxide.  Administration of 
                     corticosteroids to 6 patients, and vitamin B12 
                     to 4  patients did not appear to influence the 
                     extent of  recovery (Layzer, 1978).
             9.4.3.3 Autonomic nervous system
                     Autonomic manifestations may vary depending on  
                     the levels of nitrous oxide. During analgesia, 
                     there is a  predominance of alpha-adrenergic 
                     stimulation (increased  peripheral vascular
                     resistance and blood pressure); by contrast, 
                     during  anaesthesia there is a predominance of 
                     beta-adrenergic  activation (raised cardiac 
                     output, heart rate, blood  pressure, muscle 
                     blood flow and reduced systemic vascular  

                     resistance) occurs (Eger, 1985). As a result of 
                     increased  sympathetic activity nitrous oxide 
                     may increase heat  production and reduce heat 
                     loss by causing cutaneous  soconstriction, 
                     contributing to malignant hyperthermia in 
                     susceptible  individuals (Brodsky, 1985).
             9.4.3.4 Skeletal and smooth muscle
                     Nitrous oxide increases skeletal muscle activity,
                      and has little if any effect on neuromuscular 
                     blockade  produced by non-depolarising muscle 
                     relaxants (Miller, 1985).
       9.4.4 Gastrointestinal
             Rarely nausea and vomiting may occur following exposure 
             to  nitrous oxide.
       9.4.5 Hepatic
             Nitrous oxide inactivates methionine synthetase in the  
             liver. Although this and other unknown factors may lead 
             to hepatic  injury there is no definite evidence of 
             clinically significant  liver damage (Brodsky,
             1985).   
       9.4.6 Urinary
             9.4.6.1 Renal
                     A small but significantly increased incidence of 
                      renal stones was found in male dentists exposed 
                     to nitrous  oxide (Cohen, 1980).
             9.4.6.2 Others
                     No data
       9.4.7 Endocrine and reproductive systems
             Impotence associated with nitrous oxide-induced  
             myeloneuropathy has been reported (Layzer, 1978).
       9.4.8 Dermatological
             Unknown.
       9.4.9 Eye, ears, nose, throat: local effects
             Hearing acuity was reduced in a few patients after  
             anaesthesia with nitrous oxide for adenotonsillectomy 
             (Reynolds,  1982).
       9.4.10 Haematological
              Bone marrow depression
              
              In a prospective study of patients undergoing cardiac 
              by-pass  surgery, 8 patients who received a mixture of 
              nitrous oxide 50% and  oxygen 50% continuously for 24 
              hours suffered megaloblastic changes  in their bone 
              marrow and abnormal deoxyuridine suppression tests  
              (indicative of abnormal vitamin B12 metabolism).  Of 9 
              similar  patients who received the nitrous oxide and 
              oxygen mixture for 5 -  12 hours only during the 
              operation, 3 had mildly megaloblastic  erythropoiesis 
              and 2 of these and 1 other patient had abnormal  
              deoxyuridine suppression tests.  In a further 5 similar 
              patients  who had not received nitrous oxide, the bone 
              marrow was  normoblastic and deoxyuridine suppression 
              tests were normal (Amess,  1978).
       9.4.11 Immunological
              Although nitrous oxide appears to depress the 
              production,  motility and chemotactic response of 

              leukocytes, the significance  of nitrous oxide in 
              interfering with the cell mediated immunity is  not 
              known (Brodsky, 1985).
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
              9.4.12.2 Fluid and electrolyte disturbances
              9.4.12.3 Others
       9.4.13 Allergic reactions
              Unknown.
       9.4.14 Other clinical effects
              Unknown.
       9.4.15 Special risks
              Unknown.
     9.5 Others
       Unknown.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         A patient with nitrous oxide poisoning should be removed 
         from the  source of exposure.  Establish airway and maintain 
         respiration.  Administer  oxygen.  Maintain blood pressure .
      10.2 Relevant laboratory analyses and other investigations
         10.2.1 Sample collection
         10.2.2 Biomedical analysis
         10.2.3 Toxicological analysis
                Measurement of nitrous oxide concentrations in blood 
                or  urine has no value in the management of a 
                patient. Arterial blood  gases, complete blood counts 
                and bone marrow biopsies may be  indicated depending 
                on clinical
                manifestations.
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic treatment
         Inhalation
         
         Remove the patient from further exposure.  Then establish 
         airway and  maintain respiration.  Administer 100% oxygen.
         
         Respiratory depression should be treated with assisted 
         respiration.
         
         Maintain blood pressure.
         
         Maintain body warmth.
         
         Treat cerebral oedema.
         
         Eye contact: Not relevant.
         
         Ingestion: Not relevant.
         
         Skin contact: Not relevant.
      10.4 Decontamination
         Inhalation: Remove patient from the source of exposure. 
         Maintain  adequate airway and assist respiration if 
         impaired. Administer 100% oxygen.

         
         Eye contact: not relevant.
         
         Ingestion: not relevant.
         
         Skin contact: not relevant.
      10.5 Elimination
         Inhalation: Nitrous oxide may be removed by forced 
         ventilation. 
         
         Eye contact: Not relevant.
         
         Ingestion: Not relevant.
         
         Skin contact: Not relevant.   
      10.6 Antidote treatment
         10.6.1 Adults
                There is no specific antidote.
         10.6.2 Children
                There is no specific antidote.
      10.7 Management discussion
         Artificial respiration with oxygen and carbon dioxide can 
         also be  used.  If pure carbon dioxide is used, the mask or 
         tube must be held some  distance from the subject's face to 
         allow free mixing with air to achieve  adequate oxygenation. 
          A high concentration of carbon dioxide is itself  
         depressant and anaesthetic.  Adrenaline (epinephrine) should 
         not be used to treat shock  because of the risk of 
         ventricular fibrillation (Thienes and Haley, 1972).
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         In a study where information was recorded on every occasion 
         Entonox  was administered, no side effects were experienced 
         on 61 occasions. But on  30 further occasions there were 
         minimal side effects, although never  sufficient to stop the 
         use of Entonox.  Side effects included drowsiness (10  
         patients), dizziness (13 patients), tingling of fingers and 
         toes (5 patients),  disorders of smell or taste (3 patients),
          and nausea (2 patients), one  patient said he felt "stoned",
          and another "disembodied".  A few patients  experienced 
         more than one symptom (Johnson, 1979).
         
         Irritating oxides occur rarely in the nitrous oxide 
         formulations now  marketed for anaesthesia.  However, 
         atmospheric nitrogen is present in  excessive amounts more 
         frequently than is generally appreciated.  Because of  the 
         greater volatility of nitrogen, it escapes from the 
         liquefied gases in the  cylinders more rapidly than nitrous 
         oxide.  Therefore, the first patient  anaesthetized from 
         such cylinders suffers a dangerous degree of asphyxia as  
         anaesthesia is induced. The delayed toxic effect of nitrous 
         oxide anaesthesia occasionally seen in large hospitals may 
         be attributable to the   prolonged cerebral anoxia due to 
         the free nitrogen present in nitrous oxide.  Degeneration of 
         the basal ganglia and cortex has been demonstrated in fatal  
         cases (Thienes and Haley, 1972).

      11.2 Internally extracted data on cases
         No data
      11.3 Internal cases
         To be completed by each centre
    12. ADDITIONAL INFORMATION
      12.1 Availability of antidotes
         Not relevant.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
         To some extent, the use of basal anaesthetics along with 
         nitrous oxide  allows a lower concentration of the gas to be 
         used for induction, so that  the degree of induced asphyxia 
         is lower. The continued cyanosis is  responsible for most of 
         the toxic effects of these gases and contraindicates  their 
         prolonged use (Thienes and Haley, 1972).
    13. REFERENCES
    Adriani J (1983).  General Anaesthetics. In: Haddad LM, 
    Winchester JEF. Clinical  Management of Poisoning and Drug 
    Overdose.  Canada, WB Saunders Company,  762-763.
    
    Aldridge LM & Tunstall ME (1986).  Br J Anaesth 58: 1348.
    
    Amess JAL, Burman JF, Rees GM, Nancekievill DG, Mollin DL (1978). 
     Megaloblastic erythropoiesis in patients receiving nitrous 
    oxide. Lancet 2: 339-342.
     
    Baden JM (1985). In: Nitrous oxide. Eger EI, ed.  Edward Arnold 
    (Publishers) Ltd,  London, 235-247.
    
    Brodsky JB (1985). In: Nitrous oxide. Eger EI, ed.  Edward Arnold 
    (Publishers) Ltd, 
    London, 259-279.
    
    Budavari S (1989).  The Merck Index, USA, Merck and Co Inc, 1051.
    
    Cohen EN, Brown BW, Wu ML, Whitcher CE, Brodsky JB, Gift HC, 
    Greenfield W, Jones TW, Driscoll EJ (1980).  Occupational disease 
    in dentistry and chronic exposure to trace  anaesthetic gases. J 
    Am Dental Assoc 101: 21-31.
         
    Eisele JH (1985).  In: Nitrous oxide. Eger EI, ed. Edward Arnold 
    (Publishers) Ltd,  London, 126-156.
    
    Ellenhorn MJ & Barceloux DG, eds (1988). Medical Toxicology; 
    Diagnosis and Treatment  of Human poisoning.  USA, Elsevier 
    Science Publishing Company, 843.
    
    Ellis FR, Clarke IMC, Appleyard TN, Dinsdale RCM (1974).  
    Malignant hyperthermia induced by nitrous oxide and treated with 
    dexamethasone. Br Med J 4:  270-271.
         
    Frost EAM (1985).  In: Nitrous oxide. Eger EI, ed. Edward Arnold 
    (Publishers) Ltd, London, 157-176.
    
    Fukunaga AF & Epstein RM (1973).  Sympathetic excitation during 

    nitrous  oxide-halothane anaesthesia in the cat.  Anaesthesiology 
    39: 23-36. 
    
    Johnson RAA (1979).  Entonox in general practice.  Practitioner 
    222: 681-682.
    
    Layzer RB (1978).  Myeloneuropathy after prolonged exposure to 
    nitrous oxide.  Lancet  2: 1227-1230.
    
    Mellor JW (1967).  Mellor's Comprehensive Treatise on Inorganic 
    and Theoretical  Chemistry Vol VIII, Supplement II. Nitrogen, 
    Part II. London, Longmans Green Co Ltd,  189-195.
    
    Miller RD (1985). In: Nitrous oxide.  Eger EI, ed. Edward Arnold 
    (Publishers) Ltd, London, 177-184.
    
    Naito H, Gillis CN (1973).  Effects of halothane and nitrous 
    oxide on removal of norepinephrine from the pulmonary 
    circulation.  Anaesthesiology 39: 575-580.
    
    Nunn JF, Sharer NM, Gorchein A, Jones JA, Wickramasinghe SN 
    (1982). Megaloblastic erythropoiesis after multiple short-term 
    exposure to nitrous oxide.  Lancet 1: 1379.
    
    Prasad AB (1988).  British National Formulary. British Medical 
    Association and Royal Pharmaceutical Society of Great Britain 15: 
    417-419.
    
    Prideaux BR & Lambourne H, eds (1928). Textbook of Inorganic 
    Chemistry Vol VI,  Part I.  London, Charles Griffin & Co, 142-
    145.
    
    Reynolds JEF, ed (1982).  Martindale, The Extra Pharmacopoeia. 
    The Pharmaceutical Press, London, 755-756.
         
    Reynolds JEF, ed (1989)  Martindale, The Extra Pharmacopoeia, The 
    Pharmaceutical Press, London, 1123-1124.
    
    Sidgwick NV (1962).  The Chemical Elements and Other Compounds 
    Vol I. Great Britain, Oxford University Press.
    
    Suruda AJ & McGlothlin JP (1990).  Fatal abuse of nitrous oxide 
    in the workplace.  J  Occup Med 32: 682-684.
         
    Thienes CH & Haley TJ, eds (1972).  Clinical Toxicology.  Great 
    Britain, Henry   Kimpton Publishers.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
    ADDRESSES
    Authors:       Dr Ravindra Fernando
                   National Poisons Information Centre
                   Faculty of Medicine
                   Kynsey Road
                   Colombo 8
                   Sri Lanka
    
                   Miss Shiromini Nissanka

                   National Poisons Information Centre
                   Faculty of Medicine
                   Kynsey Road
                   Colombo 8
                   Sri Lanka
    
         Date:     December 1991
    
         Reviewer:
    
         Peer Review: Newcastle-upon-Tyne, United Kingdom, February 1992




    See Also:
       Toxicological Abbreviations
       Nitrous oxide (ICSC)
       NITROUS OXIDE (JECFA Evaluation)