Acetylsalicylic acid

   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
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
   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
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data Adults Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens Toxicological analyses Biomedical analyses Arterial blood gas analysis Haematological analyses Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens Simple Qualitative Test(s) Advanced Qualitative Confirmation Test(s) Simple Quantitative Method(s) Advanced Quantitative Method(s) Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis Blood, plasma or serum Urine 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
   9.1 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 CNS Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
   10.1 General principles
   10.2 Relevant laboratory analyses
      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/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
   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
    1. NAME
     1.1 Substance
       Acetylsalicylic acid
     1.2 Group
     1.3 Synonyms
       2-Acetoxybenzoic acid
       Acidum salicylicum
       Aspirin (BP, EurP, BPVET, USP)
       O-Acetylsalicylic acid
       Salicylic Acid Acetate
     1.4 Identification numbers
       1.4.1 CAS number
       1.4.2 Other numbers
     1.5 Brand names, Trade names
       Argentina: A.A.S., Adiro, Asperinetas, Bayaspiraria, Enteretas,
       Australia: Bi-prin, Codral Junior, Ecotrin, Elsprin, Novosprin,
        Prodol, Provoprin, Rhusal, Sedalgin, Solusal, SRA, Winsprin
       Belgium:   Acentrine, Adiro, Aspegic (lysine acetylsalicylate),
        Dispril, Dolean pH 8, Enterosarin, Primaspan, Rhodine, Rhonal,
       Canada:    Acetophen, Asadrine C-200, Astrin, Coryphen, 
       Ecotrin, Entrophen, Neoprine-25, Nova-Phase, Novasen, Rhonal, 
       Salt Adult, Sal-Infant, Supasa, Triaphen-10
       Denmark:   Acetard, Albyl, Albyl-Selters, Globentyl, Idotyl, 
       Kalcatyl, Niaguyl, Reumyl
       France:    Aspegic (lysine acetylsalicylate), Aspirisucre,
       Aspisol (lysine acetylsalicylate), Catalgene, Claragine, 
       Iv_pirine, Juv_pirine, Rhonal
       Germany:   Acetylin, Colfarit, Contreuma retard, Delgesic 
       (lysine acetylsalicylate), Godamet, Halgon, Monobeltin (with 
       aluminium acetylsalicylate), Pyracyl (magnesium 
       acetylsalicylate), Trineral 600
       Hungary:   Istopirine
       Italy:     Asatard, Aspegic (lysine acetylsalicylate), Cemerit,
        Dolean pH 8, Domupirina, Endydol, Flectadol (lysine 
       acetylsalicylate), Kilios, Longasa, Rectosalyl
       Japan:     Rhonal, Salitison
       Netherlands: Acenterine, Acetyl Acidum Acetylsalicylicum Daro, 
       Alka-Seltzer, Asp_gic (lysine acetylsalicylate), Asperine, 
       Aspro Darosal, Dispid, Durasil, Enterosarine, Rhonal, 
       Norway:    Albyl, Dispril, Globentyl, Licyl, Magnyl, Novid
       South Africa: Aquapin, Aspasol, Aspegic (lysine 
       Spain:     AAS, Adiro, Calmo Ver Analgesio, Casprium Retard, 
       Codalgina Retard, Dolomega (lysine acetylsalicylate), Lafena, 
       Mejoral, Infantil, Rhonal, Riane (arginine acetylsalicylate), 
       Salicilina, Soluspril (lysine acetylsalicylate)
       Sweden:    Acetard, Albyl, Albyl-Selters, Apernyl, Bamyl, 
       Bamyl S, Dispril, Magnecyl, Premaspin, Rheumyl
       Switzerland: Acenterine, Acetylo, Aspegic (lysine 

       acetylsalicylate), Asrivo, Bebesan, Dispril, Dolean pH 8, 
       Enterosarine, Rhonal
       USA:     Aluprin, Ecotrin, Empirin
       (Reynolds, 1989)
     1.6 Manufacturers, Importers
       To be completed by the PCC.
    2. SUMMARY
     2.1 Main risks and target organs
       The toxic effects of salicylate are complex.  The following 
       appear to be the principal primary effects of salicylate in 
            stimulation of the respiratory centre
            inhibition of citric acid cycle (carbohydrate metabolism)
            stimulation of lipid metabolism
            inhibition of amino acid metabolism
            uncoupling of oxidative phosphorylation
       Respiratory alkalosis, metabolic acidosis, water and 
       electrolyte loss occur as the principal secondary consequences 
       of salicylate intoxication.  Central nervous system toxicity 
       (including tinnitus, hearing-loss, convulsions and coma), 
       hypoprothrombinaemia and non-cardiogenic pulmonary oedema may 
       also occur, though for some the mechanism remains uncertain 
       (see Section 7 for further details).
       Target organs: all tissues (whose cellular metabolism is 
       affected), but in particular the liver, kidneys, lungs and the 
       VIIIth cranial nerve.
     2.2 Summary of clinical effects
       Nausea, vomiting, epigastric discomfort, gastrointestinal 
       bleeding (typically with chronic and rarely with acute 
       Tachypnoea and hyperpnoea.
       Tinnitus, deafness, sweating, vasodilatation,  hyperpyrexia 
       (rare), dehydration.
       Irritability, tremor, blurring of vision,  subconjunctival 
       Non-cardiogenic pulmonary oedema.
       Confusion, delirium, stupor, asterixis, coma, cerebral oedema 
       (with severe intoxication only).
       Acute renal failure.
       Cardio-respiratory arrest (with severe intoxication only).
       (Meredith & Vale, 1986)
     2.3 Diagnosis
       Symptoms of mild poisoning include tinnitus, dizziness, 

       sweating and vomiting. Severe poisoning is characterised by 
       hyperventilation, fever and restlessness. Metabolic acidosis 
       and respiratory alkalosis occur.
       Effects on blood glucose: hyper- or hypoglycaemia
       Effects on blood: hypoprothrombinaemia
       Effects on liver: increased serum aminotransferase  activities 
       (SGOT and SGPT).
       Urine is very suitable for rapid screening for the presence of 
       a salicylate.  Plasma (or serum) is the specimen of choice for 
       determination of total salicylates using Trinder's reagent 
       ( to be repeated on at least one occasion, 4 - 6 hours 
       after the initial measurement.  HPLC methods are only useful 
       when  toxicokinetic analyses are required; they do not 
       otherwise offer any advantage over the simple and very rapid 
       Trinder's method.
     2.4 First aid measures and management principles
       Prevention of further absorption by inducingesis and/or 
       gastric lavage.  Salicylates delay gastric emptying, and 
       gastric lavage may therefore be useful up to 12, and possibly 
       24, hours after the ingestion of a large salicylate overdose.
       Enhancement of elimination using repeat-dose activated 
       Correction of dehydration, hypokalaemia and acidosis.
       Urinary alkalinization and, when indicated, haemodialysis or 
       charcoal haemoperfusion.
     3.1 Origin of the substance
       Usually prepared by acetylation of salicylic acid with acetic 
       anhydride, using a small amount of sulphuric acid as catalyst.
     3.2 Chemical structure


                  2-acetoxy-benzoic acid
       Molecular weight 180.15
     3.3 Physical properties
       3.3.1 Properties of the substance
             Colourless or white crystals or white crystaline 
             powder or granules; odourless or almost 
             odourless with a slight acid taste. Melting 

             point about 143o. Soluble 1 in 300 of water, 1 
             in 5 - 7 in alcohol, 1 in 17 of chloroform and 1 
             in 20 of ether; soluble in solutions of acetates 
             and citrates and, with decomposition, in 
             solutions of alkali hydroxides and carbonates. A 
             solution in water is acid to methyl red.
             Incompatible with free acids, acetanilide, 
             aminopyrine, phenazone,  hexamine, iron salts, 
             phenobarbitone sodium, quinine salts, potassium 
             and sodium iodides, and alkali hydroxides, 
             carbonates, and stearates.
             Acetylsalicylic acid is stable in dry air, but 
             gradually hydrolyses in contact with moisture to 
             acetic and salicylic acids. In solution with 
             alkalis, the hydrolysis proceeds rapidly and the 
             clear solutions formed may consist entirely of 
             acetate and salicylate.
             Acetylsalicylic acid decomposes rapidly in 
             solutions of ammonium acetate or of the acetates,
             carbonates, citrates or hydroxides of the 
             alkali metals (Reynolds, 1989).
       3.3.2 Properties of the locally available formulation
             To be completed by the PCC.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Shelf-life is highly dependent on the manner of storage. 
             It is recommended that the active ingredient is tested 
             on a yearly basis using the principles outlined in the 
             relevant monograph of the European Pharmacopoeia. When 
             all the appropriate tests have been undertaken with 
             satisfactory results and when the active ingredient is 
             stored in the manner recommended by monograph, extension 
             of the period of storage for a further year may be 
       3.4.2 Shelf-life of the locally available formulation
             To be completed by the PCCTo be completed by the PCC
       3.4.3 Storage conditions
             Store in air-tight containers.
       3.4.4 Bioavailability
             After oral administration, 80 - 100% will be absorbed in 
             the stomach and in the small intestine. However, 
             bioavailability is lower because partialhydrolysis 
             occurs during absorption and there is a "first-pass" 
             effect in the liver.
             The non-protein bound fraction of salicylate increases 
             with the total plasma concentration, and the binding 
             capacity of albumin is partially saturated at 
             therapeutic concentrations of salicylate (Borga et al., 

             1976). The greater proportion of unbound drug found at 
             high concentrations will mean that greater toxicity will 
             result than would be expected from the total salicylate 
             concentration (Alvan et al., 1981).
             Absorption after rectal administration is slow and 
             unpredictable.  Timed-release preparations are 
             therapeutically of limited value because of the 
             prolonged half-life of elimination of salicylate.
             Absorption of enteric-coated tablets is sometimes 
       3.4.5 Specific properties and composition
             To be completed by the PCC.
    4. USES
     4.1 Indications
       As an analgesic for the treatment of mild to moderate pain, 
       as an anti-inflammatory agent for the treatment of soft tissue and 
       joint inflammation, and as an antipyretic drug.
       In low doses salicylate is used for the prevention of 
     4.2 Therapeutic dosage
       4.2.1 Adults
             (Informatorium Medicamentorum, 1990)
             Oral (Na- or Ca- or lysine acetylsalicylate):
             Indication: pain and fever: 300-1000 mg every 4 h; max 4 
             g a day.
             Indication: acute polyarthritis rheumatica: 1 g 6 times 
             a day; max 8 g a day.
             Indication: rheumatoid arthritis: 0.5-1 g 6 times a day; 
             max 8 g a day.
             Compounds with controlled release: 1 g 2-3 times a day, 
             if necessary 6 times a day.
             Indication: to prevent transient ischaemic attacks and 
             to prevent arterial thrombosis: 300-1200 mg a day in 2-3 
             Indication: pain and fever: 500-1000 mg every 6 h; max 4 
             g a day.
             Indication: rheumatoid arthritis: 0.5-1 g, 6 times a 
             day; max 8 g a day.
             Intramuscular or intravenous (lysine 
             acetylsalicylate):500 mg, 1-4 times a day.
       4.2.2 Children
             CAUTION see 9.4.14
             Oral (Na- or Ca- or lysine acetylsalicylate):

             Indication: pain and fever: the use of acetylsalicylic 
             acid in young children for these indications is no 
             longer advocated because of the risk of Reyes Syndrome.
             Indication: acute polyarthritis rheumatica: to start 
             with 100-15 mg/kg a day; after one week 60 mg/kg a day.
             Indication juvenile arthritis: children up to 25 kg, 60-
             90 mg/kg a day; children over 25 kg, 2.4-3.6 g a day.
             Indication: pain and fever:
             Age < 2 years, 20 mg/kg, max 2 times a day
             Age > 2 years, 20 mg/kg, max 3 times a day
             Intramuscular, intravenous (lysine acetylsalicylate): 5-
             25 mg/kg a day.
     4.3 Contraindications
       Active peptic ulcer
       Febrile/post-febrile illness in children
       Haemostatic disorders, including anticoagulant and 
       thrombolytic treatment
       Asthma induced by acetylsalicylic acid or other non-steroidal 
       anti-inflammatory drugs. 
       Caution is indicated in patients with:
            a history of peptic ulceration or gastro-intestinal 
            hepatic or renal insufficiency
            children < 2 years, especially in those who are 
       (Informatorium Medicamentorum, 1990)
     5.1 Oral
       Ingestion of acetylsalicylic acid tablets is the most frequent 
       cause of salicylate poisoning; in neonates, infants and 
       children other less common causes include application of 
       teething gels to gums (Paynter & Alexander, 1979), placental 
       transfer (Ahlfors et al, 1982; Lynd et al, 1974) and breast-
       milk (Clark & Wilson, 1981).
       Methyl salicylate is particularly toxic because of rapid 
       absorption and 1 teaspoonful (5 ml) contains the equivalent of 
       6.9 g acetylsalicylic acid (Johnson & Welch, 1984); methyl 
       salicylate intoxication has also been reported following its 
       use as candy flavouring (Howrie et al, 1985).
     5.2 Inhalation
       Maximum permissible atmospheric concentration 5 mg per m3 
       (Reynolds, 1989).

     5.3 Dermal
       The quantity absorbed after 10 hours dermal application of 
       salicylated vaseline under occlusive dressing was more than 
       60% (Taylor & Halprin, 1975). Salicylate poisoning has been 
       reported after application of salicylate ointment to burns 
       (Pluskwa et al, 1984) and other dermatological disturbances 
       (Editorial, 1964; Treguerer et al, 1980).
       Percutaneous absorption of methyl salicylate ('oil of 
       wintergreen') may also cause toxicity (Davies et al, 1979).
     5.4 Eye
     5.5 Parenteral
       Lysine acetylsalicylate is the conventional means of 
       administering salicylate by this route; acetylsalicylic acid 
       has also been used as an admixture with other drugs given 
     5.6 Other
       Rectal administration of salicylic acid suppositories may be 
       necessary in infants or when oral dosing is either not 
       possible or is contraindicated.
     6.1 Absorption by route of exposure
       Salicylic acid is a weak acid (pKa 3); following oral 
       administration, almost all salicylate is found in the 
       unionized form in the stomach.  Acetylsalicylic acid is poorly 
       soluble in the acid media of the stomach and precipitates may 
       coalesce to form concretions, thereby delaying absorption for 
       8 to 24 hours. Despite the higher pH of the small bowel, the 
       larger surface area allows absorption of salicylate, and this 
       occurs rapidly at therapeutic doses. However, absorption 
       following overdose commonly occurs more slowly, and blood 
       concentrations can continue to rise for up to 24 h after 
       ingestion (Ferguson & Boutros, 1970; Kaufman & Dubanksy, 1972; 
       Levy, 1978).  Absorption of salicylate will be further delayed 
       if an enteric-coated preparation has been ingested (Wortzmann 
       & Grunfeld, 1987).
     6.2 Distribution by route of exposure
       About 50 - 80% of salicylate in the blood is bound by protein 
       while the rest remain in the active, ionized state; protein 
       binding is concentration-dependent. Saturation of binding 
       sites leads to more free salicylate and increased toxicity.
       The volume of distribution is 0.1-0.2 l/kg. Acidosis increases 
       the volume of distribution because of enhancement of tissue 
       penetration of salicylates (Levy & Tsuchiya, 1972).
     6.3 Biological half-life by route of exposure
       Acetylsalicylic acid is hydrolyzed in the stomach and in blood 
       to salicylic acid and acetic acid; the biological half-life is 
       therefore only 20 minutes.
       The plasma salicylate half-life following therapeutic doses is 
       2 to 4.5 h, but in overdose increases to 18 to 36 h (Done, 

     6.4 Metabolism
       Approximately 80% of small doses of salicylic acid is 
       metabolised in the liver. Conjugation with glycine forms 
       salicyluric acid and with glucuronic acid forms salicyl acyl 
       and phenolic glucuronide. These metabolic pathways have only a 
       limited capacity. Small amounts of salicylic acid are also 
       hydroxylated to gentisic acid.  With large salicylate doses 
       the kinetics switch from first order to zero order (Michaelis-
       Menten kinetics) (Levy & Tsuchiya, 1972).
     6.5 Elimination by route of exposure
       Salicylates are excreted mainly by the kidney as salicyluric 
       acid (75%), free salicylic acid (10%), salicylic phenol (10%) 
       and acyl (5%) glucuronides, and gentisic acid (< 1%). When 
       small doses (less than 250 mg in an adult) are ingested, all 
       pathways proceed by first order kinetics, with an elimination 
       half-life of about 2-3 hours (Hartwig-Otto, 1983). When higher 
       doses of salicylate are ingested (more than 4 g), the half-
       life becomes longer (15-30 hours) because the 
       biotransformation pathways concerned with the formation of 
       salicyluric acid and salicyl phenolic glucuronide become 
       Renal excretion of salicylic acid becomes increasingly 
       important as the metabolic pathways become saturated, because 
       it is extremely sensitive to changes in urinary pH above pH 6. 
       The use of urinary alkalinization exploits this particular 
       aspect of salicylate elimination.
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Nausea and vomiting occur as a result of stimulation of 
             mucosal receptors by gastric irritation and stimulation 
             of receptors accessible from the cerebrospinal fluid, 
             probably in the medullary chemoreceptor ("chemoreceptor 
             trigger zone").
             Marked hyperventilation occurs as a result of direct 
             stimulation of the respiratory centre. Indirect 
             stimulation of respiration is caused by increased 
             production of CO2 as a result of salicylate-induced 
             uncoupling of oxidative phosphorylation.  A respiratory 
             alkalosis develops as a result of the direct and 
             indirect stimulation of the respiratory centre.  In an 
             attempt to compensate, bicarbonate, accompanied by 
             sodium, potassium and water, is excreted in the urine.  
             Dehydration and hypokalcaemia result but, more 
             importantly, the loss of bicarbonate diminishes the 
             buffering capacity of the body and allows the 
             development of a metabolic acidosis (see below).
             The pyretic effect of toxic doses of salicylate is a 
             direct result of the uncoupling of oxidative 
             phosphorylation, and the sweating that results further 
             contributes to dehydration.

             High doses of salicylates have additional toxic effects 
             on the central nervous system consisting of stimulation 
             (including convulsions) followed by depression, 
             confusion, dizziness, asterixis, delirium, psychosis, 
             stupor and coma (Anderson et al. 1976; Anderson et al, 
             Very high doses of salicylate have a depressant effect 
             on the medulla and may cause central respiratory 
             paralysis as well as sudden circulatory collapse 
             secondary to vasomotor depression.
             The loss of buffering capacity (see above), and the 
             effects of salicylate on carbohydrate, lipid and protein 
             metabolism lead to the development of a metabolic 
             acidosis, or more commonly in practice, a mixed acid-
             base disturbance.  Competitive inhibition  of NAD+-
             dependent dehydrogenases in the citric acid cycle will 
             lead to the accumulation of acid intermediates.  
             (Grisolia et al, 1969).  Salicylate enhances the entry 
             and oxidation of fatty acids in liver cells, leading to 
             increased ketogenesis, and will also inhibit amino acid 
             incorporation into protein (Smith & Dawkins, 1971) 
             causing amino-acidaemia.  In the presence of an acidosis,
              entry of salicylate ion into cells is promoted, and the 
             metabolic effects exacerbated.
             Both hypo-and hyperglycaemia occur in salicylate 
             poisoning, the former most probably being due to 
             increased tissue demand for glucose oxidation due to 
             uncoupling of oxidative phosphorylation; neuroglycopenia 
             can occur in the presence of normal blood sugar 
             concentrations (Thurston et al, 1970).  If hepatic 
             glycogen stores are adequate, catecholamine production 
             stimulates glycogenolysis leading to hyperglycaemia 
             which may persist for several days (Cotton & Fahlberg, 
             1964; Mortimer & Lepow, 1962); raised plasma 
             corticosteroid concentrations probably augment this 
             Salicylate intoxication is often accompanied by 
             hypoprothrombinaemia due to a warfarin-like action of 
             salicylate on the vitamin K1-epoxide cycle, though this 
             rarely causes clinical problems (Bell, 1978).
       7.1.2 Pharmacodynamics
             The salicylates alleviate pain by virtue of both a 
             peripheral and a central nervous system effect. 
             Salicylates, by inhibiting the synthesis 
             ofprostaglandins that occur in inflamed tissues, prevent 
             the sensitization of pain receptors to mechanical 
             stimulation or to chemicals, such as bradykinin, that 
             appear to mediate the pain response. Direct effects on 
             the central nervous system have been described and 
             suggest a hypothalamic site for the analgesic as well as 
             the antipyretic effects (Woodbury & Fingl, 1975).
             Acetylsalicylate decreases platelet adhesiveness for the 
             life-time of the platelet (Brantmark et al. 1981).

     7.2 Toxicity
       7.2.1 Human data
                     Mild to moderate toxicity     150-300 mg/kg
                     Serious toxicity              300-500 mg/kg
                     Potentially lethal            > 500 mg/kg
                     (Temple, 1981)
                     In a child, ingestion of 240 mg/kg will cause 
                     moderately severe poisoning, but deaths rarely 
                     occur when less than 480 mg/kg has been taken 
                     (Done, 1978).
                     Salicylate poisoning in small children (< 4 
                     years) is often more serious than in older 
                     children because of the early development of a 
                     metabolic acidosis rather than a respiratory 
                     alkalosis (Winters et al. 1959).
       7.2.2 Relevant animal data
             None relevant.
       7.2.3 Relevant in vitro data
             None relevant.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       In an embryo culture system, malformations were observed at 
       plasma salicylate concentrations approaching those after 
       single doses of salicylate (Greenaway et al., 1984).
       Reputedly, the rat is sensitive to the teratogenic effects of 
       salicylates, whereas humans and non-human primates are 
       regarded as being resistant (Shepard, 1983; Wilson et al., 
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Potentiating effects
       Aspirin potentiates the ulcerogenic effects of caffeine, 
       indomethacin and phenybutazone (Goodman & Gilman, 1990).  
       Acetylsalicylic acid is also reported to potentiate the 
       effects of warfarin and other anticoagulants of the coumarin 
       type.  Phenothiazines, and chlorpromazine in particular, are 
       potentiated by salicylates (Huang & Hirano, 1967).
       Acetylsalicylic acid is highly protein-bound and may increase 
       the unbound or free drug concentrations of other drugs, for 
       instance hypoglycaemic drugs will be displaced from the bound 
       state (Hecht & Goldner, 1959) and cases of hypoglycaemic coma 
       have been reported (Bergman, 1965; Peaston & finnegan, 1965).  
       Aspirin displaces methotrexate from protein binding sites and 
       increases tissue concentrations, reaching toxic levels rapidly 
       because the therapeutic index of methorexate is very low 
       (Baker, 1970).

       Antagonistic effects
       The uricosuric activity of phenylbutazone, probenecid and 
       sulfinpyrazone is strongly antagonized and may be completely 
       abolished by aspirin even after small doses (Yu et al., 1963; 
       Pascale et al., 1955; and Oyer et al., 1966).
       The mineralocorticoid blocking properties of spironolactone 
       are inhibited (Tweedale & Oglivie, 1971).
       In a report of two cases of severe salicylate poisoning, 
       asystole occured shortly after the intravenous administration 
       of diazepam (Berk & Andersen, 1989).
     7.7 Main adverse effects
       The most common adverse effects seen following therapeutic 
       doses of acetylsalicylic acid are gastrointestinal in origin, 
       including nausea, epigastric discomfort and vomiting. 
       Irritation of the gastric mucosa with erosion, ulceration, 
       haematemesis and melaena may occur; occult blood loss may 
       occur in about 70% of patients unaccompanied by dyspepsia. 
       Slight blood loss whilst not usually of clinical significance, 
       may result in iron deficiency anaemia.
       Some individuals, especially asthmatics, exhibit sensitivity 
       to acetylsalicylic acid. Urticaria, angioneurotic oedema, 
       rhinitis and severe, even fatal, paroxysmal bronchospasm and 
       dyspnoea may occur (Reynolds, 1989).
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
    Toxicological analyses
                     Screen residues or suspected materials, plasma, 
                     urine and stomach contents.  Avoid sodium azide 
    Biomedical analyses
    Arterial blood gas analysis
    Haematological analyses
    Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
    Toxicological analyses
                     Keep biological samples in a refrigerator prior 
                     to analysis.
    Biomedical analyses
    Arterial blood gas analysis
    Haematological analyses
    Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
    Toxicological analyses
                     No special conditions.
    Biomedical analyses
    Arterial blood gas analysis
    Haematological analyses
    Other (unspecified) analyses

     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
    Simple Qualitative Test(s)
                     For detection of salicylate ion:
                     Acetylsalicylate ion is not present in 
                     plasma/serum and urine; in plasma, 
                     acetylsalicylate ion is only present when 
                     fluoride is added to the blood sample.
                     (1)  Principle of test: Direct colour reaction 
                     on urine. Serum residues and stomach contents 
                     require preliminary acid hydrolysis to 
                     (2)  Sampling: 2 ml of urine and small portion 
                     of suspected material (+/-200 mg).
                     (3)  Chemicals and reagents:
                          Mercuric chloride (Hg(II)Cl2)
                          Ferric nitrate 9 aq (Fe(NO3)3).9 H2O)
                          Hydrochloric acid 1 mol/L and 0.1 mol/L
                          Sodium hydroxide 0.1 mol/L
                          Sodium salicylate p.a.
                          Acetylsalicylic acid p.a.
                          Trinder's Reagent: Dissolve 40 g of 
                     Hg(II)Cl2 in 850 ml of  hot water.  After 
                     cooling down add 120 ml of HCl 1 mol/L and 40 g 
                     of hydrated ferric nitrate. When the ferric 
                     nitrate has been dissolved, add water to 1000 
                     (4)  Equipment:
                          No special equipment needed
                     (5)  Sample preparation:
                          Stomach contents and serum residues
                          1.   Boil a portion of the specimen with 2 
                     ml of hydrochloric acid 0.1 mol/L for 10 
                          2.   Cool and filter if necessary.
                          3.   Neutralise with sodium hydroxide 0.1 
                     (6)  Procedure
                          1. Add 100 uL Trinder's Reagent to 1 ml of 
                     urine and mix.
                          2. A violet colour indicates the presence 
                     of salicylates.

                          Stomach contents and serum residues
                          1. Add 100 uL of Trinder's Reagent to the 
                     clear neutralized solution obtained under (5) 
                     "Sample preparation".
                          2. A violet colour indicates the presence 
                     of salicylate.
                     (7)  Calibration procedure
                          Not applicable
                     (8)  Quality control
                          Quality control can be achieved by running 
                     spiked samples as a comparison.
                     (9)  Specificity
                          Azide preservatives interfere strongly. 
                     High concentrations of urinary ketone bodies may 
                     give weak false positives.
                          Salicylamide, p-aminosalicylic acid and 4-
                     aminoantipyrin also react.
                          Acetylsalicylic acid and methylsalicylic 
                     acid only react after preliminary acid 
                     (10) Detection limit
                          Approximately 20 mg salicylate/L urine.
                     (11) Analytical assessment
                          A positive result may indicate the presence 
                     of a salicylate.
                     (12) Medical interpretation
                          A positive result indicates the possibility 
                     of salicylate poisoning.
    Advanced Qualitative Confirmation Test(s)
                     Acetylsalicylic acid is only present in stomach 
                     contents and serum residues.  Confirmation may 
                     be obtained by TLC (DFG, Report VII, 1987) or 
                     GLC (DFG, Report II, 1985); the same applies to 
                     the salicylate ion.
    Simple Quantitative Method(s)
                     ..... to be completed
    Advanced Quantitative Method(s)
                     ..... to be completed
       8.2.2 Tests for biological specimens
    Simple Qualitative Test(s)
                     (1)  Principle:
                          Measurement of red-violet complex of ferric 
                          and salicylate ions at 530 or 546 nm
                     (2)  Sampling:
                          Plasma or serum.

                     (3)  Chemicals and reagents:
                          As for -(3).
                          Salicylate stock solution 2000 mg/L:
                          Dissolve 580 mg of sodium salicylate in 250 
                          ml of distilled water.
                          Salicylate calibration samples:
                          Dilute appropriate volumes of the stock 
                          solution with distilled water to salicylate 
                          concentrations of 100, 200, 300, 400 and 500 
                     (4)  Equipment:
                          Pipettes, glass tubes, cuvettes, centrifuge 
                     and (spectro)photometer.
                     (5)  Sample preparation:
                          Not applicable.
                     (6)  Procedure:
                          1.   Pipette into glass tube:
                                         Blank     Sample    
                     Calibration points
                     Plasma (serum)      -         0.5 ml    -
                     Calibration points  -         -         0.5 ml
                     (100-500 mg/l)
                     Distilled water     0.5 ml    -         -
                     Trinder's Reagent   2 ml      2 ml      2 ml
                          2.   Mix by vortexing for 30 seconds, 
                     centrifuge and measure the extinction of the 
                     clear supernatant at 530 or 546 nm against the 
                     (7)  Calibration procedure:
                          A calibration curve is constructed by 
                     plotting the  concentration of the calibration 
                     samples (100-500 mg/L) against the measured 
                     extinction. From this curve the concentration in 
                     the sample is read.
                     (8)  Quality control:
                          The use of a plasma (serum) sample with a 
                     known concentration is advised. This specimen 
                     can be obtained commercially or made by 
                     appropriate spiking of pre-tested blank plasma 
                     (9)  Specificity:
                          As for -(9).

                     (10) Detection limit:
                          The limit of detection of the method is 70 
                     mg salicylate/L plasma(serum) using a 0.5 ml 
                     sample size.
                     (11) Analytical assessment:
                          If no interfering substances are present 
                     and if the procedure has been followed, an 
                     accurate measurement of total salicylates 
                     content will be made.
                     (12) Medical assessment:
                          The total salicylate plasma (serum) 
                     concentration and the expected severity of 
                     intoxication should be related to the interval 
                     that has elapsed between sampling and ingestion.
                          (a)  Time interval 6 hours: Salicylate  
                      <400 mg/L: usually
                               Salicylate 400-800 mg/L: mild to 
                     moderate toxicity
                               Salicylate >800 mg/L: severe toxicity
                          (b)  Time interval 12 hours:
                               Salicylate <300 mg/L: usually 
                               Salicylate 300-600 mg/L: mild to 
                     moderate toxicity
                               Salicylate >600 mg/L: severe toxicity
                          (c)  Time interval 24 hours:
                               Salicylate <200 mg/L: usually 
                               Salicylate 200-500 mg/L: mild to 
                     moderate toxicity
                               Salicylate >500 mg/L: severe toxicity
    Advanced Qualitative Confirmation Test(s)
    Simple Quantitative Method(s)
                     In plasma (serum) or urine only salicylate can 
                     be determined.
                     Acetylsalicylic acid can only be quantitated in 
                     plasma when  sufficient sodium fluoride has been 
                     added to the blood collection tube.  Any HPLC 
                     method described in the literature is suitable.
    Advanced Quantitative Method(s)
    Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation

       8.3.1 Biochemical analysis
    Blood, plasma or serum
                     Tests of platelet function and coagulation to 
                     determine/exclude presence of: inhibition of 
                     platelet aggregation and  hypoprothrombinaemia.
    Other fluids
       8.3.2 Arterial blood gas analyses
             In adults an initial respiratory alkalosis is followed 
             in severe salicylate poisoning by metabolic acidosis; 
             typically the acid-base disturbance is mixed in nature.
             Young children tend to develop a metabolic acidosis but, 
             by the age of 12 years, the usual adult picture of a 
             mixed respiratory alkalosis and metabolic acidosis is 
       8.3.3 Haematological analyses
             Electrolytes and urea to determine/exclude presence of: 
             hypernatraemia due to water loss (sweating, vomiting, 
             osmotic diuresis) and hypokalaemia due to renal and 
             extrarenal factors.
             Blood sugar level to determine/exclude presence of: 
             hypoglycaemia or hyperglycaemia.
             Urinary pH (typically alkaline in the early stages of 
             salicylate overdose and then subsequently becomes acid).
       8.3.4 Interpretation of biomedical investigations
             Not relevant.
     8.4 Other biomedical (diagnostic) investigations and their 
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
       The plasma salicylate concentration should be determined on 
       admission, provided that more than 4 to 6 hours have elapsed 
       from the time of ingestion of the overdose because 
       measurements made before this time are difficult to interpret. 
        In addition, it is important to repeat the measurement to 
       make sure that the salicylate concentration is not continuing 
       to rise because of continued absorption (Vale et al, 1985).
       In adults, plasma concentrations 6 hours after an overdose: 
       300-500 mg/l:  mild toxicity
       500-750 mg/l:  moderate toxicity
       > 750 mg/l:    severe toxicity               (Proudfoot, 
       The presence or absence of symptoms and signs and the type of 
       acid-base disturbance should be considered when interpreting 
       the plasma salicylate concentration and deciding upon 
       management (Meredith & Vale, 1986).
       The DONE-nomogram (fig.) categorizes the severity of poisoning 
       for single ingestions based on peak salicylate concentrations. 
       In patients with a significant acidosis and in patients who 

       ingest multiple doses or sustained release preparations, the 
       DONE-nomogram will tend to underestimate the severity of 
       intoxication (Todd et al., 1981).
       The validity of the DONE-monograph was evaluated in 54 cases 
       by Dugandzic et al. (1989).  The predictive index for the 
       moderate and severe classifications were poor.  Development of 
       the nomogram was based on the assumption that salicylates are 
       eliminated by a first order process, whereas in fact they are  
       partially eliminated through saturable processes.  This may 
       lead to overprediction of severity.  For this reason the DONE-
       monograph is not commonly used.
       After ingestion of enteric coated tablets, plasma salicylate 
       concentrations on admission are unreliable guides to the 
       severity of poisoning.  Salicylate levels may not peak until 
       more than 12 hours after such an overdose (Todd et al., 1981; 
       Springer & Groll, 1980).
     8.6 References
     9.1 Acute poisoning
       9.1.1 Ingestion
             Early symptoms are nausea, vomiting, epigastric pain and,
              sometimes, haematemesis. Additional characteristic 
             features include hyperventilation,elevated body 
             temperature, irritability and tinnitus. Less commonly, 
             cardiac dysrhythmias may occur because of hypokalaemia, 
             and tetany and paraesthesiae due to low ionised calcium 
             levels. In serious poisoning hallucinations, stupor, 
             convulsions, papilloedema and coma may be observed 
             together with metabolic acidosis; hepatotoxicity may 
             also occur and non-cardiogenic pulmonary oedema is well 
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure
             Severe poisoning has been reported as a result of use of 
             salicylic acid ointment for dermatological problems 
             (Editorial, 1964; Taylor & Halprin, 1975) and in the 
             treatment of skin burns (Pluskwa et al. 1984).
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             Acetylsalicylic acid suppositories can cause rectal 
             irritation; absorption is slow and unpredictable.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Chronic salicylate poisoning occurs as a result of 
             excessive therapeutic administration over a period of 12 
             hours or more (Dove & Jones, 1982) because the metabolic 
             pathways become saturated and salicylic acid is 
             eliminated by zero order kinetics. Plasma salicylate 
             concentrations then increase, producing toxicity. Small 
             children are at particular risk of well-intentioned but 

             over-enthusiastic treatment by their parents. The risk 
             is further increased when the fever, sweating and 
             tachycardia of salicylate intoxication are attributed to 
             the underlying illness and are used as indications for 
             increasing the dose (Proudfoot, 1983). Children may 
             become intoxicated through breast milk (Clark & Wilson, 
             1981), and chronic salicylate poisoning has also been 
             described in the elderly (De Groen, 1989).
             Neurological features in adults occur more frequently 
             with chronic salicylate poisoning than as a result of 
             acute overdose, and may lead to extensive investigations 
             before the correct diagnosis is reached, often late 
             after hospital admission (Anderson et al. 1976). Older 
             patients present with breathlessness, and pulmonary 
             oedema caused by salicylate poisoning can be mistakenly 
             attributed to cardiac or respiratory disease (and vice 
             The mortality from chronic salicylate poisoning in 
             adults is considerably greater than from acute overdose 
             (Anderson et al. 1976).  In children, chronic salicylism 
             is accompanied by a greater morbidity than is acute 
             salicylate poisoning. Hyperventilation, dehydration and 
             severe central nervous system manifestations occur more 
             frequently in those chronically poisoned (Gaudreault et 
             al. 1982).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             The application of teething gels to the gums (Paynter & 
             Alexander, 1979), or percutaneous absorption of 
             salicylic acid from ointments used for such skin 
             disorders as psoriasis or methyl salicylate may cause 
             salicylate poisoning.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Adults seldom lose conciousness and are typically miserable 
       and uncomfortable. If a sufficient quantity of a salicylate 
       has been taken, nausea, vomiting, tinnitus, deafness, sweating,
        vasodilatation and hyperventilation develop.
       Cause of death.
       A review of 51 fatal cases of acute salicylate poisoning in 
       Ontario during 1983 and 1984 disclosed that salicylates was 
       the most common cause of death due to the ingestion of single 
       drugs. Autopsy results showed that 50% of the patients had 
       pulmonary abnormalities, 28% had lesions of the 
       gastrointestinal tract, 18% had nervous system abnormalities 
       and 25.6% had no pathologic changes (McGuigan, 1987).

       Mortality from chronic salicylate intoxication is considerable 
       higher (25%) than from acute overdose (1-2%) (Anderson et al. 
       1976). Death is often due to sudden cardiac arrest or, 
       occasionally, to multiple complications following severe brain 
       damage (Proudfoot, 1983).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Abrupt cardiovascular collapse is a recognized 
             complication of salicylate poisoning (Anderson et al. 
             1976; Benowitz et al. 1979; Beveridge et al. 1964; Pei & 
             Thomson, 1987). Two patients with severe salicylate 
             intoxication developed asystole shortly after 
             intravenous diazepam administration (Berk & Andersen, 
       9.4.2 Respiratory
             Non-cardiogenic pulmonary oedema can occur in salicylate-
             intoxicated patients who are over 30 years of age. 
             Cigarette smoking, chronic salicylate ingestion, 
             metabolic acidosis and the presence of neurological 
             symptoms and signs on admission are strong risk factors 
             for the subsequent development of pulmonary oedema. In 
             the absence of these risk factors, salicylate-induced 
             pulmonary oedema is rare. The exact mechanism is 
             unknown. Three possible explanations include: a direct 
             toxic effect on pulmonary microvasculature by 
             salicylates, interaction with endogenous mediators such 
             as prostaglandins, and a central nervous system mediated 
             effect (Walters et al. 1983; Liebman & Katz, 1981).
       9.4.3 Neurological
                     High doses of salicylates cause stimulation 
                     (irritability, convulsions) followed by 
                     depression of the CNS. Confusion, dizziness, 
                     delirium, psychosis, asterixis, stupor and coma 
                     occur usually when metabolic acidosis is the 
                     dominant acid-base  abnormality (Proudfoot & 
                     Brown, 1969; Gabow et al. 1978; Anderson, 1981). 
                     These features are thought to be due to reduced 
                     ionisation of salicylic acid and a shift of 
                     salicylate from plasma into the brain. Dominant 
                     metabolic acidosis is common in young children 
                     who are therefore more likely to experience 
                     serious intoxication at relatively low plasma 
                     salicylate concentrations (Proudfoot, 1983).
                     Very high doses of salicylate have a depressant 
                     effect on the medulla and may cause central 
                     respiratory paralysis as well as sudden 
                     circulatory collapse secondary to vasomotor 
    Peripheral nervous system
                     No data available.
    Autonomic nervous system
                     No data available.
    Skeletal and smooth muscle
                     No data available.

       9.4.4 Gastrointestinal
             The ingestion of salicylate may result in epigastric 
             discomfort, nausea and vomiting. It may also cause 
             gastric ulceration.  Perforated peptic ulcer occurs 
             extremely rarely (Robins et al. 1985; Christensen & 
             Schmidt, 1987).
       9.4.5 Hepatic
             Hepatotoxicity may occur both after therapeutic use of 
             salicylate or following salicylate overdose (Wolfe et 
             al. 1974). Liver biopsy in such cases reveals acute 
             hepatocellular necrosis with periportal inflammation and 
             fatty changes in hepatocytes.
       9.4.6 Urinary
                     Oliguria is sometimes seen; the most common 
                     cause is dehydration (Temple et al. 1976) but 
                     renal failure may rarely occur in individuals 
                     without pre-existing renal disease, systemic 
                     disease, or volume depletion (Rupp et al. 1983).
                     No data available.
       9.4.7 Endocrine and reproductive systems
             Influence on adrenal medulla:
             High doses of salicylate cause release of adrenaline  
             from the adrenal medulla; this is thought to be partly 
             responsible for the observed hyperglycaemia due to 
             glycogenolysis that sometimes occurs.
             Influence on the adrenal cortex:
             Large doses of salicylate stimulate corticosteroid 
             secretion by the adrenal cortex.
       9.4.8 Dermatological
             Thirteen cases of toxic epidermal necrolysis have been 
             reported associated with the use of either 
             acetylsalicylic acid or methylsalicylate (Lowney et al. 
       9.4.9 Eye, ear, nose, throat: local effects
             Ear: tinnitus and hearing loss caused by salicylate in 
             overdose are due to increased labyrinthine pressure 
             (Waltner, 1955) and/or an effect on the hair cells of 
             the cochlea. There is a relation between the hearing 
             loss and the plasma salicylate concentration (Myers et 
             al. 1965).
             Eye: transient myopia occurred in a patient following 
             ingestion of 2.7 g acetylsalicylic acid (Sandford-Smith, 
             1974). Bilateral subconjunctival haemorrhages have been 
             described (Black & Bensinger, 1982).
       9.4.10 Haematological
              Ingestion of salicylic acid by normal individuals 
              causes prolongation of the bleeding time due to 
              inhibition of collagen glucosyltransferase present in 
              membranes of platelets. As a result, the adherence of 
              platelets to connective tissue or collagen fibres is 

              Salicylate in large therapeutic doses (over 6 g per 
              day) and in overdose reduces the concentration of 
              vitamin K-dependent coagulation factors and in 
              particular that of prothrombin.
       9.4.11 Immunological
              In vitro, acetylsalicylic acid is an efficient 
              suppressor of the lymphocyte-transformation reaction.  
              An association with the mechanism by which it exerts 
              its anti-inflammatory, anti-rheumatic and anti-pyretic 
              effect could be postulated (Teraski et al., 1973; 
              Twomey et al., 1973).  Similar results were observed in 
              rats (Loveday et al., 1973).  In 19 normal volunteers, 
              marked and statistically significant suppression of 
              blastogenesis has been reported (Crout et al., 1975). 
       9.4.12 Metabolic
     Acid-base disturbances
                       In adults there is an initial respiratory 
                       alkalosis which is compensated for by 
                       excretion of bicarbonate in urine. In infants 
                       and children the respiratory alkalosis does 
                       not occur and metabolic acidosis develops 
                       (Proudfoot & Brown, 1969; Winters et al., 
                       1958). In severe salicylate poisoning in 
                       adults, metabolic acidosis may also result 
                       from a number of factors.  Even when present 
                       in high concentrations, salicylate will not 
                       displace more than 2-3 mmol of bicarbonate; 
                       the acidosis is not therefore due to the 
                       presence of salicylic acid itself.  The 
                       principal cause is competitive inhibition of 
                       NAD+-dependent dehydrogenases, including 
                       lactate and oxoglutarate dehydrogenases and of 
                       other oxidative enzymes such as succinate 
                       dehydrogenase (Grisolia et al., 1969; Hines & 
                       Smith, 1964; Koplan et al., 1954).  
                       Consequent impairment of the oxidation of fuel 
                       substrates leads to the accumulation of acid 
                       intermediates, notably lactate and pyruvate.  
                       Acidaemia caused by the effect of salicylate 
                       on carbohydrate metabolism is compounded by 
                       effects on lipid and amino-acid metabolism.  
                       Salicylate enhances entry and oxidation of 
                       fatty acids in liver cells, leading to 
                       increased ketogenesis.  Competitive inhibition 
                       of amino-acyl-tRNA synthetases in pairs and 
                       amino-acid incorporation (Smith & Dawkins, 
                       1971); amino-acidaemia results.
                       Finally, dehydration and vasomotor depression 
                       results in poor renal perfusion and 
                       accumulation of sulphuric and phosphoric acids 
                       (Tenney & Miller, 1955; Winters et al., 1959).

     Fluid and electrolyte disturbances
                       Decreased renal tubular reabsorption of 
                       bicarbonate occurs as a result of respiratory 
                       alkalosis. Increased renal secretion of sodium,
                        potassium and water accompanies loss of 
                       bicarbonate in the urine. Fluid loss also 
                       results from vomiting, sweating and 
                       hyperventilation; dehydration is commonly 
                       associated with hypernatremia.
                       Water losses may be considerable: from 2 - 3 
                       l/m2 surface area in moderate severe poisoning,
                        up to 6 l/m2 in severely poisoned patients 
                       (Temple, 1978).
                       Influence on oxidative phosphorylation.
                       The uncoupling of oxidative phosphorylation by 
                       salicylate results in the inhibition of a 
                       number of ATP-dependent reactions and:
                            an increase in O2 uptake and CO2 
                            depletion of hepatic glycogen; with
                            the energy normally used for the 
                       conversion of inorganic phosphate to ATP being 
                       dissipated as heat, hence the pyretic effect 
                       of toxic doses of salicylate.
                       Influence on carbohydrate metabolism.
                       Multiple factors appear to be involved.  Hyper-
                        or hypoglycaemia may result from the 
                       mechanisms listed above at A. (see 9.4., 
                       Influence on nitrogen metabolism.
                       Salicylate in toxic doses causes a significant 
                       negative nitrogen balance, characterized by 
                       amino-aciduria, though this is due in part to 
                       inhibition of active tubular absorption 
                       because of reduced ATP formation.
                       Influence on fat metabolism.
                       Increased entry and enhanced oxidation of 
                       fatty acids in muscle, liver and other tissues 
                       occur, together with a lowering of 
                       concentrations of plasma free fatty acids, 
                       phospholipid and cholesterol (Woodbury & Fingl,
       9.4.13 Allergic reactions
              Some persons, particularly asthmatics, exhibit marked 
              sensitivity to acetylsalicylic acid which provokes 
              various reactions including urticaria and other skin 
              eruptions, angioneurotic oedema, rhinitis and severe, 
              even fatal, paroxysmal bronchospasm and dyspnoea, 
              hypotension, shock and syncope (Reynolds, 1989).

       9.4.14 Other clinical effects
              The relationship between the use of acetylsalicylic 
              acid and Reye's syndrome (Reye et al., 1963) remains 
              controversial. Reye's syndrome is a disease with a high 
              mortality characterized by encephalopathy and fatty 
              degeneration of the viscera, especially the liver.
              Similar findings were noted (Starko & Mullick, 1983) in 
              the histology and necropsy records of 13 children with 
              accidental or iatrogenic salicylate intoxication. 
              The clinical features most often observed are severe 
              vomiting followed by increasing drowsiness and coma. 
              Transaminase activities and ammonia levels in the blood 
              become elevated but jaundice does not occur. In severe 
              cases, hypoglycaemia and hypoprothrombinaemia develop. 
              Reye's syndrome may be seen in children and adolescents,
               the peak incidence being between 5-15 years.  Often 
              varicella or influenza precede the development of the 
              syndrome (Sullivan-Bolyai & Corey, 1981), but some 
              cases reported have been in children with chronic 
              inflammatory disorders such as juvenile rheumatoid 
              arthritis or lupus erythematosis (Young et al., 1984; 
              Hansen et al., 1985).
              A possible pointer to a causal relationship between 
              acetylsalicylic acid use and Reye's syndrome is the 
              declining incidence in the USA that has occurred 
              following a  reduction in use of acetylsalicylic acid 
              during the period 1980-1987 (Remington et al., 1986; 
              Banco, 1987); for this reason, the use of the drug in 
              young children in the UK is now restricted (Notes and 
              News, 1986).
       9.4.15 Special risks
              Salicylate intoxication may occur through placental 
              transfer (Ahlfors et al., 1982; Lynd et al., 1976) and 
              breast milk (Clarke & Wilson, 1981).
     9.5 Other
       No data available.
     9.6 Summary
      10.1 General principles
         Treatment of acute salicylate poisoning is directed 
         primarily towards prevention of absorption, correction of 
         acid-base and fluid and electrolyte balance; and in patients 
         with features of moderate or severe intoxication, towards 
         enhancing elimination of the drug. Respiratory alkalosis 
         needs no specific treatment, but severe acidosis requires at 
         least partial correction with bicarbonate. Bicarbonate 
         should be administered carefully because hypokalaemia may be 
         aggravated and, if large quantities are administered, the 
         sodium and water load may precipitate pulmonary oedema. 
         Sedatives and respiratory depressant drugs must be avoided. 
         Tetany may be corrected with the use of calcium gluconate 
         (10 ml of a 10% solution, intravenously) (Merdith & Vale, 

         If it is thought that an enteric-coated or other slow-
         release salicylic acid preparation has been taken, then the 
         patient must be kept under observation for at least twenty-
         four hours; abdominal ultrasonoscopy may help to identify 
         concentrations or retained enteric-coated tablets.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                See section 8.
         10.2.2 Biomedical analysis
                Hypokalaemia is usual. Hypoglycaemia can be a feature 
                of salicylate intoxication, it is more common in 
                children than in adults and is often severe. 
                Hyperglycaemia may also occur and persist for several 
                days (Cotton & Fahlberg, 1964; Mortimer & Lepow, 
         10.2.3 Toxicological analysis
                See section 8.
         10.2.4 Other investigations
                No data available.
      10.3 Life supportive procedures and symptomatic/specific 
         If non-cardiogenic pulmonary oedema is present, mechanical 
         ventilation with positive end-expiratory pressure (PEEP) may 
         be indicated
         Fluid and electrolyte replacement is important with special 
         attention being paid to potassium depletion;
         ECG monitoring may be indicated
         Correction of metabolic acidosis by sodium bicarbonate 
         Sponging for hyperpyrexia.
      10.4 Decontamination
         In those cases where vomiting has not already occurred 
         further absorption of the drug may be prevented by inducing 
         emesis and/or undertaking gastric lavage, as appropriate.
         Acetylsalicylic acid is poorly soluble in an acid 
         environment and may coalesce to form a mass or coating in 
         the stomach, from which absorption may continue slowly over 
         many hours. Thus gastric lavage may be indicated more than 
         12 hours following ingestion of the overdose.
         Although activated charcoal proved to be equally effective 
         as emesis and gastric lavage in volunteers (Danel & Henry, 
         1988), it may only be exploited therapeutically if the 
         patient presents soon after the overdose and is not vomiting 
         - which is unlikely in those who are at least moderately 
         severely poisoned. Moreover substantial quantities of 
         activated charcoal (50-100 g) need to be administered if 
         significant absorption is to be prevented.  Repeated doses 
         of activated charcoal (50-75 g immediately and 50 g 4-
         hourly) will increase the non-renal elimination of 
         salicylate and will greatly diminish the plasma half-life 
         (Hillman & Prescott, 1985; Boldy & Vale, 1986).

         The administration of activated charcoal may be of 
         particular value in those adults who have ingested 
         substantial quantities of an enteric-coated or sustained-
         release preparation of acetylsalicylic acid, and it has been 
         employed in repeated doses to increase the non-renal 
         elimination of acetylsalicylic acid (Meredith & Vale, 1986).
         The addition of sodium sulphate (as a saline cathartic 
         agent) to activated charcoal was not found to have any 
         additional effect on the prevention of acetylsalicylic acid 
         absorption in six healthy volunteers (Sketris et al. 1982).
      10.5 Elimination
         Whilst (forced) alkaline diuresis has been employed in the 
         management of salicylate poisoning for the last two decades 
         (Berg, 1977; Cumming et al. 1964; Dukes et al., 1963; Lawson 
         et al., 1969) fluid retention may occur during forced 
         diuresis, and increase the risk of pulmonary oedema in 
         severely intoxicated patients (Proudfoot & Brown, 1969; 
         Heffner & Sahn, 1981).  It is now recognized that the urine 
         pH is of far greater importance than the volume of urine 
         excreted (Meredith & Vale, 1981; Prescott et al., 1982). To 
         achieve maximum excretion of salicylate a urine pH of 7.5 or 
         higher is indicated (careful monitoring of urine pH is 
         Urinary alkalinization requires close supervision in an 
         intensive care area.  It is sometimes difficult to 
         alkalinize the urine so that maximum excretion is achieved 
         without creating a potentially dangerous alkalaemia (Done, 
         1978), but in these cases adequate potassium repletion will 
         normally allow urinary alkalinization.  In patients with 
         cardiac and/or renal impairment, and in those who are in 
         shock, dialysis should be considered (Meredith & Vale, 
         Haemodialysis should be considered in severely poisoned 
         patients with features of central nervous system toxicity, 
         pulmonary oedema, renal failure, cerebral oedema and in 
         cases with plasma levels higher than 800 mg/l, haemodialysis 
         should be considered.
         Haemodialysis is preferred to haemoperfusion because it more 
         rapidly corrects acid-base and electrolyte abnormalities and 
         may avoid the need for the administration of large amounts 
         of sodium bicarbonate (Winchester et al. 1981).
         Peritoneal dialysis is less effective than alkaline diuresis,
          is 2 - 3 times less effective than haemodialysis, and its 
         use is not recommended (Winchester et al. 1977).  Similarly, 
         charcoal haemoperfusion is less effective than haemodialysis 
         and again its use is not advocated (Meredith & Vale, 1986).
      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
         Alkalinization of the urine is considerably more effective 
         in promoting salicylate excretion than induced diuresis and 
         the need for the latter requires reappraisal (Prescott et 
         al. 1982). 
         The use of gastroscopic and other measures to break up 
         enteric-coated tablets requires further evaluation.
      11.1 Case reports from literature
      11.2 Internally extracted data on cases
         To be added by the PC.
      11.3 Internal cases
         To be added by the PC using the monograph.
    12. Additional information
      12.1 Availability of antidotes
         No antidotes available.
      12.2 Specific preventive measures
         Flavoured tablets are attractive to children and, to avoid 
         temptation, the use of this type of medication should be 
         The use of child resistant closures, smaller pack sizes and 
         the elimination of attractive coloured products will help to 
         reduce the problem of salicylate poisoning.
         Parents need to be warned of the potential risks of chronic 
         administration of salicylates.
         Physicians should be made aware that chronic salicylate 
         poisoning in hospitalized patients occurs almost as 
         frequently as acute poisoning, and may result in more severe 
     12.3 Other
         No data available.
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    Authors:  Professor A.N.P. van Heijst
              Baarnseweg 42a
              3735 MJ Bosch en Duin
              Tel: 31-30-287178
              Dr A. van Dijk
              Central Hospital Pharmacy
              University Hospital Utrecht
              P.O. Box 85500
              3508 GA Utrecht
              Tel: 31-30-507190
              Fax: 31-30-516756
    Date:     22 June 1990
    Reviewer: Dr T. Meredith
              Department of Health
              Hannibal House Room 913
              Elephant & Castle
              London SE1 6TE
              United Kingdom
              Tel: 44-71-9722449
              Fax: 44-71-7039565
    Date:     12 January 1991
    Peer Review: Newcastle-upon-Tyne, United Kingdom, January 1991

    See Also:
       Toxicological Abbreviations