Summary for UKPID


    Phil Young, BSc (Hons) Msc MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP

    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information



         Generic                  Aspirin
         Proprietary              Caprin (R)
                                  Disprin CV (R)
                                  Nu-Seals Aspirin (R)

         Compound preparations    Co-codaprin
                                  Roboxisal forte

         Aspirin is also available to purchase in many different


         Acetylsalicylic acid
         Salicylic acid, acetate
         Acetosalic acid

    Chemical group/family

         Non-steroidal anti-inflammatory
         BNF 4.7.1

    Reference number1

         CAS 50-78-2


         Available from most generic manufacturers, including;

         A.H. Cox & Co Ltd
         Whiddon Valley
         EX32 8NS

         Tel: 01271-311257.


         Tablets & Dispersible tablets ; 300 mg, 75 mg ; Pack size 100, 20

    Physico-chemical properties 3

         2-acetyloxybenzoic acid

    Molecular weight

    pKa (-COOH)

         in alcohol          1 in 5
         in water            1 in 300

    Hazard / risk classification




    1.   Mild to moderate pain
    2.   Chronic disease accompanied by pain and inflammation
    3.   As an antipyretic for symptomatic use in adults with febrile
    4.   Prophylaxis against arterial occlusive events including stroke
         and myocardial infarction in patients at high risk (unstable
         angina, following myocardial infarction and transient cerebral

    Therapeutic Dosage

         Analgesia, antipyrexia
         Adults    300-900 mg every 4-6 hours (Max. 4 grams daily)
         Children  Not recommended <12 years

         Adults    75-150 mg daily.
         Children  Not recommended <12 years


    Known hypersensitivity to aspirin
    Aspirin should not be used in patients with active gastrointestinal

    Relative contraindications

    A past history of ulceration or dyspepsia
    Avoid use in children under 12 years of age, because of an association
    with Reye's syndrome. However, aspirin may be appropriate in certain
    situations (e.g. Juvenile rheumatoid arthritis)
    Bleeding diathesis (e.g. haemophilia) and concurrent use of
    History of intolerance to aspirin or other non-steroidal anti-
    inflammatory drugs.


    Oral absorption               68%
    Plasma half-life
     range                        15-20 mins
    Time to Peak conc.            25 mins             Soluble
                                  4-6 hours           Enteric-coated
    Volume of distribution        9.6-12.7 L
    Protein binding               80-90%
    Metabolism                    Hepatic

    Special populations


    Prospective studies of aspirin use during pregnancy have involved low
    doses (40-150 mg/day) rather than analgesic doses. Large retrospective
    studies of aspirin (varying doses) use in women during pregnancy have
    failed to demonstrate a teratogenic effect.

    Aspirin should be avoided during the third trimester due to possible
    bleeding complications and premature closure of the ductus arteriosus,
    which may lead to pulmonary vasculature abnormalities and pulmonary
    hypertension in the newborn.5

    In pregnancies at risk for the development of pregnancy-induced
    hypertension and pre-eclampsia, and in fetuses with intra-uterine
    growth retardation, low-dose aspirin (40-150 mg/day) may be

    Use of low dose aspirin may reduce the risk of pre-eclampsia by
    approximately 25%, but study findings have been inconsistent.

    Breast milk

    Salicylate penetrates into breast milk, being present at around 1.5
    times the concentration in blood. The dose to a suckling infant is
    likely to be small from occassional aspirin use by the mother.


    The pharmacokinetic characteristics of salicylate taken in overdosage
    have important implications for the genesis and treatment of


    Salicylates are rapidly and completely absorbed from the jejunum and
    small bowel when administered in aqueous solutions. However, ingestion
    of excessive doses does not always occur in the fasting state, so
    absorption and the attainment of peak plasma salicylate concentrations
    may be delayed by the presence of food in the stomach and by prolonged
    gastric emptying. It has also been suggested that salicylates cause
    pyloric spasm, thus delaying gastric emptying and absorption, but
    variability in the rates of disintegration and dissolution of
    different formulations is probably more important. About 10 per cent
    of adults who ingest overdoses show a rise in plasma salicylate
    concentrations after gastric lavage, almost certainly due to flushing
    salicylate from the stomach into the small bowel thus facilitating

    Absorption of large, potentially lethal doses may be slower than
    therapeutic doses partly due to the inhibitory effect of aspirin on
    gastric emptying and the impaired dispersion of the drug in
    gastrointestinal fluids. In overdose, salicylate levels may rise for
    12 hours or more.1

    When enteric-coated aspirin formulations are taken, the onset of toxic
    features and the attainment of peak plasma concentrations may be
    delayed for 12 or more hours.6

    Salicylates are rapidly hydrolysed by first pass metabolism in the
    intestinal mucosa and liver. Acetylsalicylic acid can only be detected
    in the plasma for a few hours after an overdose while plasma
    concentrations of salicylic acid, the principal product of hydrolysis,
    decline slowly with a half-life of the order of 20 to 30 hours.

    Protein Binding

    Salicylates are extensively bound to two receptor sites on plasma
    albumin, one of which has a high affinity and is saturated at low
    plasma salicylate concentrations while the second has a less marked
    affinity and only contributes significantly as plasma concentrations
    increase. It has been calculated that a total concentration of about
    800 mg/l is required before free and bound salicylate concentrations
    would be equal.7 However, the extent of protein binding is variable
    even between individuals with comparable plasma albumin
    concentrations. In one report, in a 14 year old, free salicylate
    decreased from 60% to 17% as total plasma concentrations fell from 925
    to 83 mg/l.8

    Volume of Distribution

    The volume of distribution of salicylate is reported to be about 10
    litres after therapeutic doses4,9, but may increase with increasing
    plasma concentrations.9

    Metabolism and Excretion

    Therapeutic doses of salicylic acid are mainly eliminated by
    conjugation with glycine and glucuronic acid to form salicyluric acid
    and salicylphenolic and acyl glucuronides, respectively. A small
    proportion is also hydroxylated to gentisic acid. However, overdose
    patients with plasma salicylate concentrations in the range 250-699
    mg/l have been found to eliminate a significantly smaller proportion
    of their salicylate load as salicyluric acid than volunteers taking
    therapeutic doses.10 This has been attributed to saturation of the
    metabolic pathway but recent evidence from acutely poisoned adults
    suggests that glycine depletion may be the explanation.11 Whatever
    the truth, repeated administration of salicylate, particularly in
    children, may lead to accumulation and intoxication within a few days.

    Renal excretion is the most important mechanism for salicylate
    elimination as plasma concentrations rise.

    Kinetics in Children

    Neonates absorb salicylate as rapidly as any other age group but
    metabolise it more slowly than young teenagers because of
    comparatively immature hepatic function. Renal excretion is also
    slower and neonates therefore attain higher plasma concentrations.
    Reduced plasma albumin concentrations in this age group may increase
    the volume of distribution, particularly as plasma concentrations

    Kinetics in the Elderly

    Absorption of therapeutic doses of salicylate is not impaired in the
    elderly but the elimination half-life and volume of distribution may
    be significantly increased. These observations may be explained by
    impaired hepatic and renal function despite the normal results of
    conventional laboratory function tests.13

    Adverse effects

    Aspirin in therapeutic doses may induce hypersensitivity, asthma,
    urate kidney stones, chronic gastro-intestinal blood loss, tinnitus,
    nausea, vomiting, and Reyes syndrome.


    Anticoagulants or NSAIDs      increased risk of bleeding
    Methotrexate                  reduced excretion
    Diuretics                     antagonism of spironolactone
                                  reduced excretion acetazolamide
    Corticosteroids               increased risk GI bleeding/ulceration
    Antiepileptics                increased effect of phenytoin and


    Acetylsalicylic acid 300 mg, 75 mg

        Ingested dose             Likely toxicity
        (mg/kg body weight)

         150                      Mild
         250                      Moderate
         500                      Severe - possibly fatal



    Salicylates cause vomiting, tinnitus, deafness, sweating, warm
    extremities with bounding pulses, increased respiratory rate and
    hyperventilation. Some degree of acid-base disturbance is present in
    every case.

    Common acid-base changes

    Adults and children over the age of 4 years:

    A mixed respiratory alkalosis and metabolic acidosis is the rule with
    normal or high arterial pH (normal or reduced hydrogen ion

    Children aged 4 years or less

    A dominant metabolic acidosis with low arterial pH (raised hydrogen
    ion concentration) is common.

    Uncommon features

    Haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, renal
    failure, and non-cardiac pulmonary oedema.

    Central nervous system features are also uncommon and include
    confusion, disorientation, coma and convulsions.

    Assessment of the severity of poisoning

    The severity of poisoning cannot be assessed from plasma salicylate
    concentrations alone, although most adult deaths occur in patients
    whose concentrations exceed 700 mg/L (5.1 mmol/L). The mortality is
    about 5% in this group.

    Late presentation, age over 70 years, hyperpyrexia and pulmonary
    oedema are more common in those who die.

    Neurological features, acidosis and high salicylate concentrations
    indicate severe poisoning.


    1.   Consider gastric lavage if more than 120 mg/kg body weight has
         been ingested within 4 hours
    2.   Give multiple dose oral activated charcoal to adults and children
         who have ingested more than 120 mg/kg
    3.   Measure the plasma salicylate concentration. It may be necessary
         to repeat this after a few hours because of continuing
    4.   Carry out arterial blood gas analysis if the patient shows CNS
         features or other signs of severe poisoning.
    5.   Correct any metabolic acidosis with intravenous bicarbonate.
    6.   Give sodium bicarbonate (1.26%) to enhance urinary salicylate
         excretion if the plasma concentration is :

         a) in children > 350 mg/L (2.5 mmol/L)

         b) in adults > 500 mg/L (3.6 mmol/L)

         For adults 1.5 L of 1.26% intravenously over 3 hours should be
    7.   Haemodialysisis the treatment of choice for severe poisoning and
         should be seriously considered in patients with plasma salicylate
         concentrations greater than 700 mg/L (5.1 mmol/L)
    8.   Attempting to force a diuresis probably does not enhance
         salicylate excretion and may cause pulmonary oedema
    9.   Repeat plasma salicylate concentrations will be required to
         ensure that treatment has been effective



    1.   Nawata Y et al. Chronic salicylate intoxication and
         rhabdomyoloysis in a patient with sclerodoma and Sjogren's
         Syndrome. J Rheumatol 1994; 21: 357-359
    2.   Watson JE & Tagpua ET. Suicide attempt by means of aspirin enema.
         Ann Pharmacother 1994; 28 : 467-469

    3.   Yip L, Dart RC & Gabow PA. Concepts and controversies in
         salicylate toxicity. Emerg Clin N Am 1994; 12: 351-364
    4.   Giri AK. The genetic toxicity of paracetamol and asprin: a
         review. Mutat Res 1993; 296: 199-210
    5.   Gittelman DK. Chronic salicylate intoxication. South Med J 1993;
         86: 686-685
    6.   Krause DS, Wolf BA, Shaw LM. Acute aspirin overdose: mechanisms
         of toxicity. Ther Drug Mon 1992; 14: 441-451
    7.   Chapman BJ & Proudfoot AT. Adult salicylate poisonings: deaths
         and outcome in patients with high plasma salicylate
         Quart J Med 1989; 268: 699-707
    8.   Thisted B et al. Acute salicylate self-poisoning in 177
         consecutive patients treated in ICU. Acta Anaesthesiol Scand
         1987; 31: 312-316
    9.   Meredith TJ & Vale JA. Non-narcotic analgesics: problems of
         overdosage. Drugs 1986; 32 (suppl 4): 177-205
    10.  Needs CJ & Brooks PM. Clinical Pharmacokinetics of the
         salicylates. Clin Pharmacokinetics 1985; 10: 164-177
    11.  Beringer TRO. Salicylate intoxication in the elderly due to
         benorylate. BMJ 1984; 288: 1344-1345.
    12.  Temple AR. Acute and chronic effects of aspirin toxicity and
         their treatment. Arch Intern Med 1981; 141:364-369
    13.  Leading article. Poisoning with enteric coated aspirin. Lancet
         1981; 2: 130
    14.  Snodgrass W, Rumack BH et al. Salicylate toxicity following
         therapeutic doses in young children. Clin Toxicol 1981; 18:
    15.  Paynter AS & Alexander FW. Salicylate intoxication caused by
         teething ointment. Lancet 1979; ii: 1132
    16.  Marcus SM. Non-accidental poisoning with salicylate. J Med Soc
         New Jersey 1978; 76: 524-525


    1.   Ralston ME et al. Transient myocardial dysfunction in a child
         with salicylate toxicity. J Emerg Med 1995; 13: 657-59
    2.   Rupp DJ. Acute polyuric renal failure after aspirin intoxication.
         Arch Intern Med 1983; 143: 1237-38
    3.   Dove DJ & Jones T. Delayed coma associated with salicylate
         intoxication. J Pediatrics 1982; 100: 493-96
    4.   Heffner JE & Sahn SA. Salicylate induced pulmonary edema. Ann
         Intern Med 1981; 95: 405-409
    5.   Zimmerman GA & Clemmer TP. Acute respirtaory failure during
         therapy for salicylate intoxication. Ann Emerg Med 1981; 10: 104-
    6.   Hormaechea E et al. Hypovolaemia, pulmonary edema and protein
         changes in severe salicylate poisoning. Am J Med 1979; 66: 1046-


    1.   Danel V et al. Activated charcoal, emesis, and gastric lavage in
         aspirin overdose. BMJ 1988; 296: 1507
    2.   Prescott LF et al. Diuresis or alkalinisation for salicylate
         poisoning? BMJ 1982; 285: 1383
    3.   Winchester JF et al. Extracorporeal treatment of salicylate or
         acetaminophen poisoning - is there a role? Arch Intern Med 1981;
         141: 370-4

    Skin Absorption

    1.   Davies MG et al. Systemic toxicity from topically applied
         salicylic acid. BMJ 1979; 1: 661

    Acid-Base Abnormalities

    1.   Gabow PA et al. Acid-base disturbances in the salicylate
         intoxicated adult. Arch Intern Med 1978; 138: 1481-84

    Reye's Syndrome

    1.   Starko KM & Mullick FG. Hepatic and cerebral pathology findings
         in children with fatal salicylate intoxication: further evidence
         for a causal relation between salicylate and Reye's syndrome.
         Lancet 1983; 1: 326-29
    2.   Daniels SR et al. Scientific uncertainties in the studies of
         salicylate use and Reye's syndrome.

    Epidemiology of poisoning

    For many years salicylates have been among the most important drugs
    ingested in overdosage; in 1980 aspirin and aspirin substitutes still
    comprised the single most important group of drugs involved in
    children under the age of five years and in teenagers15 Aspirin,
    alone or in combination with other drugs, was involved in 19,240 out
    of 900,513 poison exposures reported to the American Association of
    Poison Control Centers National Data Collection System in 1985.16
    However, the incidence of poisoning with them appears to be
    decreasing. Comparison of the 1968 and 1977 reports of the National
    Clearinghouse for Poison Control Centers shows that the proportion
    contributed by salicylates to all ingestions below the age of 5 years
    fell from 21.7 to 3.4 per cent. Similarly, the percentage of all drug
    overdoses with salicylates in older age groups decreased from 14 to
    4.6 per cent. In England, these figures are 6.5% for adults 17,18, and
    3% for children17. Other reports indicate the declining popularity of
    salicylates for self-poisoning in Australia16 and in Britain.19,20

    Deaths from salicylate overdosage still occur.21,22 Twenty-eight of the
    aspirin ingestions reported to the Poison Control Centers National
    Data Collection System in 1985 were fatal, the mortality from aspirin
    alone being less than when other drugs were involved (<0.1% c.f.
    0.3%).15 In the United States however, the number of salicylate

    deaths in children under the age of five years fell from 140 in 1962
    to 12 in 1980.23 This improvement has in part been attributed to the
    introduction of child-resistant containers.24 The number of
    accidental childhood deaths from salicylate poisoning in Britain has
    also fallen, but this antedated the introduction of safety




    The pharmacological actions of salicylates are almost entirely the
    result of inhibition of the cyclooxygenase enzyme of the prostaglandin
    synthetase complex. Acute salicylate poisoning causes a wide variety
    of features but tinnitus, some degree of deafness, profuse sweating,
    and flushing with warm extremities and bounding pulses are almost
    invariably present. There may be obvious hyperventilation, with both
    the rate and depth of respiration being increased. Nausea and vomiting
    may result from direct gastrointestinal irritation.

    The mechanisms whereby these features are produced are incompletely
    understood. Electrocochleographic recordings in two overdose patients
    showed an elevation of hearing threshold (most marked in the 30-60 db
    range) which was completely and rapidly reversible.28 Uncoupling of
    oxidative phosphorylation has traditionally been held to account for
    the increases in heat production, basal metabolic rate, oxygen
    consumption, and carbon dioxide output, with the resulting increased
    cardiac output and hyperpyrexia. Some animal studies have suggested
    that the hyperventilation of salicylism is probably also secondary to
    increased body metabolism rather than to inhibition of prostaglandin
    synthetase while others indicate that it is due to a mechanism other
    than the ability to inhibit oxidative phosphorylation. Studies of
    plasma concentrations of Kreb's cycle organic acids in poisoned humans
    (see below) have also cast doubt on the role of the uncoupling of
    oxidative phosphorylation.

    Acid-Base Disturbances

    Characteristic changes

    Acid-base disturbances in salicylate poisoning are common and complex.
    Hyperventilation leads to respiratory alkalosis while uncoupling of
    oxidative phosphorylation and interference with glycolysis is thought
    to be reponsible for some degree of metabolic acidosis. This may cause
    a reduction in plasma bicarbonate concentrations. Some degree of
    respiratory alkalosis and metabolic acidosis is present in virtually
    every moderate or severe poisoning and alter arterial hydrogen ion
    concentration (pH) in opposing directions. The age of the patient
    seems to be the most important factor in determining which
    predominates. In children under the age of 4 years the metabolic
    component is usually the more important and these patients are almost

    invariably acidotic.29 In contrast, the respiratory component tends
    to dominate the acid-base change in older children and most adults
    who, as a result, usually have either normal or reduced arterial
    hydrogen ion concentrations.30 Occasionally, adults have been
    observed to have a dominant metabolic acidosis. The arterial hydrogen
    ion concentration resulting from these complex changes is undoubtedly
    more important in determining the severity of poisoning and outcome
    than the nature of the acid-base disturbance per se.22

    Development of acid-base disturbances

    It is commonly held that in human salicylate poisoning a dominant
    metabolic acidosis follows an initial respiratory alkalosis. However
    the evidence for this sequence of events is less than satisfactory,
    and as long ago as 1959 Winters and his colleagues commented that in
    children this sequence did not always occur and that the phase of
    alkalosis may be very brief.29 They found acidosis in all of their
    patients who had intoxication of longer than 24 hours' duration but
    were unable to say that the two observations were causally related
    since nearly all these children developed intoxication in the course
    of treatment of an underlying illness. Similarly, it has been shown
    that adults may develop severe and fatal acidosis within as little as
    3 or 4 hours of massive aspirin overdosage.

    Causes of acidosis

    Salicylates are weak acids, but with the concentrations of free
    salicylate commonly encountered in acute poisoning it is unlikely that
    this makes an important contribution. Increased urinary excretion of
    keto-acids and Kreb's cycle organic acids in poisoned children was
    reported many years ago31 but has not been confirmed, and plasma
    concentrations of these acids have not been measured sufficiently
    often to warrant firm conclusions about their importance. Bartels and
    Lund-Jacobsen found that although increased blood lactate and ketone
    body concentrations were demonstrated in 15 out of 45 adults with
    acute intoxication (serum salicylate concentrations 207-815 mg/l, mean
    470 mg/l) it was considered that their quantitative importance in
    respect of the acid-base changes was modest.32 Moreover, they also
    concluded that the hyperlactataemia was more probably due to
    inhibition of liver lactate elimination than to overproduction
    secondary to hyperventilation or uncoupling of oxidative

    Both salicylate in the cerebrospinal fluid and acidosis are powerful
    stimuli to respiration.33 The combination of the two might therefore
    be expected to cause greater hyperventilation than in patients with
    normal or low arterial hydrogen ion concentration. Chapman and
    Proudfoot however, found that the mean PaCO2 was higher in fatal cases
    (most of whom were acidemic) than in the survivors (most of whom had
    normal or low arterial hydrogen ion concentrations) and although the
    difference was not statistically significant, they considered that
    failure to hyperventilate commensurate with the magnitude of the
    stimuli may be a factor in the development of acidosis.22 In most of

    their cases relative hypoventilation could not be ascribed to
    concomitant ingestion of central nervous system depressant drugs,
    although there isf a lower incidence of alkalosis and a higher
    incidence of respiratory acidosis in salicylate poisoned patients who
    had also ingested central nervous system depressant drugs.35

    Differential diagnosis of a high anion gap acidosis

    Salicylate poisoning may be the final diagnostic consideration in the
    lengthy investigation of a complex acidosis in patients who do not
    give a history of aspirin ingestion. Salicylates produce a high
    anion-gap acidosis, which also occurs with poisons such as ethylene
    glycol, methanol, and paraldehyde. In addition, a high anion gap is
    also observed in diabetic ketoacidosis, lactic acidosis (which may
    occur in iron, ethanol, isoniazid, or phenformin overdosage),
    starvation, alcoholic ketoacidosis, nonketotic hyperosmolar coma, and
    acute and chronic renal failure.

    Central Nervous System Features

    Central nervous system toxicity is an important indicator of severe
    salicylate poisoning. Serious depression of consciousness is rare, and
    patients are more often agitated, restless, and uncommunicative before
    coma supervenes. These features are most frequently seen in children
    under the age of 5 years and are commonly accompanied by acidaemia in
    this group.29,34 Adults seldom show central nervous system (CNS)
    toxicity but when they do, it is again usually associated with
    acidosis.22,30 Animal studies have provided a rational basis for the
    CNS toxicity of salicylates in the presence of acidosis by showing
    that the latter facilitates the shift of salicylates from the
    extracellular fluid into cells, particularly the brain.33 This in
    turn is due to the pH-dependent ionization of salicylates, which are
    non-ionized to a greater extent when blood pH falls. They are then
    more lipid soluble and able to cross cell membranes. Studies in
    children have confirmed that the more severe the acidosis, the more
    salicylate is present in the cerebrospinal fluid. However, altered
    consciousness in salicylate poisoning has not always occurred in
    patients who have been acidotic. Some have been alkalotic, but in many
    of these cases plasma salicylate concentrations have been very high,
    and it seems possible that this alone may allow sufficient salicylate
    to enter the brain.

    The concomitant ingestion of CNS depressant drugs reduces the
    respiratory stimulant effect of salicylates and encourages the
    development of acidosis and neurological features.30 It has been
    known for many years that CNS depressants increase the mortality from
    salicylates in animals.

    Convulsions may occur in severe salicylate poisoning but are uncommon.
    Animal studies suggest that they may be the result of hyperventilation
    or reduced brain glucose concentrations, which may occur in the
    absence of hypoglycaemia. Cerebral oedema also has been reported on
    rare occasions.

    Fluid Retention and Pulmonary Oedema

    Vomiting, sweating, and hyperventilation, perhaps accentuated by
    coexistent hyperpyrexia, produce some degree of dehydration in
    salicylate poisoning and could conceivably account for the common
    observation that urinary output lags behind the rate of fluid
    administration when attempts are made to force a diuresis. However,
    fluid retention and oliguria despite apparently adequate hydration has
    been reported in two children and was thought to be the result of
    inappropriate secretion of antidiuretic hormone, though other
    mechanisms were not excluded.35

    The mechanism of fluid retention is of considerable importance since
    attempts to force a diuresis may lead to pulmonary oedema. The finding
    of normal pulmonary capillary wedge pressures in most cases suggests
    that the oedema is noncardiac in origin and not the result of fluid
    overload. This view is supported by observations from two other
    sources. First, studies in sheep showed that salicylates increased the
    rate of pulmonary lymph flow and lymph protein clearance, indicating
    increased lung vascular permeability, perhaps as the result of
    impaired platelet function, a direct toxic effect on capillary
    epithelium, or inhibition of prostaglandin synthesis.36 Second,
    measurement of the protein content of plasma, pulmonary oedema fluid,
    and urine in two poisoned adults also supports the concept of
    increased vascular permeability and confirms that pulmonary oedema is
    noncardiac despite administration of intravenous fluids.37

    Radiological studies in salicylate intoxication indicate that
    pulmonary oedema occurs in about 5% of patients.38 In patients over
    the age of 30 years this incidence may increase to 35%; cigarette
    smoking, chronic ingestion of the drug, metabolic acidosis and the
    presence of neurological features on admission are major risk factors
    for the development of pulmonary oedema.38 However, there is
    controversy over how frequently pulmonary oedema complicates
    salicylate intoxication in children. Two studies suggest that
    pulmonary oedema occurs in between 0% and 10% of children38,39 A high
    anion gap was noted to be a predisposing factor.

    Rarely, oliguria may be due to acute tubular necrosis and not
    dehydration. Urinalysis may not be helpful in the diagnosis of tubular
    necrosis, since hyaline casts and excessive tubular cells even appear
    in the urine of nonoliguric patients.


    Some patients, particularly young women, develop petechial
    haemorrhages during the course of acute salicylate poisoning. They are
    most commonly seen on the eyelids but may spread to the rest of the
    face and neck but not to the trunk of limbs. There may be associated
    with subconjunctival haemorrhages. The purpura are probably due to a
    combination of increased capillary permeability, decreased platelet
    stickiness, and a marked rise in venous pressure during retching or
    struggling in the course of gastric emptying. The patient and there

    relatives can be reassured that the unsightly rash is of no serious
    significance and that the lesions will disappear within a few days.
    Investigation is unnecessary.


    Hyperprexia is said to be a common complication of salicylate
    intoxication in children. It could be the result of metabolic
    stimulation due to uncoupling of oxidative phosphorylation but may
    more simply reflect the illness for which the salicylate was
    prescribed in the first place. Hyperpyrexia is a very uncommon
    complication of salicylate poisoning in adults but is associated with
    a worse outcome.22 The possibility that it is due to other drugs
    taken concomitantly, particularly monoamine oxidase inhibitors, must
    also be considered.

    Plasma Electrolyte Changes

    Robin and his colleagues reported six patients aged between 5 and 52
    years who presented neuromuscular abnormalities, electrocardiographic
    changes, and hypokalaemia as features of severe salicylate
    poisoning.40 In most cases hypokalaemia was present within a few
    hours of ingestion of the drug. Every patient was alkalaemic due to a
    predominant respiratory alkalosis, and it was postulated that the
    hypokalaemia resulted from subsequent shift of potassium into cells
    and excessive loss in urine. Severe hypokalaemia may also complicate
    treatment of salicylate poisoning by forced alkaline diuresis but is
    readily corrected by the administration of adequate potassium
    supplements.41 Hypocalcaemia may also complicate attempts at
    alkalinisation.42 Transient hypercalcaemia, possibly due to the
    calcium carbonate content of the tablets, has been reported after
    overdosage with soluble aspirin.43

    Hypoprothrombinaemia and Gastrointestinal Haemorrhage

    Despite the importance attributed to therapeutic doses of salicylates
    as an etiologic factor in upper gastrointestinal haemorrhage, severe
    bleeding from the stomach or duodenum is a rare complication of acute
    massive overdosage. Chronic administration of large doses of
    salicylates undoubtedly inhibits the synthesis of factors II, V, VII,
    and X but clinically significant hypoprothrombinaemia (as assessed by
    prolongation of the prothrombin time) in acute poisoning is rare.
    Therapeutic administration of vitamin K should rarely be necessary.

    Gastric Perforation

    Gastric perforation has been reported after acute salicylate
    overdosage44 but is exceedingly rare. It has also been reported after
    overdosage with enteric-coated aspirin preparations.45

    Poisoning Complicating Gastric Outlet Obstruction

    Several reports indicate that enteric-coated aspirin tablets may be
    retained in the stomach for long periods in the presence of pyloric
    stenosis. Salicylate poisoning may or may not complicate gastric
    retention of such tablets, which can often be seen as filling defects
    on barium meal examination.46



    In the majority of cases it is not difficult to make a diagnosis of
    acute salicylate poisoning. Many children poisoning themselves
    accidentally will be found ingesting the tablets. Adults seldom lose
    consciousness with salicylates alone and admit to what they have
    taken. On other occasions, however, diagnosis may be much more
    difficult, particularly when CNS depressant drugs have been ingested
    simultaneously or with therapeutic or nonaccidental poisoning in
    childhood. In such circumstances hyperventilation, sweating, and
    acid-base abnormalities are important diagnostic clues. Anderson and
    his colleagues made a detailed study of adults in whom the diagnosis
    of salicylate intoxication was delayed from 6 to 72 hours after
    admission to hospital.47 In these patients poisoning was usually
    therapeutic rather than due to acute massive overdosage and the
    patients tended to be older, with a high incidence of chronic medical
    conditions that often were the reason for taking the salicylate
    therapy, Many had altered consciousness which prevented disclosure of
    salicylate ingestion and this, together with features such as
    convulsions and hallucinations, led to many being subjected to
    detailed neurologic investigations before the diagnosis of salicylate
    poisoning was established. Delayed diagnosis was associated with a
    high morbidity and a mortality of about 25 per cent. In retrospect, it
    was apparent that the common clinical and laboratory features of
    poisoning had not always been appreciated. Occassionally patients have
    been sent for psychiatric evaluation, only to discover that in fact
    they had salicylate intoxication.48


    The severity of salicylate poisoning dictates the urgency and
    invasiveness of therapeutic intervention and the patient's clinical
    state is based on the plasma salicylate concentration, and
    particularly, the arterial hydrogen ion concentration.

    As noted above, central nervous system features are the most important
    indicators of severe salicylate intoxication but they are rarely
    encountered in older children and adults. Unfortunately, plasma
    salicylate concentrations correlate poorly with features of acute
    toxicity although clinically serious poisoning and most deaths occur
    in patients with the highest plasma concentrations.22 Patients with
    normal hearing usually experience tinnitus with concentrations greater
    than 300 mg/l, and few are likely to complain of it below 200 mg/l,

    whereas those with pre-existing hearing loss may fail to notice
    tinnitus despite plasma salicylate concentrations well in excess of
    the accepted therapeutic range. Nor is the acid-base disturbance or
    degree of hyperventilation (as assessed by arterial carbon dioxide
    tensions) closely related to salicylate concentrations. This is hardly
    surprising since toxicity is presumably related to the concentration
    of free non-ionised drug, which, in turn, depends on a number of
    factors including the total plasma concentration, the degree of
    protein binding, and the hydrogen ion concentration. The concentration
    of free salicylate is likely to comprise less than half the total
    plasma concentration in most cases of acute intoxication. Done
    attempted to circumvent these difficulties by relating the severity of
    poisoning to a theoretic plasma salicylate concentration at the moment
    of ingestion, calculated by extrapolation backward from the plasma
    half-life determined 6 or more hours after the single dose taken.49
    Measurements made before 6 hours were considered misleading since the
    drug may still be being absorbed. The Done nomogram has enjoyed wide
    popularity among paediatricians but perhaps has not been as widely
    adopted for the assessment of adult poisoning.

    The concentration of salicylate in cerebrospinal fluid reflects the
    concentration of unbound non-ionised drug in plasma; studies in
    children and animals have shown that the severity of intoxication is
    closely related to cerebrospinal fluid salicylate concentrations.
    These in turn were related to the total plasma concentration and the
    arterial hydrogen ion concentration. Though the latter does not
    influence protein binding of salicylates, high hydrogen ion
    concentrations reduce ionization and thereby facilitate shift of
    salicylate into cells. Measurement of cerebrospinal fluid salicylate
    concentrations however is impractical and potentially hazardous, and
    is never indicated in the management of acute salicylate poisoning.


    As with any form of poisoning, treatment of acute salicylate poisoning
    is directed toward prevention of further absorption of the drug,
    enhancing its elimination, and reducing its toxicity.

    Prevention of Further Absorption

    If intoxication has developed as a result of percutaneous absorption,
    it is clearly imperative to clean the skin thoroughly and withhold
    further applications of salicylic acid ointment.

    Activated charcoal

    Activated charcoal is the treatment of choice for preventing
    salicylate absorption after overdose. It is most effective if given
    early after ingestion and its value in preventing absorption declines
    rapidly as the time from ingestion increases. Although there is little
    effect on absorption from use after 2 hours regular activated charcoal
    enhances the elimination of salicylate at any time after overdose (see

    Gastric lavage

    The use of gastric lavage following large overdoses of salicylates has
    been suggested to be useful up to 12 hours after ingestion. However,
    the evidence for this is limited. This procedure is not free from
    hazard and there is no evidence that it is more effective than the
    administration of activated charcoal. Routine use cannot be advocated
    in adults or children. In children the procedure is particularly
    difficult and hazardous.

    If lavage is chosen, it is essential to use a large-diameter tube and
    to aspirate as much of the gastric contents as possible at the outset,
    since the introduction of water into the stomach may wash salicylate
    through the pylorus into the small bowel, leading to rapid absorption.
    Lavage should be carried out using as much tepid water (in aliquots of
    300 to 400 ml) as is necessary to produce a clear gastric effluent.
    The efficiency of the procedure may be increased by gentle massage
    over the left hypochondrium while it is in progress. The addition of
    alkali to the lavage fluid may facilitate dissolution of retained
    enteric-coated tablets but may also accelerate gastric emptying and
    absorption of any form of salicylate.

    Indications for Enhancing Elimination

    Measures to enhance the elimination are justified in severely poisoned
    patients with acidosis, impaired consciousness, pulmonary or cerebral
    oedema, and cardiac or renal failure. They also should be used when
    plasma salicylate concentrations are high. It is generally recommended
    that plasma salicylate concentrations exceeding 500 mg/l in adults and
    350 mg/l in children are indications for enhancing elimination - the
    lower value for children being a reflection of their tendency to
    acidosis and, therefore, central nervous system toxicity. However,
    while plasma drug concentrations provide a working guideline for
    management, it is more important to consider the severity of symptoms
    and biochemical abnormalities in each individual when considering the
    use of elimination techniques.

    A variety of techniques have been used in attempts to enhance the
    elimination of salicylate from the body. They include forced alkaline
    diuresis, administration of alkali alone, exchange transfusion,
    peritoneal dialysis, haemodialysis, charcoal haemoperfusion and, most
    recently, repeated doses of oral activated charcoal.

    Forced alkaline diuresis

    Although used historically to treat salicylate overdose, the procedure
    is hazardous and no more effective than regular oral activated
    charcoal. It is now obsolete in the management of salicylate

    Alkali administration alone

    The plasma salicylate half-life can be reduced by alkalinization
    without forcing a diuresis and avoiding the risks of fluid
    overload.51 Although, to date, this approach has only been studied in
    mild and moderate intoxication there is no reason to doubt that it
    would be effective, particularly if used in conjunction with repeated
    oral activated charcoal. Further assessment is required but the
    approach merits consideration.

    Repeated dose oral activated charcoal

    The realisation that repeated doses of oral activated charcoal can
    considerably enhance the elimination of drugs which have already been
    absorbed is one of the most exciting therapeutic advances in clinical
    toxicology in recent years. Repeated oral charcoal can reduce the
    plasma half-life of salicylates more effectively than forced alkaline
    diuresis in mild-moderately poisoned patients 52,53 and should be
    offered to any patient with salicylate intoxication. One study
    compared the half-life of salicylate in five patients treated with
    repeat doses of activated charcoal and compared this to a control
    group of six patients with mild aspirin poisoning treated with fluids
    alone. The mean salicylate half-life was 3.2 hours in patients treated
    with repeat charcoal and 27 hours in the control group.52

    Exchange transfusion

    This technique is relatively inefficient.

    Peritoneal dialysis

    This technique is also relatively inefficient. However it has a role
    in the management of severely poisoned patients who are geographically
    remote from haemodialysis centres.


    Haemodialysis is a very efficient method of eliminating salicylate
    from the circulation but its use should be reserved for very severely
    poisoned patients. It is the treatment of choice when plasma
    salicylate concentrations are very high (greater than 1000 mg/l) or
    when the patient is acidemic and unresponsive to bicarbonate therapy
    with features of central nervous system toxicity. Not only does it
    remove salicylate rapidly but also it permits control of electrolyte
    and fluid balance54.

    Charcoal haemoperfusion

    Haemoperfusion has been used relatively infrequently for the treatment
    of salicylate poisoning, but the evidence indicates that it is as
    effective as haemodialysis in removing salicylates. However, although
    it is now generally accepted that charcoal haemoperfusion is
    technically simpler than haemodialysis, it does not allow adequate

    control of fluid or electrolyte balance unless a conventional dialyzer
    is used in series with the column. Haemodialysis is therefore

    Other Measures

    Vitamin K (intravenously) rarely may be necessary for the correction
    of hypoprothrombinaemia.


    Plasma Salicylate Concentrations

    Once the possibility of salicylate intoxication is considered, it is
    easily confirmed by measurement of the plasma salicylate
    concentration. Several analytical techniques are available55 but most
    hospital laboratories use a simple colorimetric method, which
    estimates total plasma salicylate concentrations. The disadvantages of
    using a nonspecific method that also measures the very low
    concentrations of metabolites is more than counterbalanced by the ease
    and speed with which it can be carried out and by the fact that there
    is no simple assay that will measure unbound salicylic acid, the most
    important component. Acetylsalicylic acid and salicylic acid and its
    metabolites can be readily measured by high-performance liquid
    chromatography. Indiscriminately requested drug screens yield a low
    proportion of salicylate intoxications.56

    A plasma salicylate level greater than 300 mg/l is usually associated
    with clinical toxicity.


    Phil Young, BSc (Hons) Msc MRPharmS

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP

    This monograph was produced by the staff of the Newcastle Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Last updated June 1997


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    See Also:
       Toxicological Abbreviations