Summary for UKPID
SALICYLATE
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
UK
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
Service.
Summary
Name
Generic Aspirin
Proprietary Caprin (R)
Disprin CV (R)
Nu-Seals Aspirin (R)
Anadin
Compound preparations Co-codaprin
Aspav
Roboxisal forte
Equagesic
Aspirin is also available to purchase in many different
preparations.
Synonyms1
Acetylsalicylic acid
Salicylic acid, acetate
ASA
Acetal
Acetisal
Acetophen
Acetosalic acid
Methylsalicylate
Chemical group/family
Non-steroidal anti-inflammatory
BNF 4.7.1
Reference number1
CAS 50-78-2
Manufacturer/supplier2
Available from most generic manufacturers, including;
A.H. Cox & Co Ltd
Whiddon Valley
Barnstaple
Devon
EX32 8NS
Tel: 01271-311257.
Presentation2
Tablets & Dispersible tablets ; 300 mg, 75 mg ; Pack size 100, 20
Physico-chemical properties 3
2-acetyloxybenzoic acid
Molecular weight
180.15
pKa (-COOH)
3.5
Solubility
in alcohol 1 in 5
in water 1 in 300
Hazard / risk classification
None
Uses
Indications3
1. Mild to moderate pain
2. Chronic disease accompanied by pain and inflammation
3. As an antipyretic for symptomatic use in adults with febrile
illness
4. Prophylaxis against arterial occlusive events including stroke
and myocardial infarction in patients at high risk (unstable
angina, following myocardial infarction and transient cerebral
attacks)
Therapeutic Dosage
Analgesia, antipyrexia
Adults 300-900 mg every 4-6 hours (Max. 4 grams daily)
Children Not recommended <12 years
Antithrombotic
Adults 75-150 mg daily.
Children Not recommended <12 years
Contra-indications
Known hypersensitivity to aspirin
Hypoprothrombinaemia
Aspirin should not be used in patients with active gastrointestinal
disease
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
anticoagulants.
History of intolerance to aspirin or other non-steroidal anti-
inflammatory drugs.
Pharmacokinetics
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
Pregnancy
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
beneficial.
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.
Toxicokinetics
The pharmacokinetic characteristics of salicylate taken in overdosage
have important implications for the genesis and treatment of
poisoning.
Absorption
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.
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
increase.12
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.
Interactions
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
valproate
SUMMARY
Ingredients/tablet
Acetylsalicylic acid 300 mg, 75 mg
Toxicity
Ingested dose Likely toxicity
(mg/kg body weight)
150 Mild
250 Moderate
500 Severe - possibly fatal
Features
Common
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
concentration).
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.
Management
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
absorption.
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
sufficient.
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
References
General
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
concentrations.
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:
247-259
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
Complications
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-
106
6. Hormaechea E et al. Hypovolaemia, pulmonary edema and protein
changes in severe salicylate poisoning. Am J Med 1979; 66: 1046-
1050
Treatment
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
packaging.25-27
FEATURES OF POISONING
CLINICAL FEATURES
Salicylism
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
phosphorylation.
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.
Purpura
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.
Hyperpyrexia
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
DIAGNOSIS
Clinical
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
ASSESSMENT OF THE SEVERITY OF POISONING
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.
TREATMENT
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
below).50
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
poisoning.
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
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
preferred.
Other Measures
Vitamin K (intravenously) rarely may be necessary for the correction
of hypoprothrombinaemia.
Analysis
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.
Author
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
UK
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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