Poisoning with salicylates

Vermeersch and co-workers have reported the case of a 4-month-old girl who presented with agitation, hyperexcitation, fever, dehydration, polypnea and metabolic acidosis. H NMR spectroscopy of the lyophilized urine from the patient showed the presence of 2-hydroxybenzoic acid (salicylic acid), o-hydroxyhippuric acid and 2,5-dihydroxyhippuric acid, which indicated that she had been poisoned with salicylate (aspirin). It is notable that this study was completed at 80 MHz, a relatively low field strength. 

Both accidental and intentional overdose are relatively frequent and pose difficult management problems. Particular concern has been expressed for children, either because they gain access to parents tablets or have been treated for enuresis. During one year a Melbourne hospital admitted 35 children poisoned with tricyclic antidepressants (147). In 1979 it was reported that tricyclic antidepressants had replaced salicylates as the most common cause of accidental death in English children under the age of five. Concern was expressed about this (148), and Swiss federal statistics raised similar worries (149). 

Hemodialysis is recommended for acutely poisoned patients with salicylate levels greater than 80-lOOmg/ dL, acidosis, CNS dysfunction, or pulmonary edema. Chronic intoxication with levels >60 mg/ dL is a further indication. While hemoperfusion is also effective, hemodialysis is preferred to correct acid-base and electrolyte disturbances. 

MCA has nevertheless been suggested as a dermatological treatment for mosaic warts or periungual warts at a concentration of 80% or 60 g of MCA -I- 10 ml of water. Treating warts involves MCA coming into contact with a very limited area of skin, which explains the absence of poisoning when the treatment is carried out careMly. MCA has also been combined with salicylic acid and is considered more effective than dichloro- or trichloroacetic add in the treatment of warts. Because of this product s very high and potentially fatal toxicity, its use and indications should be strictly limited. 

Salicylate intoxication in adults is usually deliberate, but in children overdosage from therapeutic misuse is all too common. In many cases, aspirin is given to very young children by well-meaning but misguided parents and doctors in excessive dosage (20 ). More than half the children admitted to hospital in the USA with salicylate intoxication have been poisoned by chronic ingestion from therapeutic misuse (27 ). The recommended daily doses of aspirin for patients with juvenile rheumatoid arthritis of 100 mg/kg or 3.2 g/m are excessive. 

The interaction of ligands derived from salicylic acid and its derivatives has been extensively investigated (83, 147, 149, 160, 170, 176, 183-205). A similar situation obtains with regard to l-hydroxy-2-naphthoic acid (185, 194, 196, 198, 206-215). Salicylic acid derivatives may be useful in chelation therapy for beryllium poisoning (2). 

Urine alkalinization is a treatment modality that increases elimination of poisons by the intravenous administration of sodium bicarbonate to produce urine with a pH of more than or equal to 7.5 and must be supported by high urine flow. This technique might be useful for the elimination of drugs with an acid pKa such as salicylates (but not recommended for phenobarbital intoxication for which multiple-dose activated charcoal is better), chlorpropamide, 2,4-dichlorophenoyacetic acid, diflunisal, fluoride, mecoprop, methotrexate. Complications include severe alkalemia, hypokalemia, hypocalcemia and coronary vasoconstriction. 

The severity of poisoning correlates poorly with plasma salicylate concentration. Six hours after ingestion salicylate levels of 300-500 mg/1 may suggest mild toxicity, 500-750 mg/1 moderate toxicity, and over 750 mg/1 severe toxicity. 

Activated charcoal adsorbs salicylate effectively, and has been given in repeated oral doses (50 g 4 hourly) to enhance clearance, although its effect on outcome is unknown. Fluid and electrolyte replacement are important and special care should be taken to maintain normal potassium concentrations. Patients with signs of poisoning, especially when plasma salicylate concentration exceeds 500 mg/1, should receive specitic elimination therapy. 

When a specific antidote or other treatment is under consideration, quantitative laboratory testing may be indicated. For example, determination of the acetaminophen serum level is useful in assessing the need for antidotal therapy with acetylcysteine. Serum levels of salicylate (aspirin), ethylene glycol, methanol, theophylline, carbamazepine, lithium, valproic acid, and other drugs and poisons may indicate the need for hemodialysis (Table 58-3). 

Changes in plasma pH may also affect the distribution of toxic compounds by altering the proportion of the substance in the nonionized form, which will cause movement of the compound into or out of tissues. This may be of particular importance in the treatment of salicylate poisoning (see chap. 7) and barbiturate poisoning, for instance. Thus, the distribution of phenobarbital, a weak acid (pKa 7.2), shifts between the brain and other tissues and the plasma, with changes in plasma pH (Fig. 3.22). Consequently, the depth of anesthesia varies depending on the amount of phenobarbital in the brain. Alkalosis, which increases plasma pH, causes plasma phenobarbital to become more ionized, alters the equilibrium between plasma and brain, and causes phenobarbital to diffuse back into the plasma (Fig. 3.22). Acidosis will cause the opposite shift in distribution. Administration of bicarbonate is therefore used to treat overdoses of phenobarbital. This treatment will also cause alkaline diuresis and therefore facilitate excretion of phenobarbital into the urine (see below). 

Mercier el al. (330) administered i.v. infusions of sodium salicylate to dogs and determined the lethal dose to be 1 g/kg. Simultaneous administration of papaverine resulted in a slight increase in the toxicity. Lettr6 et al. (331) studied the synergism of mitotic poisons and found that papaverine intensified the mitotic effect of colchicine on the growth of fibroblasts in vitro. The spasmolytic effect of khelline was augmented by small doses of papaverine (332). Therapeutic doses of khelline did not produce a hypotensive effect upon dogs, but in combination with barbiturates and papaverine a hypotensive effect was observed. 

Chapman, B.J. and A.T. Proudfoot, Adult salicylate poisoning deaths and outcome in patients with high plasma salicylate concentrations. Q. J. Med., 1989, 72 699-707. 

Aspirin, salicylates, and thiazide diuretics should not be used with allopurinol. The dose of mercaptopurine should be reduced one-third or one-fourth when used with allopurinol. Acute poisoning of colchicine should be treated with gastric lavage and activated charcoal administration. Supportive maintenance measures for blood pressure and respiration should be provided. Probenecid is used by athletes to inhibit the urinary excretion of banned anabolic steroids.85... 

A survey in Britain covering the decade of the 1980s demonstrated large numbers of successful suicides using BZs, either alone or in combination with alcohol (Serfaty et al., 1993 see also Buckley et al., 1995). Serfaty and Masterton (1993) found 891 fatalities with BZs alone and 591 in combination with alcohol. The total of all poisonings attributed to BZs was 1,576 during the 10-year period, putting them ahead of aspirin/ salicylates at 1,308 as well as amitriptyline (1,083) and dothiepin at 981. 

Acute salicylate poisoning is a major clinical hazard (96), although it is associated with low major morbidity and mortality, in contrast to chronic intoxication (SEDA-17,... 

Chan TH, Wong KC, Chan JC. Severe salicylate poisoning associated with the intake of Chinese medicinal oil ( red flower oil ). Aust NZ J Med 1995 25(1) 57. 

Accidental ingestion of methylsalicylate in young children has resulted in severe salicylate poisoning, in one case with laryngeal edema (7). A suicide attempt by deliberate ingestion of about 100 ml resulted in severe salicylate poisoning (8). 

---