A Review of Management of Salicylate Intoxication in Children

A review of management of salicylate Salicylates intoxication in children

DONALD G. PELINO, D.O. Dolton, Illinois

An understanding of the principles of Among all the causes of death due to poison- successful management of salicylate ing in children under the age of 5 years, poisoning is essential for the salicylates are by far the most frequent. The reasons for this are three: (1) the lack of physician with child patients because knowledge of the proper use of aspirin by of their increased susceptibility parents; (2) the lack of knowledge of the dan- to salicylate intoxication. ger of aspirin toxicity; and (3) easy accessi- The first requisite of proper bility of aspirin for children, primarily be- management is early diagnosis. The cause of the first two factors. Children under importance of a good history 2 years of age die from salicylate poisoning because of therapeutic use, but older children is stressed. When faced with possibility are poisoned most frequently from accidental of salicylate poisoning, the ingestion. The increased susceptibility of chil- physician should conduct a thorough dren is related to their age and the concomi- physical examination and a tant tendency toward dehydration. preliminary ferric chloride test. The successful handling of salicylate intoxi- Knowledge of the blood salicylate level cation depends on early diagnosis of the condition, prompt treatment adequate for the will not necessarily indicate the degree of intoxication, and carefully planned severity of intoxication. The extent of supportive care. involvement may not be related directly to the amount of aspirin Diagnosis ingested, because of the The diagnosis of salicylate intoxication rests complex mixture of effects of the drug on two cornerstones: (1) a history of ingestion (or absorption from the skin of oil of winter- on many different organ systems green), and (2) an understanding and knowl- and variation in individual response. edge of the mechanisms causing the symptoms. Treatment involves the initiation The first prerequisite for diagnosis is obvious. of emesis or lavage and appropriate It is important to determine the number of fluid and electrolyte therapy, pills taken, the type of pill (baby aspirin, with attention to the likelihood which is 134 grains, or adult aspirin, which is 5 grains), the time since ingestion, whether of potassium depletion. the pills were taken once or several times, When severe intoxication fails whether the salicylate was actually in pills or to respond to the usual treatment, was methyl salicylate (oil of wintergreen), peritoneal dialysis should which is much more toxic, and whether they be considered. were ingested on a full or an empty stomach. An understanding and knowledge of the symptoms presented in salicylate poisoning are im- perative when a history is not available from the parents or when the child is brought into an emergency room alone and unconscious.

1249/84 The outstanding characteristic of salicylate lem: changes in fluid and electrolyte balance. intoxication is disturbance of acid-base bal- The hyperpnea results in respiratory alkalosis, ance and electrolyte status. The cardinal sign which is characterized by an increase in blood of hyperpnea is well known, but knowledge pH, a decrease in carbon dioxide, and a loss of of the processes involved in its production and extracellular sodium. The renal compensation the production of the fluid and electrolyte im- for this alkalosis is the excretion of bicarbon- balances is also necessary for thorough under- ate ion along with sodium and potassium. standing of the course of the intoxication and Chloride excretion is usually minimal. The the required treatment. What, then, are the result is a compensated respiratory alkalosis mechanisms involved? Salicylates affect res- with resulting low carbon dioxide tension and piration in two ways: indirectly through an bicarbonate, with normal or near normal pH. increase in oxygen consumption with conse- It is the loss of the bicarbonate buffer which quent increase in carbon dioxide production renders the patient susceptible to factors and directly via action on the respiratory cen- which can cause subsequent acidosis. ter in the medulla. The increase in oxygen There are, according to Goodman and Gil- consumption and carbon dioxide production man, three processes which cause the final apparently takes place as a result of salicy- metabolic acidosis. The first is actual salicylic late-induced uncoupling of oxidative phospho- acid dissociation in the blood. The second is rylation, especially in skeletal muscle. The impairment of renal function due to vaso- increase in carbon dioxides affects the medul- motor depression with consequent accumula- lary center and causes much greater increase tion of metabolic acid products. The third is in the depth of respiration than in the rate. the accumulation of organic acids such as This is a direct effect of salicylate on the pyruvic, lactic, and acetoacetic acids accom- medullary respiratory center. Goodman and panying respiratory depression. This is due Gilman stated, "CO2 stimulates depth more to derangements in carbohydrate metabolism than rate of respiration, whereas salicylate and inhibition of synthesis and enhancement stimulates rate more than depth." While stimu- of the breakdown of fatty acids. Thus, bi- lation of both rate and depth may be present carbonate is displaced, and metabolic acidosis during different stages, the clinical picture ensues. The depletion of bicarbonate which is usually of the "panting dog" type of breath- occurs in the initial phase of intoxication in- ing, that is, an increase in respiratory rate. creases the severity of the acidosis. However, Donee pointed out that the subtle To summarize, the direct and indirect ef- increase in depth without an increase in res- fects of salicylate on the respiratory center piratory rate may easily be missed unless it cause respiratory alkalosis. This is compen- is specifically sought, especially when salicylate sated for by the renal secretion of bicarbonate, intoxication is mild. The terminal effect of the effect of which is to lower the pH and salicylate on the medulla occurs with high simultaneously decrease the bloods buffering concentrations of the drug and is one of pro- capacity. The decrease in buffering capacity, found depression of the respiratory center as when challenged by the accumulation of or- well as other areas of the brain. Thus, the hy- ganic and inorganic acids resulting directly perpnea commonly seen is explained. What from salicylate poisoning, causes metabolic follows this, however, is the crux of the prob- acidosis.

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Detection in the laboratory of the combina- erythrocytes, and leukocytes in the urine and tion of respiratory alkalosis and metabolic positive tests for reducing substances, such as acidosis rests on the measurement of the blood acetone and diacetic acid, may be observed.2 pH, carbon dioxide tension, or carbon dioxide- For confirmation of the clinical impression combining capacity. The pH will be low; the of salicylate intoxication while the blood is carbon dioxide tension will be low or normal, being analyzed, several screening tests may depending on whether respiratory depression be employed. The ferric chloride test is sensi- has set in, and the carbon dioxide-combining tive to salicylate in the urine, but it is not capacity (measure of bicarbonate) always will quantitative. A few drops of a 10 per cent be low. Although both sodium and potassium solution is added to the urine. In the presence are lost, there is a large water loss from of salicylic acid, a violet to purple color devel- salicylate-induced sweating, from hyperpnea, ops. Reagent strips (Phenistix) also may be and from diuresis, so that relative hyperna- used, and, although not exact, the measure- tremia results. ment is quantitative. A pure tan color indicates Among other signs and symptoms of severe a level of less than 40 mg./100 ml., a darker salicylate poisoning are apathy, confusion, and brown color with some purplish highlights coma. These have been ascribed to cerebrovas- suggests a level of from 40 to 90 mg., and a cular vasodilatation accompanying the respira- pure purple indicates a level of more than 90 tory alkalosis.3 Although therapeutic doses of mg.2 Knowing the blood salicylate level is salicylates cause hypothermia, toxic doses of some aid, but the level is a poor indication cause hyperthermia, ostensibly from the in- of the severity of intoxication. crease in metabolism and dissipation as heat The clinical manifestations of toxicity are of the energy normally used for the conver- related not so much to the blood level of salicy- sion of inorganic phosphate to adenosine tri- late at any given moment as to the level at phosphate in the presence of the uncoupling the peak and the rapidity with which this of oxidative phosphorylation. Intense gastro- level declines. The peak blood level after in- intestinal upset may be present and is a direct gestion of a single dose usually occurs from effect of the salicylate, both locally on the 4 to 6 hours after intake, and blood levels at gastric and enteric mucosa and centrally on this time reveal significant values. Done e has the emetic centera. Large doses of salicylate formulated a nomogram for severity of salicy- reduce the level of prothrombin in the blood late intoxication based on the level of the drug and prolong the prothrombin time. This is after a specified period. If the level is 45 probably related to a decrease in clotting fac- mg./100 ml. or less at this time, the patient tor VII. Hemorrhage may thus occur as a late usually will be asymptomatic and will remain complication. Marked hypoglycemia has been so as the level declines. He may have occa- reported with severe salicyate poisoning in sional subjective, but no objective, manifesta- young children and has been attributed to in- tions at this level. If the salicylate level is be- creased utilization of glucose by peripheral tween 45 and 65 mg./100 ml. at 6 hours, mild tissues, along with decreased synthesis of car- symptoms, such as moderate hyperpnea and bohydrates. In addition to the cardinal lab- lethargy, may be present. If the level is be- oratory findings mentioned, leukocytosis, ace- tween 65 and 90 mg./100 ml., the symptoms tonemia, and the presence of albumin, casts, will be moderate and will consist of severe

1251/86 hyperpnea and obvious neurologic impairment. mary objective is, of course, to empty the Coma and convulsions will usually not be pres- stomach. This is especially true after ingestion ent. Any salicylate level above 90 mg./100 ml. of oil of wintergreen, which has a high con- at 6 hours indicates severe intoxication, and centration of readily absorbable salicylate. The coma, convulsions, and severe hyperpnea all stomach should be emptied within 4 hours of may be present. Although these levels offer salicylate ingestion.2 According to Done, 2 ad- some aid in determining the level of intoxica- ministration of emetics to initiate vomiting tion and predicting the course of the process, is more efficient, less time consuming, and less it should be remembered that they are based troublesome than gastric lavage. However, on ingestion of a single dose of salicylate. When emetics are contraindicated for the patient the drug has been taken over some time, the who is unconscious or is having convulsions. blood levels do not correlate well with the se- Syrup of ipecac, given in doses of from 10 to verity of the condition, and serial studies of 15 ml. with a glass of water and repeated in 15 blood level will correlate with clinical progress to 30 minutes, is highly efficacious and appears to a greater extent than a single determination to be the best means of producing vomiting. If and will be more useful in predicting the clin- this is not available, the child may be given a ical course. glass of warm milk, after which stroking of the I have found in records of the clinic with posterior part of the pharynx will achieve the which I am associated that the extent of in- desired response. A small child should have his volvement is not always directly related to head inverted and supported and his feet ele- the amount of aspirin ingested. Low levels in vated to prevent aspiration of vomitus. As the serum have been associated with severe noted by Arena,4 some authorities have rec- pathologic changes and fatalities, and high ommended giving apomorphine subcutaneous- serum levels with less severe or minimal con- ly in a dose of 0.03 mg./lb. to cause emesis sequences. Salicylates, like most drugs, act at and terminating the reflux and the narcotic more than one site, and their overall pharma- effects of apomorphine with levallorphan, 0.01 cologic, clinical, and toxic patterns form a mg./lb. If emesis is not achieved within 30 complex mixture of superimposed effects on minutes by any of these measures, gastric several different systems. It may be well to lavage should be instituted. This is especially remember that each person, although appear- important when the emetic was ipecac, which ing similar to others, varies to some degree is an irritant to the stomach lining and acts as and is an individual. Individuals are capable a cardiotoxin when absorbed. The presence of cf varied responses to similar circumstances coma with depression of the cough reflex is a because of the range of physiologic and patho- contraindication to gastric lavage. logic characteristics, and they must be evalu- For the patient with salicylate intoxication ated in the adjustment of basic treatment to and metabolic acidosis, the physicians first individual needs, evidenced only by the re- inclination is to replace the lost bicarbonate sponse to therapy. ion. The rationale for this is not only to replace the buffer base but to alkalinize the urine Treatment to promote salicylate excretion. It has been When the patient has clinical and laboratory shown that when the urine is alkaline, dissocia- signs of severe salicylate intoxication, the pri- tion of the salicylic acid is increased; the

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amount left in the nonionized form is reduced, This can be given as from 3 to 5 mEq./kg. in and salicylate excretion is increased. However, from 2 to 4 hours. From 3 to 5 ml. of 0.3 molar the overenergetic use of alkali is inadvisable solution of tromethamine may be preferable if for three reasons: (1) the danger of alkalosis the patient is in cardiac failure and cannot be is great, since the bodys buffering capacity is given sodium. This is given in 1 hour. Talatrol weak; (2) the measure is often unnecessary brand of tromethamine also has the advantage for patients with less than severe metabolic of combating acidosis intracellularly, and it acidosis; and (3) large amounts of bicarbon- may work when bicarbonate has failed.2 ate can be expected to produce only temporary In addition to acid-base and electrolyte im- buffering of the blood. balance, there are other problems to be dealt As long as there is a deficit of potassium, with in the treatment of salicylate intoxication. the intracellular acidotic state will return be- Hyperthermia may present an immediate cause hydrogen ions move into the cells and threat to life and should be treated vigorously, prolong intracellular acidosis. When potassium especially in a child with a rectal temperature is replenished, the hydrogen ions remain in over 104 F. Cool baths, alcohol sponge baths, the extracellular compartment and can be or a hypothermia blanket may be used. If res- excreted in the urine. Thus, potassium replace- piratory depression occurs from excessive sa- ment becomes an important step in correction licylate, oxygen should be administered. Severe of the metabolic acidosis. Unfortunately, po- convulsions may require the use of short-act- tassium cannot be administered rapidly. It ing barbiturates such as amobarbital.2 Tetany may, however, be incorporated into the paren- may appear and necessitate the intravenous teral solutions used to combat the acidosis. administration of calcium. The hemorrhage Done has formulated a plan of parenteral ad- accompanying the hypoprothrombinemia can ministration based on the severity of the acid- be stopped by administration of vitamin K. osis. For initial hydration to improve kidney Some authors have recommended the routine function via increased renal plasma flow, a use of vitamin K as a precautionary measure solution free of potassium is used. It is given for patients with severe salicylate poisoning.2 intravenously over a short period. This solu- When severe salicylate poisoning (a blood tion contains sodium, 75 mEq./liter; chloride, level of more than 90 mg./100 ml. 6 hours 50 mEq./liter; and bicarbonate, 25 mEq./liter. after ingestion) responds poorly to the usual Once urine flow has been established, potas- treatment, dialysis may be indicated. Among sium, 40 mEq./liter, is added, and the amounts the different methods, extracorporeal hemodial- of sodium, chloride, and bicarbonate are de- ysis is most effective, especially for the child creased. Although most patients with mod- under 1 year of age, but expense makes it erate or severe acidosis can be treated suc- impractical for use in a community hospital. cessfully with the latter solution, severe acid- Peritoneal dialysis is least expensive and can osis (blood pH less than 7.25) may require be continued for long periods. Since the salicy- larger doses of sodium and bicarbonate. When late is bound to serum proteins, it is not read- the pH declines below 7.18, the situation be- ily dialyzable unless protein is present in the comes so serious that straight sodium bicar- dialysate to compete with serum proteins for bonate may have to be given intravenously, binding of the drug. 2 Therefore, a solution of even though the buffering is only temporary. serum albumin is added to the normal dialy-

1253/88 sate. Schlegel and co-workers5 found in five tests of pH and carbon dioxide tension and patients undergoing peritoneal dialysis that combining capacity of the blood, sodium, po- the salicylate concentration measured in the tasium, and urea nitrogen or creatinine in the dialysate was from two to three times as great serum, blood glucose, and pH and specific when 5 per cent albumin was present in the gravity of urine should be ordered. Emesis or solution. Rapid clinical recovery of four of lavage should be instituted, and proper fluid the five patients followed peritoneal dialysis. and electrolyte therapy, with special attention to probable potassium depletion, should be Prevention initiated. Peritoneal dialysis should be consid- Not the least important element in the treat- ered in the treatment of extremely severe in- ment of salicylate intoxication is its preven- toxication. tion. Although intoxication often results from accidental ingestion, Done 2 has stated that the most severe aspirin poisoning among infants and children results from therapeutic over- 1. Goodman, L. S., and Gilman, A.: Pharmacological basis of thera- dosage. For this reason, education of the par- peutics. Ed. 3. Macmillan Co., New York, 1965 ent in the proper use of aspirin and the dan- 2. Done, A. K.: Treatment of salicylate poisoning. Mod Treatm 4:648-70, Jul 67 gers inherent in the drug, if combined with 3. Nelson, W. E.: Textbook of pediatrics. Ed. 8. W. B. Saunders improved packaging, may decrease the mor- Co., Philadelphia, 1964 4. Arena, J. M.: General principles of treatment and specific bidity and mortality associated with salicylate antidotes. Mod Treatm 4:599-624, Jul 67 intoxication. Indeed, preventive measures 5. Schlegel, R. J., et al.: Peritoneal dialysis for severe salicylism. An evaluation of indications and results. J Pediat 69:653-62, Oct 66 more than any others will determine the num- Beeson, P. B., and McDermott, W., Eds.: Cecil-Loeb textbook of ber of cases of poisoning each year for the medicine. Ed. 12. W. B. Saunders Co., Philadelphia, 1967 Brainerd, H., et al., Eds.: Current diagnosis and treatment. present and the near future. Lange Medical Publications, Los Altos, Calif., 1967 Goodale, R. H., and Widmann, F. K.: Clinical interpretation of Summary laboratory tests. Ed. 6. F. A. Davis Co., Philadelphia, 1969 Goth, A.: Medical pharmacology. Principles and concepts. Ed. A specific plan of attack must be utilized when 3. C. V. Mosby Co., St. Louis, 1966 Harper, H. A.: Review of physiological chemistry. Ed. 10. the physician is faced with possible salicylate Lange Medical Publications, Los Altos, Calif., 1966 poisoning. A precise history should be obtained Hyman, H. T.: Differential diagnosis. An integrated handbook. J. B. Lippincott Co., Philadelphia, 1965 when possible, for the information obtained Slobody, L. B., and Wasserman, E.: Survey of clinical pediatrics. may determine the management. A thorough Ed. 5. McGraw-Hill Book Co., New York, 1968 physical examination and preliminary ferric chloride test should follow. Serial laboratory Dr. Pelino, 1021 E. Sibley Blvd., Dolton, Ill. 60419

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