ASPIRIN OVERDOSE

by Glen E Hastings MD November 10, 2005 I Introduction: Intentional salicylate overdose usually occurs predominantly in adolescents & young adults. Overdoses in children are usually accidental & in the elderly they occur as therapeutic misadventures. The severity of aspirin overdose is often underestimated by ER personnel because of lack of familiarity. This is an important problem because delay in treatment of severe intoxication is associated increased mortality in severe cases 1 . With good management mortality rates are low 2 but even at best about 5% of severely toxic patients die, usually from cardiac or central nervous system complications. Elderly patients with chronic salicylate overdose tend to present with nonspecific findings such as deterioration of cognition, or self care, pulmonary edema or simply failure to thrive. Important clinical clues may be tachypnea, hyperpnea & an unexplained positive ion gap metabolic acidosis1. II History & Physical Examination: Key elements of the medical history may have to be obtained from caretakers, family members or friends because of the patients mental status, age or lack of cooperation. Key elements include: Was the drug taken over a short period of time (e.g. within an hour)? What was the time of ingestion? How much was ingested? III Pathophysiology1, 3 , 4 : One of the initial clinical manifestations of acute salicylate poisoning is gastric irritation & vomiting producing metabolic acidosis, UGI ulceration or bleeding. Stimulation of the respiratory center may produce respiratory alkalosis & secondary renal bicarbonate wasting, hypokalemia & dehydration. The respiratory center is stimulated because salicylates uncouple mitochondrial oxidative phosphorylation in the CNS as well as in the periphery, the respiratory center reads the resulting loss of ATP as hypoxemia, so it stimulates hyperpnea & tachypnea. The kidneys respond to the respiratory & metabolic alkalosis by dumping bicarbonate to maintain acid/base homeostasis. This limits the bodys capacity for buffering acid. Meanwhile organic acids (pyruvate & lactate) accumulate in the periphery because ATP is no longer being generated through the Krebs cycle, as several of the Krebs cycle enzymes are blocked by excess salicylate. The body becomes increasingly dependent on the less efficient anaerobic energy pathways by way of which more energy is dissipated as heat. This produces fever & increased utilization of glucose. This inhibition of glucose oxidative metabolism is particularly hazardous to the brain because of the inability of neuronal tissue to employ fatty acids as an alternative fuel. The resulting lipolysis increases production of ketones & organic acids culminating in metabolic acidosis when the bodys buffering capacity becomes sufficiently depleted. These metabolic changes eventually lead to renal depletion of fluid & electrolytes, hypoglycemia, hypokalemia & a mixed picture of respiratory & metabolic alkalosis coupled with metabolic acidosis which may provoke cardiac dysrhythmias, acute pulmonary edema, renal failure or neurological injury. Tinnitus & hearing loss is caused by an increase in labrynthine pressure & direct stimulation of cochlear hair cells. The hearing loss resolves 2-3 days after withdrawal of the drug. Noncardiac pulmonary edema (ARDS) is most often seen in elderly, chronically aspirin intoxicated patients. Hypoglycemia occurs both in the elderly & in children. Hypoprothrombinemia &/or acute fulminant hepatic failure reminiscent of Reyes syndrome are thankfully rare complications.

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IV Laboratory Testing1,5 : Intentional overdoses involve more than one substance in 24% of cases, so a comprehensive urine screen for drugs of abuse, acetaminophen & such other prescribed or unprescribed drugs as may be suggested by the history are strongly indicated. Baseline CMP & ABGs, urinary pH & electrolytes are indicated, & are sequential repeated to monitor the effects of treatment. Salicylate levels should be repeated until a downward trend is established. V Estimating Severity1,3,4,5,6,7: The likelihood that the patient will experience severe toxic effects can be estimated from the amount of drug ingested, expressed in mG/kG of body weight (See Table 1 6 ). Table 1: ASA Intake & Risk The most important information in assessing severity however is the mG/kG Likely Risk patients clinical condition. Patients presenting with hallucinations, convulsions, coma, heart failure, oliguria or renal insufficiency are < 125 Minimal 150-300 Moderate severely toxic, no matter how high the salicylate level may be. In young 300-500 Severe & Prolonged adults, plasma salicylate levels are usually above 75mg/dL in severe >500 Potentially Lethal cases & above 65 mg/dL in children less than 12. When the patient presents with fever, tachypnea, loss of coordination, profuse sweating or dehydration or restlessness are moderately toxic & plasma salicylate levels commonly range 50 to 70mg/dL in adults & 40-60mg/dL in children Table 2: Plasma Salicylate Levels & Clinical Symptoms Mild toxic effects are limited to Concentration Effect Symptom burning in the mouth, lethargy, 90 ARDS, Renal Failure tinnitus, dizziness, nausea or 80 Cardiovascular Shock vomiting. Salicylate levels are 70 Fever, Coma commonly 30 to 50mg/dL in adults & 60 Metabolic Acidosis 50 Respiratory Alkalosis, Tetany 20-40mg/dL in children. 40 Hyperventilation Increasingly Salicylate levels are obtained 4 to 6 30 Nausea, Vomiting Toxic Ranges hours after ingestion. Earlier samples 20 Headache, Vertigo, Tinnitus Anti-Inflammatory Effect 10 GI Intolerance, Bleeding Analgesic Effect may be unreliable because the Impaired Platelet Function CV Prophylaxis pharmacokinetics arent stable before 0 Hypersensitivity Reactions that time. The severity of the clinical Adapted with permission . Copyright 1992 Applied Therapeutics. presentation is usually related to the 7 plasma salicylate level as shown in Table 2 . VI Treatment1,3,5: Since there is no specific antidote for salicylates, treatment is aimed at restoration of fluid & electrolyte, acid-base & glycemic homeostasis while preventing absorption of drug remaining in the gut & accelerating the excretion of that already absorbed. o Gastric Lavage may be useful up to 12-24 hours after significant salicylate ingestions because massive doses sometimes cause impairment of gastric emptying, also because occasionally concretions of salicylate precipitate in the acid medium of the stomach. If this is suspected the stomach should be lavaged with a solution with pH 8.5. They can be x-ray imaged if present. o Activated Charcoal administered in dosages of 50 to 75g immediately followed by 50mg q 4 hours will increase the non-renal excretion & decrease the elimination half life of salicylates. This mode of treatment is particularly of value when an extended release form of salicylate has been ingested.indicated. There is also evidence that gastric lavage followed by serial charcoal administration reduces elimination more rapidly than either alone. Vomiting may occasionally preclude the administration of activated charcoal.

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Fluid & Electrolyte correction is paramount. Some degree of hypokalemia is invariably present & may be masked by the presence of a concomitant metabolic acidosis. If the physician begins alkalinizing the urine by infusing IV bicarbonate, without correcting & monitoring the serum potassium, the potassium may plummet & a cardiac dysrhythmia may supervene. In general, glucose containing fluids should be employed because the brain may become glucose depleted & energy deprived, even in the face of peripheral normoglycemia or only mild hypoglycemia. This occurs because neurons cant use fatty acids as alternative fuel. Plasma glucose levels must be monitored & hypoglycemia prevented. Glucose infusion is particularly important in elderly patients presenting with new onset CNS symptoms or signs. It is also prudent to add a thiamin containing solution to the glucose infusion in elderly patients in whom malnutrition is suspected (especially among alcoholics) because if severe thiamin deficiency is present the glucose infusion may precipitate the Wernicke-Korsakoff syndrome. o Alkalinization of the Urine is an effective but potentially hazardous means of accelerating the renal excretion of salicylate, so it should only be attempted in an ICU setting with continuous monitoring & frequent electrolyte determinations. It is the method of choice for seriously toxic patients (e.g. Those exhibiting clinical deterioration, escalating salicylate levels, those with severe metabolic acidosis or those with salicylate levels exceeding 50mg/dL) who do not meet the criteria for renal dialysis. Optimally the urine should be alkalinized to a pH exceeding 7.5. Severe acidosis may require as much as 300 to 500mmol of bicarbonate for correction. After correcting any potassium deficit at the existing pH, 2 ampules of sodium bicarbonate may be slowly infused, after which the serum potassium should be rechecked & again corrected. While this is in progress, a solution of 150mEq of NaHCO3 is prepared by adding 3 ampules of NaHCO3 to 1000cc of D5W (after withdrawing 150cc form the bottle). This produces a solution of 150mEq/L of D5/ NaHCO3 which is then infused at a starting rate of about 0.5mEq/kG/hour & titrated to maintain the plasma pH between 7.50 & 7.55 & the urine pH optimally at about 8.5. Renal Dialysis is the first option in all patients with all patients with a plasma salicylate level above 90 mg/dL, those with CNS signs & severe metabolic acidosis, progressive clinical deterioration, pulmonary edema, & in frail elderly patients or those with renal impairment & salicylate levels above 75mg/dL. Hemodialysis is the treatment of choice in most seriously ill patients with salicylate poisoning & those with serious comorbidities. Hemodialysis is 2 to 3 times as effective as peritoneal dialysis & probably more effective than charcoal hemoperfusion. VII Prognosis: Prognosis is related to the plasma salicylate level, age, comorbidities, complications, the presentation & the hospital management. In 1989 Chapman & Proudfoot 8 reported on 97 patients who either died from acute salicylate overdosage or survived plasma salicylate concentrations 70 mg/dL. These patients represented 4% of 2204 salicylate poisoning cases admitted between 1975 & 1985. The overall mortality rate was 0.3%. The 7 patients died were older than most survivors. The mortality was 33% among patients > 70 years of age. In addition to age, delayed presentation, coma, hyperpyrexia, pulmonary edema & acidemia were associated with fatal outcomes. In 1986, McGuigan 9 reported 7 cases of fatal salicylate poisonings seen in Ontario in 1984. The average duration of hospitalization before death in this series was 18.1 hours. Failure to administer activated charcoal & bicarbonate, to appreciate the need for hemodialysis &/or to obtain expert consultation were associated with these fatalities. o

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VIII References:
1

Durnas C, Cusack BJ. Salicylate intoxication in the elderly. Recognition and recommendations on how to prevent it. Drugs Aging. 1992;2(1):20-34. Litovitz TL, Bailey KM, Schmitz BF, et al. 1990 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med. 1991;9(5):461-509. Meredith TJ, Vale JA. Non-narcotic analgesics. Problems of overdosage. Drugs. 1986;32 Suppl 4:177-205. Temple AR. Pathophysiology of aspirin overdosage toxicity, with implications for management. Pediatrics. 1978;62(5 Pt 2 Suppl):873-6. Krause DS, Wolf BA, Shaw LM. Acute aspirin overdose: mechanisms of toxicity. Ther Drug Monit. 1992;14(6):441-51. Mueller FW, Lieberman SV. Fitting a double-exponential curve to observed salicylate concentrations in blood. Pharm Sci. 1970;59(4):514-7. Mueller FW, Lieberman SV. Fitting a double-exponential curve to observed salicylate concentrations in blood. Pharm Sci. 1970;59(4):514-7. Chapman BJ, Proudfoot AT. Adult salicylate poisoning: deaths and outcome in patients with high plasma salicylate concentrations.Q J Med. 1989 72(268):699-707. McGuigan MA. Death due to salicylate poisoning in Ontario.CMAJ. 1986;135(8):891-4. J