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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 patient’s 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 body’s 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 body’s 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.

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. also because occasionally concretions of salicylate precipitate in the acid medium of the stomach. so a comprehensive urine screen for drugs of abuse. Patients presenting with hallucinations. urinary pH & electrolytes are indicated. coma. VI Treatment1. 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. plasma salicylate levels are usually above 75mg/dL in severe >500 Potentially Lethal cases & above 65 mg/dL in children less than 12. There is also evidence that gastric lavage followed by serial charcoal administration reduces elimination more rapidly than either alone. nausea or 80 Cardiovascular Shock vomiting.4. Earlier samples 20 Headache. Tinnitus Anti-Inflammatory Effect 10 GI Intolerance. Salicylate levels are 70 Fever. tachypnea. Copyright 1992 Applied Therapeutics. If this is suspected the stomach should be lavaged with a solution with pH 8. & are sequential repeated to monitor the effects of treatment.3. ↑ 40 Hyperventilation Increasingly Salicylate levels are obtained 4 to 6 30 Nausea. 90 ARDS. They can be x-ray imaged if present. Baseline CMP & ABGs.5: Since there is no specific antidote for salicylates. Bleeding Analgesic Effect may be unreliable because the Impaired Platelet Function CV Prophylaxis pharmacokinetics aren’t stable before 0 Hypersensitivity Reactions that time. loss of coordination.Aspirin Overdose: Page 2 of 4 IV Laboratory Testing1. In young 300-500 Severe & Prolonged adults. convulsions.5. V Estimating Severity1.5 : Intentional overdoses involve more than one substance in 24% of cases. acetaminophen & such other prescribed or unprescribed drugs as may be suggested by the history are strongly indicated. Table 1: ASA Intake & Risk The most important information in assessing severity however is the mG/kG Likely Risk patient’s clinical condition. dizziness. This mode of treatment is particularly of value when an extended release form of salicylate has been ingested.5. o Gastric Lavage may be useful up to 12-24 hours after significant salicylate ingestions because massive doses sometimes cause impairment of gastric emptying. expressed in mG/kG of body weight (See Table 1 6 ). no matter how high the salicylate level may be. Tetany 20-40mg/dL in children. acid-base & glycemic homeostasis while preventing absorption of drug remaining in the gut & accelerating the excretion of that already absorbed. Salicylate levels should be repeated until a downward trend is established. Renal Failure tinnitus. Coma commonly 30 to 50mg/dL in adults & 60 Metabolic Acidosis 50 Respiratory Alkalosis.6. Vomiting may occasionally preclude the administration of activated charcoal. oliguria or renal insufficiency are < 125 Minimal 150-300 Moderate severely toxic. Vertigo.3. The severity of the clinical Adapted with permission . presentation is usually related to the 7 plasma salicylate level as shown in Table 2 . When the patient presents with fever.7: The likelihood that the patient will experience severe toxic effects can be estimated from the amount of drug ingested. treatment is aimed at restoration of fluid & electrolyte. lethargy. . heart failure. Vomiting Toxic Ranges hours after ingestion.indicated.

5mEq/kG/hour & titrated to maintain the plasma pH between 7. This produces a solution of 150mEq/L of D5/ NaHCO3 which is then infused at a starting rate of about 0. The mortality was 33% among patients > 70 years of age. without correcting & monitoring the serum potassium. In addition to age. coma. 2 ampules of sodium bicarbonate may be slowly infused.50 & 7. hyperpyrexia. o Alkalinization of the Urine is an effective but potentially hazardous means of accelerating the renal excretion of salicylate. o . Plasma glucose levels must be monitored & hypoglycemia prevented.3%. delayed presentation. pulmonary edema. The 7 patients died were older than most survivors. Some degree of hypokalemia is invariably present & may be masked by the presence of a concomitant metabolic acidosis.1 hours. After correcting any potassium deficit at the existing pH. Optimally the urine should be alkalinized to a pH exceeding 7.55 & the urine pH optimally at about 8. Failure to administer activated charcoal & bicarbonate. In 1989 Chapman & Proudfoot 8 reported on 97 patients who either died from acute salicylate overdosage or survived plasma salicylate concentrations ≥ 70 mg/dL.g. In general.Aspirin Overdose: Page 3 of 4 Fluid & Electrolyte correction is paramount.5. age. escalating salicylate levels. It is the method of choice for seriously toxic patients (e. glucose containing fluids should be employed because the brain may become glucose depleted & energy deprived. comorbidities. The average duration of hospitalization before death in this series was 18. Renal Dialysis is the first option in all patients with all patients with a plasma salicylate level above 90 mg/dL. pulmonary edema & acidemia were associated with fatal outcomes. after which the serum potassium should be rechecked & again corrected. complications. so it should only be attempted in an ICU setting with continuous monitoring & frequent electrolyte determinations. VII Prognosis: Prognosis is related to the plasma salicylate level. Hemodialysis is the treatment of choice in most seriously ill patients with salicylate poisoning & those with serious comorbidities. This occurs because neurons can’t use fatty acids as alternative fuel. progressive clinical deterioration. Hemodialysis is 2 to 3 times as effective as peritoneal dialysis & probably more effective than charcoal hemoperfusion. 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. McGuigan 9 reported 7 cases of fatal salicylate poisonings seen in Ontario in 1984.5. While this is in progress. the potassium may plummet & a cardiac dysrhythmia may supervene. those with severe metabolic acidosis or those with salicylate levels exceeding 50mg/dL) who do not meet the criteria for renal dialysis. Those exhibiting clinical deterioration. & in frail elderly patients or those with renal impairment & salicylate levels above 75mg/dL. Severe acidosis may require as much as 300 to 500mmol of bicarbonate for correction. In 1986. to appreciate the need for hemodialysis &/or to obtain expert consultation were associated with these fatalities. The overall mortality rate was 0. These patients represented 4% of 2204 salicylate poisoning cases admitted between 1975 & 1985. even in the face of peripheral normoglycemia or only mild hypoglycemia. a solution of 150mEq of NaHCO3 is prepared by adding 3 ampules of NaHCO3 to 1000cc of D5W (after withdrawing 150cc form the bottle). If the physician begins alkalinizing the urine by infusing IV bicarbonate. Glucose infusion is particularly important in elderly patients presenting with new onset CNS symptoms or signs. the presentation & the hospital management. those with CNS signs & severe metabolic acidosis.

59(4):514-7. J 2 3 4 5 6 7 J 8 9 . Litovitz TL. 1970. with implications for management. Krause DS. Problems of overdosage. Pathophysiology of aspirin overdosage toxicity. Non-narcotic analgesics.59(4):514-7. Pharm Sci. Fitting a double-exponential curve to observed salicylate concentrations in blood. Am J Emerg Med. Death due to salicylate poisoning in Ontario. 1978. 1970. Lieberman SV. 1986. Shaw LM.135(8):891-4. Mueller FW. Chapman BJ. Bailey KM. Lieberman SV. Recognition and recommendations on how to prevent it. Meredith TJ. Salicylate intoxication in the elderly. Schmitz BF. McGuigan MA. Adult salicylate poisoning: deaths and outcome in patients with high plasma salicylate concentrations.32 Suppl 4:177-205.2(1):20-34. et al.CMAJ.9(5):461-509. 1986. 1989 72(268):699-707. Fitting a double-exponential curve to observed salicylate concentrations in blood. Proudfoot AT. Vale JA. 1990 annual report of the American Association of Poison Control Centers National Data Collection System.Q J Med. Ther Drug Monit.14(6):441-51. 1992. Mueller FW. Cusack BJ. Drugs. Wolf BA. Drugs Aging. Acute aspirin overdose: mechanisms of toxicity. 1992. Pharm Sci. 1991. Temple AR. Pediatrics.62(5 Pt 2 Suppl):873-6.Aspirin Overdose: Page 4 of 4 VIII References: 1 Durnas C.