Salicylate Poisoning: recognizing and treating it.

Salicylates or “aspirin” have become so common that if you write it in your regular prescription you will have to give an explanation to your patient. Often the patient is told that it is being used as a blood thinner or that it is still the “painkiller” against which all the other NSAIDs are titrated against for efficacy. When used for the treatment of rheumatic fever what blood level should be maintained? Levels between 15 mg per deciliter [1.1 mmol per liter] and 30 mg per deciliter [2.2 mmol per liter] are considered to be therapeutic for inflammatory conditions).

Within 1 or 2 hours after a single salicylate ingestion, point plasma levels often exceed 40 or 50 mg per clinical manifestations of salicylate intoxication including tinnitus, vertigo, nausea, vomiting, and hyperpnea can occur.

Plasma levels between 50 mg per deciliter and 70 mg per deciliter (5.1 mmol per liter) indicate severe intoxication and can be associated with fever, sweating, listlessness, and incoordination.

At levels exceeding 75 mg per deciliter (5.4 mmol per liter), patients are at risk for hallucinations, seizures, cerebral edema, coma, noncardiogenic pulmonary edema, and cardiovascular collapse.

If salicylates are taken with ethanol or opioids blood levels build up slowly. When enteric coated preparations are ingested the blood levels may be low although toxicity is building up so frequent blood levels need to be measured.

The acute form of salicylate intoxication generally occurs in young adults who have a psychiatric history or who have had a previous overdose. Such persons tend to ingest salicylate alone or in combination with other drugs in a suicide attempt; when they present to the emergency department, they frequently volunteer that they have ingested salicylate or are found with partially filled containers of the drug, making the diagnosis straightforward.

A chronic form of intoxication may occur in patients who are ingesting acetylsalicylic acid therapeutically and then have an inadvertent overdose. Since the baseline tissue burden of the drug is high and pathways for salicylate elimination are nearly or fully saturated, additional intake of the drug may lead to substantial accumulation of free salicylate and extension of the normal half-life of 2 to 4 hours to as long as 20 hours. The plasma level of salicylate required to elicit symptoms tends to be lower in chronic than in acute salicylate poisoning, sometimes falling into the upper end of the therapeutic range, because of the large amount of drug previously distributed to and located within tissues, including the central nervous system (CNS). Do not rely overly on the serum levels which may not coincide the symptoms.  Serum (or plasma) levels should be used as an adjunctive consideration, along with the severity of the presenting symptoms, presence or absence of acid–base disorders, and overall clinical condition of the patient.

Chronic poisoning is more likely to occur in the elderly who are on multiple drugs some of which may contain contain salicylates; also in patients being cared for by several doctors with nobody coordinating the prescriptions. I once checked the prescription of a patient  who complained of taking too many pills. He was on 6 different vitamin B complex preparations, 3 calcium and vitamin D pills and 2 vitamin E pills and 11 painkillers for arthritis. He would see a new doctor who would give him a prescription and he would continue to take all the other drugs prescribed by his previous doctors. Fortunately his renal injury improved after stopping the NSAIDs and his frustration improved by stopping most of his vitamins and calcium. Salicylates are present in over the counter drugs such as Pepto Bismol, combination painkillers available over the counter, herbal medicines enhanced with salicylates, skin creams and ointments containing salicylic acid specially if applied to the skin and then heat is applied too. Ginger tea and mint tea are culprits too so do ask about home remedies. Heat induces skin pores to open and disperses the cream across a greater surface area, enhancing systemic absorption. If the cream comes in contact with irritated skin — or epithelium that has compromised integrity — systemic absorption is further enhanced. Naturally occurring foods and food additives contain salicylates; the highest concentration is found in herbs and spices. Administration of a drug that unbinds salicylate from protein, particularly in a patient with chronic kidney disease and hypoalbuminemia, can also increase the free salicylate level and lead to toxic effects.

Chronic salicylate poisoning is difficult to diagnose. The many conditions which may be mistaken for it are:

Encephalopathy of undetermined origin
Dementia or delirium
Viral encephalitis
Unexplained asterixis
Cardiopulmonary disease
Impending myocardial infarction
Pneumonia
Acute alcohol intoxication, alcohol withdrawal, or alcoholic ketoacidosis
Sepsis
Diabetic ketoacidosis
Unexplained decrease in capacity for self-care

Age-related decreases in hearing acuity may attenuate the perception of tinnitus or its cause. Tachypnea and rales on pulmonary examination may be attributed to preexisting lung and cardiac disease as opposed to salicylate-induced noncardiogenic pulmonary edema. Hyperpyrexia and altered mental status can be mistaken for sepsis, and metabolic acidosis accompanied by circulating ketone bodies may be ascribed to diabetic or alcoholic ketoacidosis.

Neurologic abnormalities, such as agitation, confusion, hallucinations, slurred speech, seizures, and coma, occur more frequently in patients with chronic salicylate poisoning than in those with acute intoxication. “Salicylate jag” refers to restlessness and mental aberrations that are reminiscent of alcohol intoxication. Even in the absence of a documented history of ingestion, plasma levels should be measured if salicylate intoxication is suspected.

How does the acid base disturbance cause the symptoms?

Why is there hyperventilation and respiratory alkalosis?

Toxic levels of salicylate exert a direct stimulatory effect on the respiratory center of the medulla, causing an increase in the rate and depth of respiration and the development of respiratory alkalosis as carbon dioxide , the source of carbonic acid, is breathed off.

As there is a compensatory increase in body catabolism and substrate breakdown is required to supply the energy needed for the increasingly inefficient production of ATP from ADP through glycolysis to which the muscles have shifted. This response is manifested by increased oxygen consumption, increased heat production (leading to hyperpyrexia, diaphoresis, and dehydration), depletion of liver glycogen, and increased metabolic production of carbon dioxide.

Occasionally neuromuscular irritability manifested as paratonia and extreme muscle rigidity can develop, further contributing to hyperthermia and increasing the risk of rhabdomyolysis.

The accumulation of ketoacids and other organic acids accounts for the majority of the increase in the anion gap. The contribution of salicylate is minor (<5 mmol per liter). Increased renal bicarbonate excretion in response to respiratory alkalosis decreases buffer capacity, potentially worsening the degree of acidosis as organic acids accumulate.

What acid base abnormality is likely to be seen?

An acid pH is more common in infants and young children because of an inappropriate adaptive respiratory response to the metabolic acidosis.

More than half of patients with salicylate poisoning have a mixed respiratory alkalosis and increased anion-gap metabolic acidosis.

A pure respiratory alkalosis occurs in 20 to 22% of patients. Although respiratory alkalosis facilitates the production of organic acids, it can ameliorate the toxic effects of salicylate on the CNS by slowing the entry of salicylate into tissues. 

Since salicylic acid has a pKa (negative logarithm of the acid dissociation constant) of 3, an alkaline blood pH ensures that more than 99% of the drug is in an ionized state, for which cell membranes are poorly permeable. The nonionized fraction of salicylic acid readily penetrates cells and will double in concentration if blood pH falls from 7.4 to 7.2. As a result, a greater amount of drug will leave the extracellular fluid, and intracellular concentrations will be increased in the brain, liver, and other organs.

Most affected adults who have ingested salicylates alone present with an alkaline pH, whereas coingestion of drugs that depress the CNS blunts the hypocapneic response. In one series, respiratory acidosis was present in 23% of patients who had ingested salicylates in combination with other drugs, as compared with only 2% of patients who had ingested salicylates alone.

Other fluid and electrolyte disturbances can develop in patients with salicylate poisoning.

  • Patients with severe intoxication may have fluid deficits of 4 to 6 liters.
  • Hypernatremia can develop as a result of accelerated, insensible water loss in the lung due to increased ventilation, and increased metabolism and heat production lead to cutaneous water loss from sweating.
  • Salicylate-induced emesis and urinary excretion of sodium organic acid salts cause the total-body sodium content to be reduced.
  • Excretion of these salts also causes renal potassium wasting and hypokalemia due to increased delivery of sodium to the distal nephron at a time when mineralocorticoid levels are increased.
  • High salicylate concentrations in the tubular lumen interfere with urate reabsorption in the proximal tubule, causing severe hypouricemia.
  • In the early stages of toxicity, transient or prolonged hyperglycemia can develop as a result of the combined effect of increased production of glucose and decreased use of glucose by tissues. However, depletion of glycogen stores and impaired gluconeogenic pathways confer a predisposition to hypoglycemia, particularly in patients with chronic intoxication or the later stages of acute intoxication
  • CNS hypoglycemia may be present even with normal peripheral-blood glucose levels.

Treatment

  1. Do a repeated neurological examination.
  2. Check blood pH, blood gases, bicarbonate, chloride, calculate the anion gap and blood sugar levels.
  3. Avoid intubation. The brief period of apnea associated with endotracheal intubation can lead to a rapid fall in pH, causing increased amounts of the drug to accumulate in the CNS through protonation of salicylate.
  4. Administer Lactated Ringer’s solution or isotonic saline at a rate of 10 to 20 ml per kilogram of body weight per hour for the first 2 hours, with subsequent adjustment to maintain a urine output of 1 to 1.5 ml per kilogram per hour.
  5. The goals of fluid therapy are to establish euvolemic and not force diuresis, which has been associated with an increased risk of pulmonary edema.
  6. Reduce gastric absorption of salicylate.
    1. Use activated charcoal for gastrointestinal decontamination at a dose pf 1-2/kg of body weight to a maximum of 100g in adults and 50 g in children.
    2. The dose of activated charcoal can be repeated every 4 hours until charcoal appears in the stool and clinical manifestations of salicylate intoxication resolve.
    3. Repeated doses may lower plasma salicylate levels and may be particularly useful in treating bezoars, which should be suspected when salicylate levels continue to rise or fail to decrease, despite appropriate management.
    4. In such cases, whole-bowel irrigation with polyethylene glycol may also be useful.
    5. A risk of aspiration (due to altered mental status or increasing somnolence), poor gastric motility, and salicylate-induced gastrointestinal hemorrhage are contraindications to the use of activated charcoal.
  7. Alkalinization of the urine to accelerate kidney clearance of salicylate is essential in the management of both acute and chronic intoxication.
  8. Hypokalemia is often present and can be made worse with an alkaline diuresis. If urine output is adequate and there is no evidence of acute kidney injury, 40 mmol of potassium can be added to each liter of solution to help correct the deficit. Deficits should be corrected, since hypokalemia increases the expression of hydrogen–potassium–ATPase in the collecting duct, making it more difficult to establish an alkaline urine.
  9. Hemodialysis is the most efficient way to remove salicylate from the body. The small size, low volume of distribution, and absence of tissue binding make salicylate an ideal substance for dialysis.
  10. A plasma salicylate level of more than 90 mg per deciliter (6.5 mmol per liter) is an indication for dialysis, regardless of signs and symptoms. This threshold for initiation of dialysis is particularly important in patients with acute poisoning after salicylate ingestion, since there may be few signs or symptoms in the first several hours after ingestion. Prompt removal of the drug at this stage can limit tissue accumulation and avert severe toxic effects.
  11. Continuous venovenous hemofiltration or hemodiafiltration can be used if the patient’s hemodynamic condition is unstable or if conventional hemodialysis is unavailable.

Published by

shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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