- Host: Mohammad Anzal Rehman
- Sound edits: Abdulaziz Al Nemer
- Video: Afnan Alessely
- Music by: Dr Basel Debal @Baseloud
Salicylates have been in use for over 3000 years as drugs useful for their anti-platelet, antipyretic, and analgesic effect. Aspirin, or acetylsalicylate, is the more commonly known drug in this class, but salicylates make up several over-the-counter products that are readily accessible to the public.
Generally, the prevalence and mortality from salicylate toxicity is low, with one U.S. study revealing only 148 cases of toxicity across 1 million admissions over 11 years. Furthermore, the same study showed an in-hospital mortality of approximately 1%. While it’s not often that this type of toxicity is encountered, cases that do present with significant symptoms frequently have important physiologic sequelae and clinical morbidity that should be identified by Emergency Physicians, as severe toxicity can be associated with higher mortality rates of around 10%.
The therapeutic mechanism of action of salicylates involves irreversible binding to and inhibition of the Cyclo-oxygenase (COX) enzyme. These enzymes are responsible for producing prostaglandins which propagate inflammation, fever, and pain. Inhibition of COX therefore causes reduction of pain, fever, and inflammation. Salicylates also inhibit thromboxane A2, preventing platelet aggregation.
Toxicity causes a range of physiologic changes in the body. Initially, direct stimulation of the respiratory medullary center increases its sensitivity to pH and partial pressure of CO2 (pCO2), resulting in tachypnea culminating in a respiratory alkalosis. Some compensatory buffering through the hemoglobin-oxyhemoglobin system is performed by the body, as well as hydrogen ion exchange and urinary excretion of bicarbonate, but this causes subsequent issues with acidosis (detailed below).
The primary mechanism of toxicity involves the metabolite salicylic acid uncoupling oxidative phosphorylation in mitochondria and inhibiting aerobic metabolism. This redirects glycolysis and the body switches to pyruvate and conversion to lactic acid. As in DKA, lipid stores breakdown and form ketone bodies, ATP is decreased and temperature, metabolic rate, oxygen consumption all increase. Hence, the resultant metabolic acidosis has a high anion gap. A decreased pH also de-ionizes salicylate, allowing it to cross the blood-brain barrier and enter the Central Nervous System (CNS).
Hyperventilation acts to counter acidosis, may become overwhelmed by the direct CNS toxicity and acidemia. A prolonged elevation of salicylate, respiratory fatigue, ARDS or co-ingestant effect can significantly depress the respiratory center causing respiratory acidosis which, combined with hypercapnia from inadequate ventilation and acidemia in blood, can be a vicious cycle of acidosis that is associated with high mortality.
Total potassium stores also become depleted in salicylate toxicity. GI irritation can cause vomiting which depletes potassium through H+/K+ exchange. Compensatory increases in renal excretion of bicarbonate carry with them an increase in excretion of sodium and potassium. Renal tubular damage also causes potassium ion permeation and excretion. Finally, the uncoupling of oxidative phosphorylation also inhibits the active transport chain which worsens potassium loss.
Although glycogenolysis still occurs, gluconeogenesis is inhibited in salicylate toxicity. Therefore, normoglycemia may not represent the true glucose status for patients. Salicylate toxicity has also been associated with decreases in cerebral glucose concentrations despite normal serum levels – a phenomenon termed as neuroglucopenia.
Additional areas of insult include:
- Ototoxicity, manifested classically as tinnitus
- Pulmonary edema
- Renal injury/ failure,
- Parely, hemorrhage due to anti-platelet function
Acute vs chronic toxicity
It’s important to note that acute toxicity typically presents in younger patients and is associated with intentional ingestions, warranting consideration of other co-ingested substances, such as Acetaminophen, opiates, benzodiazepines, and alcohol. Where possible, try to ascertain the type of product consumed, as salicylate concentrations between substances varies.
For example, ingestion of just a few mL of ‘oil of wintergreen’ (often found in some herbal products) equates to more than 5g of salicylate. Other products containing salicylates include ‘Tiger Balm’ and ‘Reparil’ gel.
Chronic salicylate toxicity tends to occur in older patients with multiple co-morbidities as a result of prolonged use of salicylate-containing medication that culminates in an overdose over time. Toxicity is manifested at lower doses than in acute cases, with worse prognosis and higher mortality rates.
The classic triad of hyperventilation, tinnitus and gastrointestinal irritation is rarely ever seen in clinical situations.
Gastrointestinal symptoms, when present, occurs early and manifests as nausea and vomiting.
Tinnitus is an interesting sign which can easily be missed if not specifically asked about. It occurs early and is generally reversible when associated with short term use (long term exposure may lead to permanent symptoms)
Tachypnea classically accompanies hyperventilation. However, patients may maintain normal RR by increasing tidal volume while still hyperventilating. Keep a high index of suspicion for an elevated breathing rate that is not explained by an obvious respiratory cause.
Uncoupling of oxidative phosphorylation may produce hyperthermia. CNS symptoms can include altered mental status, hallucinations, and seizures. These appear as toxicity progresses but may actually be the primary sign seen in chronic poisoning.
Always remember that co-ingested substances can confound most signs and symptoms of salicylates. Hence, maintain a high index of suspicion.
A study by Shively, et al in 2017 discovered that the strongest predictor of severe outcomes was an elevated respiratory rate. Other risk factors associated with worse prognosis include delays in presentation and diagnosis, increased age, presence of co-ingestion, and altered mental status.
In addition to primary and secondary surveys as with any patient, initial investigations often include a blood gas. Classically, the early finding is primary respiratory alkalosis followed by a primary metabolic acidosis, usually with an anion gap (use the Winter’s formula if you want to ensure the pCO2 is due to a compensatory response). As toxicity progresses, pH turns acidotic, and outcomes worsens the more pH decreases.
The standard confirmatory test in salicylate toxicity is serum salicylate concentration. Levels between 15 and 30 mg/dL are considered therapeutic. Toxicity usually manifests at 30-40 mg/dL. Up to 50 mg/dL, patients may experience tinnitus, hyperpnea or dizziness. Concentrations of 50 – 70 mg/dL are associated with more severe symptoms such as fever and altered mental status. > 75 mg/dL concentrations are accompanied by seizures, renal failure, hypotension, and dysrhythmias.
While serum concentrations have an association with severity, manifestation varies despite the levels seen, so clinical context needs always to be considered and correlated with values obtained. Also, chronic toxicity can have significant clinical manifestations at levels as low as 30 – 40 mg/dL.
An elevated level establishes salicylate toxicity in the suspected individual. Concentrations are conventionally repeated every 2 hours to monitor response to therapy and/or progression of toxicity.
Other investigative modalities include a standard metabolic panel (note that Chloride is often falsely elevated in salicylate overdoses), with checks on potassium for hypokalemia, and creatinine for acute kidney injury. Measure blood glucose, CBC, liver enzymes, magnesium, phosphorous and include Acetaminophen and blood alcohol levels to account for co-ingestion. The use of CT brain for altered mental status and Chest X-ray for pulmonary edema/ARDS will be guided by the clinical picture and physician judgement.
During resuscitation for patients with salicylate toxicity, avoid intubation where possible. Apneic time peri-intubation can be disastrous for patients already struggling to get rid of CO2 with respiratory alkalosis. Any amount of time taken away from that compensation can result in hypoventilation, hypercapnia, and consequently worsening acidosis.
High flow nasal cannula may help reduce work of breathing for some patients.
If a patient can’t protect their airway, already have hypercapnia, or worsening acidosis despite therapy, severe hypoxia or status epilepticus, intubation may be your only option, in which case, where possible, try for awake intubation to reduce apneic time and give sodium bicarbonate bolus doses of 1-2 mEQ/kg pre-intubation.
Defer to the most experienced staff member for a quick, safe procedure. Ventilator settings should match the patient’s high respiratory rate to mitigate acidosis. Use high tidal volumes of approximately 8-10 mL/kg and keep your RR high with regular blood gas measurements to gauge control over acidosis. Keep the pCO2 below 20 mmHg if possible.
Patients with salicylate toxicity are often volume depleted from the excessive work of breathing, fever, GI irritation, insensible loss and increased metabolic activity. Generally, these patients require early, aggressive fluid resuscitation.
Address refractory hypotension with vasopressors as needed. Account for hypoglycemia where applicable and always consider the presence of neuroglucopenia, especially in altered mental status.
Activated charcoal may be given within 2 hours of ingestion at a dose of 1g/kg up to 50 g if patient’s mental state allows and risk of aspiration is low. Intubated patients may receive charcoal through nasogastric or orogastric tubes.
Gastric lavage, induction of emesis and whole bowel irrigation are seldom useful, though whole bowel irrigation may be considered with extreme caution in cases of large amounts of tablet ingestion.
Call your local poison control center or toxicologist early. Consider adding the nephrologist to your call list too to discuss hemodialysis.
Unfortunately, there is no antidote to salicylate toxicity.
The goal of enhanced elimination is to prevent entry of circulating salicylate into tissues and accelerate excretion through urine. This is accomplished through serum and urine alkalinization - useful for all symptomatic patients, especially those with moderate to severe symptoms.
Salicylate exists in the body in an undissociated form and tends to move to the compartment where pH is higher. Metabolic acidosis decreases extracellular pH, driving salicylates into tissues, worsening end-organ damage in those regions.
When you alkalinize serum and urine, you increase the extracellular pH, moving salicylate out of cells and preventing further penetration into tissues.
Increasing urinary pH causes salicylate to move from plasma to urine, trapping it in ionized form which cannot be reabsorbed in the renal tubules. The target serum pH is 7.45 -7.55, whereas the target urinary pH is 7.5 – 8.5.
Alkalinization is usually done using an initial bolus of IV sodium bicarbonate 1-2 mEQ/kg over 1-2 minutes followed by an infusion of 3 amps (150 mEQ) sodium bicarbonate in 1 liter of D5W
DON’T use normal saline because the added sodium bicarbonate will result in a hypertonic solution that may worsen symptoms.
Add potassium replacement, typically 40 mEQ of potassium chloride, to address the hypokalemia from acidosis – correct to a target of 5.5.
Insert a foley catheter and titrate to target serum and urine pH, with adequate urine output of 1-2 mL/kg/hr.
If the patient is unresponsive to therapy, has renal failure and cannot excrete urine, has end-organ damage or worsening acidosis or poor hemodynamic status despite aggressive therapyà start hemodialysis.
If you are uncertain about eligibility for hemodialysis but have a patient who looks sick àCALL YOUR NEPHROLOGIST and ASK for his input. Hemodialysis works best to prevent further end-organ damage if initiated early.
General indications for dialysis include significantly altered mental status, seizures, pulmonary edema, inability to tolerate sodium bicarbonate infusions, coagulopathies, worsening or refractory acidosis or hypoxemia and initial salicylates levels exceeding 100 mg/dL.
All symptomatic patients are admitted and those with significant signs of toxicity go to the ICU.
Core Concept Summary
- Salicylates are readily available and frequently used by many patients. Consider intentional ingestion in acute toxicity, usually in younger patients, and unintentional gradual overdoses in chronic toxicity, usually in elderly individuals
- Salicylates act by causing early respiratory alkalosis, a primary anion gap metabolic acidosis and, if unchecked, a disastrous mix of respiratory AND metabolic acidosis
- Acidosis may cause hypokalemia. GI irritation causes nausea and vomiting and CNS symptoms happen from direct toxicity
- Consider neuroglucopenia, or relative glucose deficiency in the CNS, when salicylates are on board and keep an eye out for hyperthermia
- Remember that an elevated respiratory rate is strongly linked to severe outcomes, so learn to recognize it within the context of an intoxicated patient
- Establish and confirm diagnosis with blood gas and serum salicylate concentration, but don’t forget to check for electrolyte derangements, acetaminophen and alcohol levels as co-ingestion is common
- When managing patients with toxicity, prioritize your ABCs. Aggressively fluid resuscitate to account for losses. Avoid or delay intubation when possible to prevent hypercapnia during apneic time worsening acidosis
- Call your toxicologist and nephrologist early. Early decontamination with activated charcoal may be useful
- Enhanced elimination uses serum and urinary alkalization with IV sodium bicarbonate to more rapidly excrete out salicylate and prevent tissue absorption.
- Target serum pH is 7.45 – 7.55 and target urine pH is 7.5 – 8.5
- Where therapy fails or end-organ damage is significant, consider hemodialysis
About Our Guest:
Dr Lara Sulaiman
Emergency Medicine Consultant working at Rashid Hospital in Dubai and is a co-founding member of the Toxicology Consultation Service at Rashid hospital.
She obtained her medical degree from Dubai Medical College, graduated with an Arab Board Emergency Medicine residency training in 2015, with an additional certification from the European Board in Emergency Medicine. She is also a Member of the Royal College of Emergency Medicine and holds a Post graduate Diploma in Medical Toxicology from Cardiff University 2019
Currently, she works as a Teaching and Faculty member at Dubai Medical College and the Dubai Health Authority (DHA) Emergency Medicine residency training program. She maintains a special interest in medical education, open access medical education and, of course, medical Toxicology
Dr. Mohammad Anzal Rehman
Emergency Medicine Specialist at Mediclinic City Hospital, Dubai, UAE Founder/President of the Emirates Collaboration of Residents in Emergency Medicine (ECREM)
Editor-in-Chief for the Emirates Society of Emergency Medicine (ESEM) Monthly Newsletter
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- American College of Medical Toxicology. Guidance document: management priorities in salicylate toxicity. J Med Toxicol. 2015;11(1):149-152.