Salicylates in a Nutshell

Here are review notes for Salicylates/ Aspirin toxicity. Got questions, just holler.

Salicylates
Sources: ASA, Pepto-Bismol, pain-relief creams, OIL of WINTERGREEN (7.5 grams per tsp!!)
Salicylic acid is a weak acid (pKa = 3.4)
i. Ionized form cannot cross membranes, favored at basic pH
ii. UNIONIZED form crosses cell membranes, favored in acidic pH
iii. Therefore, distribution of the compound is pH dependent—acidemia favors tissue penetration into brain, heart, muscles, etc
Pharmacokinetics: hepatic metabolism is overwhelmed at high concentrations, and renal excretion becomes an important pathway for elimination
Toxic Mechanisms and Clinical Effects
i. Depletes ATP productivity by uncoupling oxidative phosphorylation (destroys proton gradient by acting as a proton shuttle between mitochondrial matrix and inner membrane). This is the primary cause of the METABOLIC ACIDOSIS and HYPERTHERMIA
ii. Central stimulation of respiratory centre in the medulla oblongata. This is the primary cause of the RESPIRATORY ALKALOSIS
iii. Enhanced lipolysis and ketone formation.
iv. Gastric irritation. Causes vomiting and dehydration.
v. Liver toxin and direct inactivator of coagulation factors.
vi. Increases capillary permeability in lungs, CNSà pulmonary and cerebral edema
vii. Central nervous system disfunction and neuroglycopenia (decreased brain glucose) results in seizures

Clinical Effects
i. Neurogenic hyperventilation (esp in adults) with primary resp alkalosis
ii. Metabolic acidosis of the high-gap variety
iii. Pure metabolic acidosis more common in children and mixed acid-base disorder in adults
iv. Hyperthermia and diaphoresis (by the way, “hyperthermia” is not the same as “fever”)
v. Nausea, vomiting, dehydration which may contribute to contraction alkalosis
vi. Ototoxicity: Tinnitus and deafness, voices can sound “muffled”
vii. In severe toxicity, altered mental status and seizures are OMINOUS developments
viii. Coagulopathy, transaminitis due to liver toxicity and hyperthermia
ix. Noncardiogenic pulmonary edema (also contributes to hyperventilation)
x. Cerebral edema, low CSF glucose, seizures
xi. Hemorrhagic gastritis and pylorospasm
xii. Rhabdomyolysis and ARF
xiii. Chronic Toxicity mimics many other diseases, such as sepsis, PE, pneumonia, DKA and is often diagnosed late. Be vigilant when patients take daily aspirin and have unexplained AMS with acidosis
Diagnostic Considerations
i. Expect death/severe effects when levels are above or approaching 100 mg/dL in acute overdose
ii. In chronic overdose, the serum salicylate level may be lower but the BODY BURDEN is HIGHER so severe toxicity occurs at or above 50-75 mg/dL
iii. A single low level is NOT ENOUGH! Levels will rise over many hours in acute overdose, esp if there are concretions in GI tract…must get ASA level every 2-3 hrs until a peak and/or plateau is established.
iv. CAUTION: Some labs will report the units as mg/L (so multiply the above numbers by ten)
v. Urine tests are largely of historical interest
1. Ferric Chloride – 2 drops in a urine sample will turn purple
2. Trinder’s Reagent: also turns a urine sample purple
3. These should not be used if the urine sample has been “dipsticked” because the dipstick chemicals can cause false positives

General Treatment Concerns
i. Volume repletion to correct dehydration (limited in cases of pulmonary edema, renal failure, or CHF) and hypotension
ii. When mechanical ventilation is required, it is IMPERATIVE to maintain hyperventilation once the patient is sedated and intubated. Hypoventilation causes acidosis, which increases the tissue distribution of salicylates. Many cases of death from salicylates occur because this principle is neglected.
iii. Get nephrology involved as soon as the diagnosis of severe toxicity is made, because it may take several hours to get the HD equipment/personnel ready
iv. Treat hyperthermia with cooling mists and other measures, not antipyretics.
v. Coagulopathy may not respond to vitamin K, use FFP if INR> 6.
vi. Maintain euglycemia and even a moderate hyperglycemia in children who are more prone to neuroglycopenia and have low glycogen stores.
Specific Treatments
i. Decontamination: Activated charcoal in the awake and compliant patient. Use multiple doses of AC to bind the large quantitiy of aspirin (up to 100 grams) as it is slowly released from concretions
ii. Whole bowel irrigation with Go-Lytely solution is also appropriate in large ingestions.
iii. Enhanced Elimination: Salicyclic acid is renally excreted and seems to undergo tubular reabsorption as an unionized compound (proton is bound to acid). The unionized form can not be reabsorbed, so depleting protons (H+) from the urine will favor urinary elimination. This is the basis for alkalinization of the urine.
1. Bolus 2 Amps IV (or 2 mEQ/kg) and then use a bicarbonate infusion (d5W + 3 amps NaHCo3 makes an alkaline, isotonic solution) and infuse adults with 200 cc/hr if tolerated (Infuse less if there is pulm edema).
2. Aim for a serum pH for 7.45 to 7.5. Do NOT overshoot!
3. Do not need to measure urinary pH. Most older texts recommend this but urine pH is titrated so much beyond the proximal tubule (where the crucial biochemistry is happening) that it makes no sense to follow this value.
4. Even if the patient has a normal pH but severely toxic, I bolus 2 amps and start an infusion. This provides volume and helps decrease any work of breathing due to blowing off acids. However, this approach requires very close monitoring of serum pH (e.g. every 2 hours) to avoid alkalemia.
iv. Hemodialysis
1. Levels above 100 mg/dL or 60-70 in chronic toxicity are considered indications for emergent hemodialysis. However, it is important to note that these levels are MERELY GUIDELINES and other clinical considerations must also weigh in the decision.
2. Lethargy, seizures, volume overload, renal failure, multiple comorbid conditions, and severe acidosis and electrolyte problems are also important factors to consider even when the levels are “too low to dialyze.” One session is usually enough, but check a post-HD level before pulling the catheter.