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aspirinExpertPeerReviewStamp2x200Salicylate is among the top 25 substances that cause the greatest number of overdose fatalities in the United States (1). Patients can present with a wide variety of complaints including tinnitus, dyspnea, vomiting, confusion, and coma. Significant toxicity occurs when a large amount of salicylate saturates the body’s protein-binding capacity and leaves free salicylate in the serum (2). The American College of Medical Toxicology (ACMT) recently published a guidance document on management priorities in salicylate toxicity, and it’s definitely worth a read (3). While not an official clinical guideline, it highlights some important concepts to consider when working up and treating patients after a significant salicylate exposure, and we’ll review five major concepts here and hopefully answer some questions that may cross your mind on shift.

1. Serum salicylate concentration: Check it early, check it often

Check a serum salicylate level with your initial labs (Table 1). While the Done nomogram is available and well-intentioned, it is NOT a reliable tool in determining level of toxicity based on time of ingestion and drug level, so you should consider the salicylate level in the context of the patient’s whole clinical picture. The number alone won’t provide enough information if the patient is well-appearing (unless it’s extremely elevated, say > 100 mg/dL, in which case you should consult with nephrology to discuss hemodialysis early). Plan to check levels every 2 hours. Important: Be familiar with your laboratory’s concentration units (e.g. mg/dL, mmol/L), as they differ between sites.

Table 1: Recommended laboratory studies in acute salicylate poisoning

For ALL patients (especially if symptomatic)
For those with MODERATE to SEVERE poisoning, add on:
Arterial blood gasComplete blood count
Renal function panel (blood urea nitrogen (BUN) and creatinine)Coagulation studies (prothrombin time, partial thromboplastin time)
Serum electrolytes (sodium, potassium, chloride, bicarbonate, calcium)Liver function panel
Serum glucose
Serum lactate
Serum salicylate concentration
Urinalysis (urine pH)
Urine pregnancy test

The serum salicylate level is low. Am I done?

If you have a history that supports salicylate poisoning, the actual serum salicylate concentration does not matter as much as the trend in serially checked levels and the correlation between changing levels and the patient’s clinical status. A stable patient with declining serum levels indicates decreasing absorption. Rarely, patients may exhibit delayed toxicity after an acute salicylate overdose, so if the history supports a massive ingestion and the initial salicylate levels are low, plan to observe or admit the patient (in conjunction with toxicology and nephrology consultations, if available) (4). 

And remember, your serum test is measuring just that – serum levels. Anything that’s in the CNS or other tissues won’t be detected, so if you have an undetectable serum level in a patient who’s becoming obtunded, this is an ominous clue that the patient may be suffering from CNS acidemia. This can lead to cerebral edema and seizures, among other neurologic sequelae.

2. Acid-base status, volume status, and electrolytes: Keep salicylate out of the CNS

Arterial blood gas (ABG) analysis and serum electrolyte measurements are crucial components in working up salicylate ingestion. Traditionally (and for boards), we learn that the classic acid-base disturbance in salicylate poisoning is a mixed (primary) respiratory alkalosis and metabolic acidosis with an elevated anion gap; however, this is not a hard and fast rule. What you should know is that an acidemic pH is BAD. Clinical toxicity correlates with serum pH, with lower pH (< 7.40) seen in sicker patients. Arguably the most important goal of treatment is achieving a slightly alkalemic pH (usually 7.50-7.55). Acidemia causes salicylates to circulate in its uncharged (or deprotonated) form, which allows it to cross the blood-brain barrier into the central nervous system (and salicylate in the CNS is what correlates with lethality) and be reabsorbed by the renal collecting system. 

But wait, the anion gap is normal!

The anion gap may appear normal possibly due to a pseudohyperchloremia due to the presence of salicylate. Assuming the patient has no other (e.g. renal or endocrine) reason to have an elevated chloride level, a false measurement is probably a product of lower selectivity of the analyzer’s chloride electrode in the face of high salicylate levels (5). While this may not have any immediate clinical implications, it’s helpful to know that patients don’t present in a textbook fashion every time.

What is the role of bicarbonate in salicylate poisoning?

Bicarbonate administration is one of the mainstays in preventing worsening illness from salicylate poisoning, not only because it promotes the alkalemia that keeps salicylate in its ionized form (and away from the CNS) but because it also replenishes the bicarbonate that is lost in the urine due to the initial respiratory alkalosis. However, effective urinary alkalinization is a multi-faceted approach that includes early crystalloid volume resuscitation and replenishment of several key electrolytes. The initial alkalosis in salicylate toxicity induces sodium, potassium, and bicarbonate excretion in the urine to conserve hydrogen ions. So, even if the serum levels of these electrolytes are normal or slightly low, supplementing your fluids with these will enhance renal flow and urine alkalinization. Glucose levels can be high, normal, or low. What’s more important is that CNS glucose utilization goes up in salicylate poisoning, and adding glucose to your fluids will decrease the risk of a bad outcome from neuroglycopenia.

Overall, the suggested approach to fluids in the ACMT document is to dissolve 3 ampules of sodium bicarbonate and 30-40 mEq of potassium chloride into 1 liter of 5% dextrose and infusing that to a urine output of 2-3 mL/kg/hr (so plan to place a bladder catheter in these patients). 

My patient is in acute renal failure. Is it safe to give them fluids? Don’t they just need dialysis?

It is important to realize that salicylate toxicity leads to significant volume depletion through vomiting, osmotic diuresis, and insensible losses (such as diaphoresis and tachypnea) of up to 4-6 liters in severe cases (6). If the patient looks dry or has other signs of hypovolemia (reduced skin turgor, tachycardia, hypotension, or a collapsible IVC on bedside ultrasound), fluid boluses may be more helpful than you think. 

3. Gastrointestinal decontamination: Consider activated charcoal

If a salicylate-poisoned patient presents within the first 4 hours after ingestion, consider a single dose of oral activated charcoal (at least 50 grams) if there are no contraindications (meaning they must have normal mental and respiratory statuses). While it’s unclear if activated charcoal actually improves outcomes, it may at least decrease absorption from the GI tract (7). Evidence for multidose activated charcoal (MDAC) is controversial. Again, you might consider giving multiple doses if the patient can tolerate it, but keep in mind it may not affect their outcome. Optimal dosing is unknown though available data suggest there is no difference in amount of reabsorption for any dosing regimen equivalent to 12.5 g/hr (such as 25 g every 2 hours or 50 g every 4 hours) (8).

4. Airway protection and respiratory status: Hyperventilate to maintain alkalemia

Just like a sick asthmatic, a patient with severe salicylate poisoning is someone for whom you want to avoid intubation, if possible. Intuitively, this should make sense. The metabolic acidosis leads to hyperventilation, which is really the only defense these patients have in the face of urinary bicarbonate excretion. Sedating and paralyzing these patients in the standard fashion, then, will eliminate this intrinsic compensatory process and acutely worsen the acidosis. There is very little available data on outcomes after mechanical ventilation in salicylate poisoning, but some case reports have documented acidemia and deaths shortly after intubation (9). While there are no prospective studies to guide our management in this critical juncture, the ACMT document recommends giving sodium bicarbonate boluses in the peri-intubation period and maintaining a high minute ventilation (by increasing your tidal volume and/or respiratory rate) to keep the serum pH alkalemic.

5. Enhanced elimination: Consider hemodialysis for signs of any end-organ dysfunction

While a stable patient with functioning kidneys can effectively eliminate salicylate with alkaline diuresis alone, this process may take days. The ACMT document recommends involving medical toxicology and nephrology consultants early to avoid delays in management and achieve the best possible outcome. Table 2 lists the general indications for considering hemodialysis in salicylate poisoning. Hemodialysis typically resolves toxicity in several hours, but it takes some time to set up. If a patient is ill or deteriorating, don’t wait for the serum salicylate level to return to decide on the next steps. Start treating toxicity as outlined above as a temporizing measure. 

Table 2: Indications for emergent hemodialysis consideration in acute salicylate poisoning (10)

For all patients
For moderate to severe poisoning
Markedly elevated serum concentrations (>100 mg/dL), even without clinical findingsSerum concentrations in or above therapeutic range and:
CNS dysfunction (e.g. delirium, lethargy, seizures, coma) with no other explanation
Renal failure
Pulmonary edema/hypoxia
Severe acid-base or electrolyte imbalance with no other explanation

There is no antidote for salicylate poisoning. The key concepts outlined in the ACMT guidance PDF document are a helpful tool in determining severity of toxicity and how to approach management. Take a look before your next shift!

References

  1. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila) 50(10):911-1164 (2012).
  2. Kerr F, Krenzelok EP. Chapter 48 – Salicylates. Shannon: Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose, 4th ed. Philadelphia (2007).
  3. Guidance Document: Management Priorities in Salicylate Toxicity. ACMT (2013). 
  4. Herres J, Ryan D, Salzman M. Delayed salicylate toxicity with undetectable initial levels after large-dose aspirin ingestion. Am J Emerg Med 27(9):1173.e1-3 (2009).
  5. Jacob J, Lavonas EJ. Falsely normal anion gap in severe salicylate poisoning caused by laboratory interference. Ann Emerg Med 58(3):280-281 (2011).
  6. Temple AR. Acute and Chronic Effects of Aspirin Toxicity and Their Treatment. Arch Intern Med 141(3):364-369 (1981).
  7. Chyka PA, Seger D, Krenzelok EP, Vale JA; American Academy of Clinical Toxicology; European Association of Poison Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 43(2):61-87 (2005).
  8. Ilkhanipour K, Yealy DM, Krenzelok EP. The comparative efficacy of various multiple-dose activated charcoal regimens. Am J Emerg Med 10(4):298-300 (1992).
  9. Stolbach AI, Hoffman RS, Nelson LS. Mechanical ventilation was associated with academia in a case series of salicylate-poisoned patients. Acad Emerg Med 15(9):866-869 (2008).
  10. Fertel BS, Nelson LS, Goldfarb DS. The underutilization of hemodialysis in patients with salicylate poisoning. Kidney Int 75(12):1349-1353 (2009).

Expert Peer Review 

November 1, 2013

Salicylate toxicity, whether acute or chronic, represents one of most challenging overdoses that an emergency practitioner or medical toxicologist can confront. The difficulties start with making the diagnosis in the first place. As Dr. Fontes mentions in her excellent review of managing these cases, salicylate poisoning can present with varied and confusing manifestations, not only tinnitus, dyspnea, vomiting and altered mental status, but also respiratory alkalosis, metabolic acidosis, hyperglycemia, fever and noncardiogenic pulmonary edema. Without a clear history, these cases can be misdiagnosed initially as viral pneumonia, sepsis, or diabetic ketoacidosis, among others. In such cases, it is important to avoid cognitive errors such as premature closure and anchoring, and consider salicylate toxicity in the differential diagnosis.

There are many potential pitfalls in treating these patients. Careful attention to fine points can make the difference between a bad clinical outcome and complete recovery. Both Dr. Fontes, and the American College of Medical Toxicology guidance document discuss these considerations in detail, but it is important to re-emphasize some key points: 

  1. Seek help! Patients who present with minimal symptoms and a low (or even undetectable) salicylate level can still deteriorate suddenly and catastrophically. The local poison control center should be consulted in almost all these cases.
  2. Rehydrate aggressively and appropriately! Fluid losses in these patients are often underestimated. This would be an excellent setting to use bedside ultrasound to look at the inferior vena cava. A small IVC that collapses significantly with inspiration (in the non-intubated patient) indicates significant dehydration and need for volume repletion. Remember, though, that a plump, non-collapsible IVC does not necessarily mean that the patient will not respond to fluids, especially in the presence of complicating conditions such as chronic pulmonary hypertension.
  3. But don’t overhydrate! Although it is important to correct volume deficits and maintain urine output, I’m not sure that there is a major benefit from forced diuresis, or that the value of placing a urinary catheter in most patients would outweigh the negatives (e.g., patient discomfort). With ultrasound, we now have better ways of evaluating fluid status.
  4. Pay attention to contraindications to administrating activated charcoal! As Dr. Fontes rightly points out, the benefit of giving single-dose or multi-dose activated charcoal in these cases has never been demonstrated. Because salicylates can form concretions or bezoars in the stomach, there is theoretical justification for giving a charcoal bolus and then several smaller doses (e.g., 25 gm every 2 hours in an adult). However, if there is any indication of progressive deterioration, altered mental status, or inability to protect the airway, this should be withheld. The ACMT guidance document mentions that whole bowel irrigation can be considered. This is, in my opinion, nonsense. WBI has never been shown to improve outcome in this situation, and is associated with significant complications. Dr. Fontes is wise in not repeating that knee-jerk but meaningless suggestion.
  5. Consider carefully before intubating! For the reasons stated in Dr. Fontes’ review, intubating a patient with severe salicylate toxicity for respiratory failure is very hazardous but sometimes necessary. Even a short period of increasing respiratory acidosis can be lethal in this situation. The available clinician with the most skill and experience in airway control should do the procedure — it’s not the time to let the intern make the first attempt and the junior resident the second.  After the airway is secure, the patient must be hyperventilated to prevent accelerating academia. I would do this primarily by increasing the respiratory rate, NOT the tidal volume. The ACMT document does not offer support for their recommendation for an IV bolus of sodium bicarbonate at the time of intubation. It seems like speculation, possibility based on the feeling that it would buy a small amount of time, and that paradoxical intracellular acidosis might not necessarily be bad since it could decrease the amount the salicylate trapped in tissues.

I’d point out that the ACMT document covers both acute and chronic salicylate toxicity. Although 100 mg/dl is the level usually mentioned at which to consider hemodialysis in acute overdose, a level even as low as 40 mg/dl would be concerning in the setting of chronic overdose and any symptoms.”

Reference: Bora K, Aaron C. Pitfalls in salicylate toxicity. Am J Emerg Med 2010 Mar;28(3):383-4. PMID 20223401

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Kristin Fontes, MD

Kristin Fontes, MD

PGY-3 and Chief Resident
Stanford-Kaiser EM Residency Program
Kristin Fontes, MD

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