Chronic salicylate toxicity
The case
A 65-year-old woman presents with altered mental status and shortness of breath. According to her roommate, the patient has had more confusion and disorientation over the last few days. She had gone to her primary care physician to be evaluated and was subsequently referred to the Emergency Department to rule out an acute cerebrovascular accident. Her medical history is significant for hypertension, hyperlipidemia, hypothyroidism, and panic disorder. She is on chronic tricyclic antidepressant (TCA) therapy.
She was seen in the ED three weeks prior after a syncopal episode, monitored in the observation unit overnight, and discharged home with the diagnosis of pneumonia. She had negative cardiac stress testing at that time. She was treated with a 10-day course of antibiotics, and yet continued to report dyspnea.
Her current exam is notable for tachypnea, but otherwise is unremarkable. She seems to be taking deep breaths while speaking to the providers, but her O2 sat is 97-100%. She has no risk factors for pulmonary embolism.
Her chest X-ray and head CT are unremarkable. Her urinalysis is mildly concerning for infection, so she receives a dose of empiric ceftriaxone.
Now for the interesting part - the labs:
Why does she have an elevated anion gap metabolic acidosis? The providers next checked a venous blood gas:
So she actually has what looks like a compensated respiratory alkalosis (based on the degree of HCO3 compensation in the setting of several days of hyperventilation).
On further questioning, the patient reports taking up to six 325 mg aspirin tablets daily for the past several weeks.
The brush up
Chronic salicylate toxicity is more common than acute in older patients; we often overlook it because of its subtle clinical presentation and the fact that most patients are taking regular therapeutic doses. Consider this in your differential diagnosis for older patients presenting with altered mental status/delirium or respiratory symptoms. Cerebral and noncardiogenic pulmonary edema are more common with chronic salicylate toxicity, and these may increase the need for intubation for airway protection or respiratory failure. If at all possible, however, you should AVOID intubating any patient with severe salicylate poisoning. More on this in a moment.
Another challenging aspect of diagnosis is that the serum salicylate level does not necessarily correlate with symptoms. The value is usually lower than that seen in acute toxicity, but don't let this fool you. Generally speaking, a level greater than 60 mg/dL with associated symptoms and lab findings should get you worried about severe toxicity. Don't use of the Done nomogram, especially in chronic toxicity; it's not reliable.
The mainstays of therapy for chronic salicylate toxicity are aggressive fluid resuscitation (to correct volume/insensible losses) and urinary alkalinization (to a urine pH of at least 7.5). In other words, we aim to keep salicylate out of the central nervous system (CNS) and encourage renal excretion.
Not surprisingly, overdose and acidemia significantly affect the pharmacokinetics (and subsequently your ability to treat toxicity). With therapeutic doses, the liver does most of the metabolism via first order kinetics (meaning the rate of metabolism is proportional to the serum drug concentration, and a constant proportion of the drug is eliminated per unit of time). In overdose (i.e. hepatic metabolism is maxed out), there is more reliance on renal excretion, and metabolism is now independent of serum concentration and will not increase despite serum levels (zero order kinetics). In a relative sense, metabolism slows down (and now a constant amount of drug is eliminated per unit of time).
This results in a prolonged half-life (up to 18-36 hours). Additionally, acidemia will increase the volume of distribution (and promote movement of the unionized drug into tissues including the CNS, see below), which creates an additional barrier for elimination.
Remember that these patients develop tachypnea as a compensatory reaction to metabolic acidosis (in the acute setting, respiratory center stimulation will also result in hyperventilation). This is critical; it's what's keeping them alive. Therefore, you must avoid impairing the patient's respiratory drive with sedation/anxiolysis or paralysis. An even transient pH dip into acidemia will neutralize salicylate ion to its unionized form, which easily crosses the blood-brain barrier. CNS salicylate concentration directly correlates with mortality.
Here is a suggested way to administer sodium bicarbonate (8.4%, 1 mEq/mL commonly supplied in 50 mL (50 mEq) ampules):
* Bolus: 1-2 mEq/kg (generally at least 1 ampule for adults); infuse over 1-2 minutes
* Infusion: 3 ampules (150 mEq) in 1 liter 5% dextrose in either water or quarter-normal saline + 30-40 mEq potassium; infuse at 150-200 mL/hr
Of course, you will need to use extreme caution with IV fluids if there is any evidence of cerebral or pulmonary edema. In these cases, enhanced elimination with hemodialysis may be more effective. The best available evidence suggests that extracorporeal treatment for salicylate toxicity is beneficial for patients with signs of severe toxicity including altered mental status, acute respiratory distress syndrome, or in cases refractory to standard therapy (level 1D recommendations).
If you want to brush up on the management of acute salicylate toxicity, check out my expert peer-reviewed post on ALiEM.
The conclusion
The providers contacted the regional Poison Control Center. They started the patient on a sodium bicarbonate continuous infusion and admitted her to the internal medicine service. She did not require hemodialysis. She had progressively declining serum salicylate levels during therapy, and concomitantly her mental status and respiratory symptoms normalized. She was discharged on hospital day 4 with no residual symptoms.
References
1. Olson KR & California Poison Control System. (2012). Poisoning & drug overdose. New York: Lange Medical Books/McGraw-Hill.
2. Boyer EW and Weibrecht KW. Salicylate (aspirin) poisoning in adults. In: UpToDate, Grayzel J (Ed), UpToDate, Waltham, MA, 2016.
3. Long, N. Life in the Fast Lane: Salicylates. [blog post]. Retrieved from:
http://lifeinthefastlane.com/tox-library/toxicant/analgesia-and-anti-inflammatories/salicylates/
4. Juurlink DN, Gosselin S, Kielstein JT, Ghannoum M, Lavergne V, Nolin TD, Hoffman RS. Extracorporeal treatment for salicylate poisoning: systematic review and recommendations from the EXTRIP workgroup. Ann Emerg Med 2015 Aug;66(2):165-81.