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A 61-year-old woman presents to the emergency department (ED) at the University of Nebraska Medical Center in Omaha with left-sided hemiparesis. The patient explains that she awoke that morning with extreme weakness on her left side, in both her arms and legs.

She notes that when she went to bed at about 10:00 pm the night before, her strength was normal. She is not experiencing numbness or tingling in her extremities, nor does she report headache, changes in vision, or difficulty speaking.

Asked about the state of her health recently, she notes that she has felt anxious and generally unwell in the past month or so. This worsened, however, about 2 weeks previously, when she began feeling persistent pressure in her chest; this did not worsen with exertion or breathing deeply. She says she has been taking aspirin, which relieves the discomfort.

During the assessment in the ED, the patient begins to burst into fits of laughter. When speaking to clinicians, she wanders from one topic to another without ever returning to the original topic – in short, demonstrating disorganized thought processes.

She tells clinicians that about a week earlier, she fainted in public and was rescued by "masked angels." During the history taking, the patient repeatedly returns to this story, no matter the line of questioning. The clinicians note that it becomes difficult to gather further history, although she then begins to complain of blurred vision, shortness of breath, and ringing in her ears.

The woman's past medical history includes essential hypertension and generalized anxiety disorder. She has also suffered an ischemic stroke due to occlusion of the right middle cerebral artery. After the stroke, the patient developed a seizure disorder, but recovered except for residual neurologic deficits including mild left upper and lower extremity dystonia.

Her records show that she has not had a seizure for many years, since starting to take diazepam and phenobarbital to control the disorder. On reviewing her medication use, clinicians learn that she has not taken either of her seizure medications for the past week due to her sudden illness. Similarly, the patient admits that she has not been taking her prescribed antiplatelet or anticoagulant medications.

An initial neurologic examination in the ED notes slow movement and hyperreflexia in the left upper and lower extremities in the absence of objective weakness or sensory deficits. Cranial nerve examination reveals bilateral horizontal nystagmus.

The patient's vital signs are as follows:

• Temperature: 36.5°C

• Blood pressure: 102/83 mm Hg

• Heart rate: 92 bpm

• Respiratory rate: 20/min

• Oxygenated hemoglobin: 97%

The lungs are clear on auscultation, but there is a Kussmaul breathing pattern. The heart rate is regular, and the rhythm is without murmurs. The patient says she has no discomfort on palpation of the chest wall, in contrast to her reports of chest pressure and discomfort in the weeks before her arrival at the hospital.

Laboratory Results

Clinicians perform an electrocardiogram, which shows no evidence of abnormalities, and chest x-ray is normal. Due to the possibility of a recurrent stroke or transient ischemic attack (TIA), clinicians order brain magnetic resonance imaging (MRI), which shows changes from the patient's previous stroke, but no evidence of acute cerebral infarction.

The calculated serum anion gap is increased at 20 (anion gap=sodium–chloride–bicarbonate). To further assess the wide anion gap metabolic acidosis, urinalysis and measurement of serum osmolality, lactic acid, and venous blood gas are performed.

There is no evidence of a significant increase in ketone levels on urinalysis. However, blood gas testing reveals the unexpected finding of alkalosis. Based on this finding, clinicians suspect a mixed acid-base disorder with a wide anion gap metabolic acidosis and respiratory alkalosis.

Further laboratory results include the following:

• Osmolality 295 (normal range 275–295)

• Lactic acid 0.9 (0.5–2.0)

Venous blood gases:

• pH 7.46 (7.33–7.43)

• Partial pressure of carbon dioxide 21 (38–50)

• Partial pressure of oxygen 32 (30–50)

• Bicarbonate 15 (22–30)

Based on the typical acid-base findings, her tinnitus, and the Kussmaul breathing pattern, the clinicians arrive at a provisional diagnosis of salicylate toxicity. On further questioning, the patient recounts that to relieve her chest pain, she has been taking two 325 mg aspirin tablets approximately every 2 hours during her waking hours for the previous 3 weeks.

A subsequent test shows that her initial serum salicylate level was significantly increased at 78.1 mg/dL (upper therapeutic limit of 19.9 mg/dL).

Clinicians make the diagnosis of salicylate toxicity, and consult both the local poison control center and the nephrology service. Considering the evolution of symptoms in the ED, clinicians suspect the patient has some degree of acute toxicity in addition to that caused by chronic salicylate ingestion.

She receives immediate treatment with oral activated charcoal, in order to prevent systemic absorption of the salicylate taken just prior to coming to the hospital. The patient also receives intravenous crystalloid with dextrose, potassium, and sodium bicarbonate.

As recommended for patients with severe salicylate toxicity who have intact renal function, clinicians proceed with urinary alkalinization. They administer intravenous sodium bicarbonate, given as a 1,000 ml bolus followed by a continuous infusion; given that the patient is now alert and cooperative, they consider this a low-risk intervention. Clinicians also consider hemodialysis, but because the patient's neurologic manifestations are not severe and her renal function is normal, they decide it is unnecessary in this case.

They also treat the patient with intravenous dextrose, to offset the increase in central nervous system (CNS) utilization of glucose associated with salicylate toxicity, since serum glucose concentrations may not reflect those in the CNS. Dextrose supplementation is standard in management of salicylate toxicity, since damage to the CNS via neuroglycopenia can occur at normal serum glucose concentrations.

Over five serial measurements, the patient's serum salicylate levels gradually decline to 16.5 mg/dL – within the therapeutic range – about 25 hours after the initial measurement. Her metabolic acidosis, respiratory alkalosis, delirium, and hemiparesis improve significantly – at 48 hours after initial presentation, these symptoms are completely resolved. She also reports that she is no longer experiencing the chest pain, which clinicians suspect may have been related to anxiety.

Discussion

Clinicians reporting this arising from salicylate toxicity urge physicians to maintain a high index of suspicion for this cause in patients with acute neurologic symptoms, and to ask directly about salicylate use when taking a medication history.

Given this patient's age and her history of neurologic disease, she was initially diagnosed with a (new) stroke until a cerebral MRI excluded this possibility, and serum toxicology confirmed . The delay in diagnosis was a concern, the authors write, considering the potentially fatal nature of salicylate toxicity and the importance of early treatment.

Aspirin is contained in many commonly used over-the-counter medications for treatment of conditions such as osteoarthritis and headache, as well as for prevention of thromboembolism. Because these medications are often assumed to be harmless, however, patients may not report use in their medication history.

Despite these beliefs, however, salicylate overdose can cause metabolic acidosis, respiratory alkalosis, pulmonary edema, platelet dysfunction, hypokalemia, and acute kidney injury. Mortality from salicylate toxicity remains a significant clinical concern, and the risks of salicylate toxicity may be even greater in elderly patients, the authors note.

Despite the availability of alternative analgesics and recent evidence against primary prophylaxis with aspirin to prevent thrombosis, salicylate use remains widespread. Elderly patients in particular may be frequent users of salicylate-containing products. A found that almost half of individuals over age 65 reported using aspirin at least every other day.

In addition, the case authors note, accidental or intentional salicylate toxicity is not an uncommon reason for ED visits, and is often reported to poison control centers.

Timely diagnosis and treatment of salicylate toxicity is crucial to avoid fatalities, the authors warn, citing a linking salicylates with 30 fatalities and 1.3% of all medication-related deaths. Severe salicylate toxicity has been associated with a risk of mortality as high as 15%-25% when diagnosis is delayed, the authors state.

Treatment

Bicarbonate containing crystalloid has been shown to enhance urinary excretion of salicylate through alkalinization of the urine. Concomitant alkalization of blood and urine helps prevent salicylates from entering the brain tissue, while enhancing urinary excretion. Urinary excretion of salicylates increases more than 10-fold when a urinary pH of 7.5-8.0 can be maintained, the authors note.

Indications for hemodialysis include severe neurologic manifestations such as coma, hallucinations, and seizures, in conjunction with renal impairment or inability to tolerate bicarbonate infusion.

In this patient's case, and given her history of stroke, lack of suspicion of salicylate toxicity delayed assessment of her serum salicylate level for 7 hours after her presentation to the ED.

Chronic salicylate toxicity occurs more commonly in elderly patients and often . Furthermore, depending on the timing of ingestion, salicylate toxicity may present without an increased anion gap or even with a normal initial serum salicylate level. As well, neurologic manifestations of salicylate toxicity such as delirium are often unrecognized as such. Chronic ingestion can masquerade as other neurological conditions such as stroke or movement disorders.

In this case, the neurologic presentation resulted in consideration of several diagnoses other than salicylate toxicity. The authors note that once a brain MRI had eliminated potential stroke or TIA, some of her presenting features and her admitted lapse in taking her anti-epileptic medication suggested postictal paresis, also known as Todd's paresis -- this, however, would be unlikely without a history of prolonged seizures or status epilepticus. The patient said she had not had any recent seizure activity.

Based on this patient's history of previous ischemic stroke and her recent illness, the most likely diagnosis is thought to be a toxic or metabolic disturbance resulting in an exacerbation of existing neurologic deficit. Exacerbation of an existing neurologic deficit is well recognized as a manifestation of both infection and hypoglycemia, but has not previously been associated with salicylate toxicity, the case authors note.

In addition, they said, because the case illustrates that atypical neurologic symptoms may precede both delirium and tinnitus in the course of salicylate toxicity, awareness is crucial to avoid potentially fatal delays in diagnosis.

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