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NAC therapy is generally indicated in 3 different

patient cohorts. Start NAC in patients with (1) acute

ingestions and 4-hour levels that lie above the nomogram

cutoff, (2) in patients who report significant ingestions if

obtaining a level will be significantly delayed, and (3) in

those with evidence of hepatoxicity presumed secondary

to APAP regardless of APAP level.

ACETAMINOPHEN TOXICITY

Seek early consultation with a liver transplant center if

the patient shows any signs of deterioration ( eg, altered

mental status, acidosis, worsening liver function) . I deally,

the patient should be transferred before meeting liver

transplantation criteria.

DISPOSITION

� Admission

Admit all patients who require treatment with NAC or

demonstrate any signs of hepatotoxicity. Patients with

hemodynamic instability, altered mental status, systemic

acid-base derangements, and evidence of end-organ

damage require admission to a critical care setting. Patients

with intentional overdoses require psychiatric assessment.

� Discharge

Patients with unintentional ingestions who exhibit no signs

of hepatotoxicity and have downtrending serum APAP levels

in the nontoxic range can be safely discharged home.

SUGGESTED READING

Dart RC, Rumack BH. Patient-tailored acetylcysteine adminis ­

tration. Ann Emerg Med. 2007;50:280-28 1.

Kanter MZ. Comparison of oral and IV acetylcysteine in the

treatment of acetaminophen poisoning. Am ] Health Syst

Pharm. 2006;63:1821-1827.

Rumack BH. Acetaminophen hepatotoxicity: the first 35 years.

J Toxicol Clin Toxicol. 2002;40:3-20

Salicylate Toxicity

Steven E. Aks, DO

Key Points

• Salicylate toxicity causes a mixed respiratory alkalosis,

metabolic alkalosis, and elevated anion gap metabolic

acidosis.

• Chronically intoxicated patients will be more seriously

ill at lower salicylate concentrations than their acutely

poisoned counterparts.

• Pursue hemodialysis in patients with refractory acidosis,

pulmonary edema, renal insufficiency, and altered

INTRODUCTION

Analgesics are among the most commonly ingested

substances in patient overdose. According to the National

Poison Data System, there were more than 300,000 cases of

analgesic overdose reported in the year 2009, with salicylates

accounting for the 1 3th most common cause of isolated

drug ingestion and 62 total fatalities. Aspirin is most often

ingested in some form of aspirin-containing combination

product such as over-the-counter cold remedies. It can also

be found as a component in various prescribed combination

products such as Fiorinal, Soma Compound, and Percodan.

Methyl salicylate, the major component of oil of wintergreen,

is commonly found as a rubefacient in various medical

products such as Ben Gay and in multiple household items,

including air fresheners and mouthwash. One teaspoon of

98o/o methyl salicylate can contain as much as 7 g of salicylate

(>20 tablets of 325 mg aspirin).

Aspirin absorption can be very erratic with peak

concentrations occurring > 20 hours after ingestion. That

said, levels obtained six hours after ingestion generally

reveal evidence of toxicity. Salicylate metabolism follows

Michaelis-Menten kinetics. At concentrations over

30 mg/dL, salicylates are metabolized by zero-order kinetics

due to enzyme saturation. This means that a constant

mental status or seizure, regardless of the actual serum

salicylate level.

• Match the ventilation rate in intubated patients with

severe sal icylate poisoning to their pre-intu bation

minute ventilation, as most req uire rema rkably high

rates for adequate respiratory compensation.

amount will be eliminated per unit of time. Below this

concentration, salicylate metabolism follows first-order

kinetics, with elimination rates proportional to serum

salicylate concentrations.

In overdose scenarios, salicylates induce a mixed acidbase disorder. They cause an initial respiratory alkalosis by

directly stimulating the medullary respiratory center. In

addition, excessive circulating salicylate induces lipolysis,

inhibits the Krebs cycle, and uncouples oxidative

phosphorylation. This process impairs normal cellular

respiration, resulting in the accumulation of organic acids and

a secondary elevation in the anion gap. Furthermore, volume

depletion secondary to excessive vomiting can lead to a

concurrent metabolic alkalosis. Therefore, the classic

(although far from uniformly present) acid-base disorder

with salicylate poisoning is a mixed respiratory alkalosis,

metabolic alkalosis, and elevated anion gap metabolic acidosis.

CLINICAL PRESENTATION

� History

It is very important to determine the amount ingested and

the timing of exposure. In addition, try to distinguish

between acute, chronic, and acute on chronic ingestions.

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SALICYLATE TOXICITY

Patients with chronic intoxication often present with more

subtle signs of toxicity. For example, elderly patients may

present with isolated signs of altered mental status or tinnitus. Conversely, acutely poisoned patients typically present

with more dramatic findings, including nausea, vomiting,

tachypnea, diaphoresis, and altered mental status. Attempt

to identify the exact type of product ingested. Immediaterelease aspirin will produce much more rapid symptom

onsets and elevated salicylate concentrations compared to

the enteric-coated variety. Patients who ingest combination

products may exhibit toxic effects from the secondary agent

( eg, a concurrent opiate toxidrome from ingestion of a combined salicylate-opioid analgesic).

� Physical Examination

Pay very careful attention to patient vital signs. Patients are

frequently tachycardic due to significant volume loss.

Tachypnea is common secondary to stimulation of the

medullary respiratory center and as a compensation for

the metabolic acidosis. Fever can occur as a result of uncoupiing of the oxidative phosphorylation chain. Finally,

hypoxia may be present secondary to salicylate-induced

acute lung injury (ALI).

The remainder of the exam should focus on the skin,

abdomen, and neurologic systems. Diaphoresis is an

important sign in moderate to severe salicylate toxicity.

Abdominal tenderness can be present because of the

erosive effects of salicylate on the gastric mucosa. Patients

may display alterations in their mental status. This can be

a presenting sign in the chronically intoxicated patient or

may accompany significant acute poisonings. Seizures may

also be present in advanced cases.

DIAGNOSTIC STUDIES

� Laboratory

Obtain a complete blood count, chemistry panel, urinalysis, and bedside urinary pregnancy test. Calculate the

anion gap and follow it serially. Order a serum blood gas to

look for evidence of a mixed acid-base disorder. Check

salicylate concentrations every 2 hours until a peak concentration and subsequent decline has been observed, as

pharmacobezoar formation is not uncommon with sec ­

ondary erratic absorption. It is also wise to obtain a serum

acetaminophen concentration because of the prevalence of

readily available combination analgesics and their high

rates of use in patient overdoses.

� Imaging

Imaging studies are generally unrewarding to detect

ingested salicylates. A routine chest radiograph should be

obtained to assess for ALI.

PROCEDURES

Meticulous attention should be paid to the airway. The

decision to intubate a patient in the face of salicylate overdose is truly a life or death decision. Many patients with

severe salicylate poisoning have very high minute ventilations exhibited by both an increased depth of respiration

and a high respiratory rate. It is sometimes difficult, if not

impossible, to mechanically reproduce a salicylate-poisoned

patient's minute ventilation. If you are forced to intubate a

salicylate-poisoned patient, the ventilator rate needs to be

set very high to replicate the pre-intubation minute ventilation. Frequent post-intubation blood gases should be

obtained to be sure that the pH does not drop.

MEDICAL DECISION MAKING

Always obtain a thorough history from the patient, family,

and paramedics on what substances may be ingested.

Determine whether the patient's presentation is consistent

with an acute or chronic exposure.