Figure 66.1. Rumack–Matthew nomogram. (Courtesy of Graham Walker, MD.)

Critical management

• Activated charcoal can be given as a gastric decontaminant:
  
  
  
  • It is most effective if given in the first hour.
    
  • It can absorb co-ingestants as well.
    
  • It is harmful if aspirated. The patient must be alert and cooperative.
  
  
• Gastric lavage is rarely indicated.
  
  
  
  • It can be considered in cases of recent highly toxic co-ingestions.
  
  
• N-Acetylcysteine (NAC) is life saving if given early enough.
  
  
  
  • Draw an acetaminophen level and plot it on the nomogram if the time of ingestion is known.
    
    
    
    • Note that the nomogram starts at 4 hours post ingestion. Levels drawn earlier than this will generally not be helpful to guide treatment.
    
    
  • Begin treatment if the level is above the treatment line on the nomogram.
    
  • Preparing the appropriate NAC infusion should be done after discussion with a pharmacist.
    
  • N-Acetylcysteine has been shown to completely reverse the effect of an acetaminophen overdose if administered within 8 hours after the ingestion. It still offers protective effects up to 24 hours after ingestion although the success rate decreases proportionally to the delay.
    
  • If a patient presents at 8 hours or later after a toxic ingestion, do not delay treatment while waiting for an acetaminophen level.
    
  • NAC can be given orally or intravenously (IV).
    
    
    
    • Oral NAC can cause nausea and vomiting, making its administration sometimes difficult.
      
    • IV NAC can rarely cause anaphylactoid reactions.
      
    • The intravenous route has not been shown to be superior to the oral regimen, but intravenous treatment is usually preferred.
    
    
  • Therapy is discontinued once acetaminophen metabolism is complete (level <10 micrograms/mL) and liver injury is resolving (normal or near normal enzymes, absence of encephalopathy or coagulopathy).
  
  
• Some patients with severe overdoses and meeting certain criteria may be candidates for liver transplantation. Various scoring systems exist to help decide which patients should be referred to a liver transplantation center:
  
  
  
  • King’s College Criteria (Table 66.1)
    
  • Lactic acidosis >3.5 mg/dL after early fluid resuscitation
    
  • Phosphorus >3.75 mg/dL at 48 hours
    
  • Apache II score >15.

Sudden deterioration

• These patients can develop sepsis with multi-organ failure.
  
  
  
  • Initiate hemodynamic support with intravenous fluids and vasopressors or inotropes as per the early goal-directed therapy protocol.
    
  • Respiratory support with oxygen, noninvasive ventilation, or intubation may be required.
  
  
• ARDS should be managed by endotracheal intubation and ventilator settings in accordance with the ARDSNet guidelines.
  
• Patients with evidence of renal failure should have their electrolytes checked and corrected. Hemodialysis may have to be initiated after consultation with a nephrologist.
  
• Cerebral edema and herniation are very difficult to treat successfully. Mannitol, hypertonic saline, or cranial decompression can be attempted in the rapidly decompensating patient.

Aspirin

Overview

• Aspirin (acetylsalicylic acid, ASA) is a weak acid that is widely used and is present in many mixed preparations.
  
• It is rapidly absorbed in its uncharged, nonionized form, in the acidic environment of the stomach.
  
• In nontoxic ingestions, the majority of the salicylate is protein-bound and free salicylate is mostly ionized.
  
• In overdose, albumin becomes saturated and free salicylate concentration increases:
  
  
  
  • As acidosis worsens, more salicylate exists in nonionized form.
    
  • This crosses into tissues and exerts toxicity, especially in the central nervous system (CNS).
  
  
• Aspirin is normally metabolized by the liver through conjugation.
  
  
  
  • In overdose, enzymes become saturated and renal elimination becomes important.

Presentation

Classic presentation

• May be asymptomatic
  
• Tinnitus or impaired hearing
  
• Hyperventilation
  
• Nausea and vomiting
  
• Hyperthermia
  
• Dehydration
  
• Mixed acid–base disturbance:
  
  
  
  • Respiratory alkalosis from direct stimulation of the medulla
    
  • Anion gap metabolic acidosis from uncoupling of oxidative phosphorylation.

Critical presentation

• Cerebral edema resulting in altered mental status, coma, convulsions
  
• Pulmonary edema
  
• Coagulopathy
  
• Acute renal failure
  
• Gastrointestinal (GI) hemorrhage
  
• Severe acid–base imbalance.

Diagnosis and evaluation

• A good history is critical, including the amount of drug taken and the time of ingestion.
  
• Early signs usually include tinnitus, nausea, and vomiting.
  
• On examination the patient may be hyperthermic, tachycardic, hyperpneic, diaphoretic, and confused.
  
• A salicylate level should be ordered even though it does not always correlate with toxicity.
  
• Electrolytes should be checked specifically for renal function and potassium level:
  
  
  
  • Renal failure will prevent elimination of salicylates.
    
  • Hypokalemia will hinder urinary alkalinization.
  
  
• Arterial or venous blood gas to monitor pH.
  
• Lactic acid concentration.
  
• Always check an acetaminophen level in any suspected toxic overdose as co-ingestion is common.

Critical management

• Activated charcoal should be given as gastric decontaminant.
  
  
  
  • It can absorb co-ingestants as well.
    
  • It is harmful if aspirated. The patient should be alert and cooperative.
  
  
• Gastric emptying with lavage can be considered in early presentations of massive overdoses.
  
• Aggressive fluid resuscitation is indicated as most patients are hypovolemic due to vomiting, tachypnea, and hyperthermia.
  
• Airway management:
  
  
  
  • Although endotracheal intubation may be necessary for airway protection, attempt to avoid intubation if possible as it is difficult for the ventilator to maintain as high a minute ventilation as a tachypneic person.
    
  • The patient may not tolerate even a brief episode of apnea if severely acidemic.
    
  • Consider awake intubation.
    
  • If awake intubation is not possible, consider a sodium bicarbonate bolus with 100 mEq of sodium bicarbonate prior to the initiation of rapid sequence intubation.
  
  
• Ventilator settings:
  
  
  
  • These patients are usually acidemic and will require a high minute ventilation to compensate for the metabolic acidosis.
    
  • An arterial or venous blood gas should be drawn 10–15 minutes after intubation and the tidal volume and respiratory rates should be adjusted to achieve a PaCO₂ of 35–40 mmHg.
  
  
• Urinary alkalinization is the mainstay of therapy.
  
  
  
  • It is achieved by administering a sodium bicarbonate bolus followed by a drip:
    
    
    
    • Bolus 1–2 mEq/kg IV.
      
    • Prepare a drip by mixing three ampules (50 mEq each) of sodium bicarbonate in 1 liter of D5W. Run at twice the maintenance rate.
      
    • Titrate to a urine pH >7.5.
      
    • Consider adding 40 mEq of potassium chloride to fluids.
      
    • Do not mix the sodium bicarbonate into normal saline or the solution will be hypertonic.
    
    
  • Alkaline urine will trap salicylate ions and allow for excretion.
    
  • Alkalinization of serum relative to CSF will prevent transfer of salicylate into the brain.
    
  • Maintain normal potassium levels by repleting if necessary as hypokalemia will prevent the excretion of acid into the urine.
  
  
• Serial salicylate levels should be checked to monitor therapy effects.
  
  
  
  • Continue therapy until the levels are at or below 30 mg/dL.
    
  • Concretions of aspirin may exist in the GI tract and cause a delayed peak of salicylate level.
  
  
• Hemodialysis is the definitive treatment:
  
  
  
  • Treats acid–base disturbances and removes salicylate from blood.

Sudden deterioration

• Decline in mental status, coma, or seizure can be caused by cerebral edema.
  
  
  
  • Any alteration in mental status should lead to consideration for hemodialysis.
  
  
• Fluid overload can result in pulmonary edema and respiratory failure.
  
  
  
  • Dialysis should be initiated in patients that are not able to tolerate the fluid load necessary for urine alkalinization.
    
  • Intubation may be necessary and should be done early before the development of severe acidemia.
  
  
• Patients with salicylate overdose are also at risk of life-threatening GI bleeding and administration of blood product should be initiated in those patients.

Tricyclic antidepressants

Overview

• Tricyclic antidepressants (TCAs) are mostly used for the treatment of neuropathic and chronic pain.
  
• TCAs are rapidly absorbed in the GI tract.
  
• They have multiple physiological effects.
  
  
  
  • Sodium channel blockade:
    
    
    
    • Type Ia (quinidine-like) dysrhythmic effect: blocks fast inward sodium channels at phase 0 of myocyte depolarization.
      
    • Decreases conduction with QRS prolongation.
      
    • Negative inotropy.
    
    
  • Anticholinergic effect: mental status changes, seizures, coma.
    
  • Alpha-1 adrenergic blockade: vasodilation, hypotension.
    
  • Antihistamine effect: sedation.
    
  • Serotonin, norepinephrine, and dopamine reuptake inhibition:
    
    
    
    • Antidepressant effect at therapeutic doses.
      
    • In overdose, transient hypertension is followed by hypotension and bradycardia as catecholamines are depleted.
      
    • Also contributes to agitation and seizures.
  
  
• Death is most often due to refractory hypotension and cardiovascular collapse.

Presentation

Classic/critical presentation

• Anticholinergic effects initially predominate:
  
  
  
  • Sinus tachycardia, hypertension, agitation, pupillary dilation, dry and flushed skin, hyperthermia.
  
  
• QRS complex widening on ECG with terminal R wave in lead aVR.
  
• Rapid deterioration usually occurs within 30–60 minutes of presentation.
  
• Altered mental status, coma, seizures.
  
• Ventricular dysrhythmias.
  
• Hypotension.

Diagnosis and evaluation

• The diagnosis is made based on history, clinical presentation and ECG findings (Figure 66.2).
  
• A dose of >10 mg/kg of most TCAs is considered life-threatening.
  
• ECG findings:
  
  
  
  • The most common findings are sinus tachycardia and a right axis deviation.
    
  • QRS prolongation (>100 milliseconds):
    
    
    
    • <100 milliseconds: no significant toxicity.
      
    • >100 milliseconds: 30% will have seizures.
      
    • >160 milliseconds: 60% will have ventricular dysrhythmias.
    
    
  • Rightward deviation of the terminal 40 milliseconds of QRS.
    
    
    
    • Lead aVR: large (>3 mm) terminal R wave or R/S ratio >0.7.
  
  
• Quantitative and qualitative tests for TCAs are not helpful in the acute management.

Figure 66.2. Classic ECG changes after TCA overdose: sinus tachycardia, QRS duration >100 milliseconds, right axis deviation, terminal R wave in aVR (or S wave in I or aVL).

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