Chapter 58: Management of the Poisoned Patient

Toxic substances include therapeutic agents as well as agricultural and industrial chemicals that have no medical applications. Most chemicals are capable of causing toxic effects when given in excessive dosage; even for therapeutic drugs, the difference between a therapeutic action and a toxic one is most often a matter of dose. Many toxic effects of therapeutic agents have been discussed in previous chapters. Common toxic syndromes associated with major drug groups are summarized in this chapter. This chapter also reviews the principles of management of the poisoned patient.

A. Toxicokinetics

This term denotes the disposition of poisons in the body (ie, their pharmacokinetics). Knowledge of a toxin’s absorption, distribution, and elimination permits assessment of the value of procedures designed to remove it from the skin or gastrointestinal tract. For example, drugs with large apparent volumes of distribution, such as antidepressants and antimalarials, are not amenable to dialysis procedures for drug removal. Drugs with low volumes of distribution, including lithium, phenytoin, and salicylates, are more readily removed by dialysis and diuresis procedures. In some cases, renal elimination of weak acids can be accelerated by urinary alkalinization, whereas renal elimination of some weak bases can be accelerated by urinary acidification. Acidification of urine can be achieved by NH₄Cl, vitamin C, or cranberry juice, whereas sodium bicarbonate will alkalinize the urine. The clearance of drugs may be different at toxic concentrations than at therapeutic concentrations. For example, in overdoses of phenytoin or salicylates, the capacity of the liver to metabolize the drugs is usually exceeded, and elimination changes from first-order (constant half-life) to zero-order (variable half-life) kinetics.

B. Toxicodynamics

Toxicodynamics denotes the injurious effects of toxins (pharmacodynamic effects). Knowledge of toxicodynamics can be useful in the diagnosis and management of poisoning. For example, hypertension and tachycardia are typically seen in overdoses with amphetamines, cocaine, and antimuscarinic drugs. Hypotension with bradycardia occurs with overdoses of calcium channel blockers, β blockers, and sedative-hypnotics. Hypotension with tachycardia occurs with tricyclic antidepressants, phenothiazines, and theophylline. Hyperthermia is most frequently a result of overdose of drugs with antimuscarinic actions, the salicylates, or sympathomimetics. Hypothermia is more likely to occur with toxic doses of ethanol and other central nervous system (CNS) depressants. Increased respiratory rate is often a feature of overdose with carbon monoxide, salicylates, and other drugs that cause metabolic acidosis or cellular asphyxia. Overdoses of agents that depress the heart are likely to affect the functions of all organ systems that are critically dependent on blood flow, including the brain, liver, and kidney.

C. Cause of Death in Intoxicated Patients

The most common causes of death from drug overdose reflect the drug groups most often selected for abuse or for suicide. Sedative-hypnotics and opioids cause respiratory depression, coma, aspiration of gastric contents, and other respiratory malfunctions. Drugs such as cocaine, phencyclidine (PCP), tricyclic antidepressants, and theophylline cause seizures, which may lead to vomiting and aspiration of gastric contents and to postictal respiratory depression. Tricyclic antidepressants and cardiac glycosides cause dangerous and frequently lethal arrhythmias. Severe hypotension can occur with any of these drugs. A few intoxicants directly damage the liver and kidney. These include acetaminophen, mushroom poisons of the Amanita phalloides type, certain inhalants, and some heavy metals (see Chapter 57).

Management of the poisoned patient consists of maintenance of vital functions, identification of the toxic substance, decontamination procedures, enhancement of elimination, and in a few instances, administration of a specific antidote.

A. Vital Functions

The most important aspect of treatment of a poisoned patient is maintenance of vital functions, as indicated by the mnemonic, ABCDs. The most commonly endangered or impaired vital function is respiration. Therefore, an open and protected airway (A) must be established first and effective ventilation (B for breathing) must be ensured. The circulation (C) should be evaluated and supported as needed. The cardiac rhythm should be determined, and if ventricular fibrillation is present, it must be corrected at once. The blood pressure should be measured but rarely needs immediate treatment except in cases of traumatic hemorrhage. Because of the danger of brain damage from hypoglycemia, intravenous 50% dextrose (D) should be given to comatose patients immediately after blood has been drawn for laboratory tests and before laboratory results have been obtained. Thiamine should be administered to prevent Wernicke’s syndrome in patients with suspected alcoholism or malnourishment. In patients with signs of respiratory or CNS depression, intravenous naloxone offsets possible toxic effects of opioid analgesic overdose. Flumazenil, an antidote to benzodiazepines, is not used routinely, as it can trigger seizures.

B. Identification of Poisons

Many intoxicants cause a characteristic syndrome of clinical and laboratory changes. Table 58–1 summarizes toxic syndromes associated with major drug groups and the key interventions called for. The toxic features of selected individual agents are listed in Table 58–2. When the toxic agent cannot be directly examined and identified, the clinician must rely on indirect means to identify the type of intoxication and the progress of therapy. In addition to the history and physical examination, certain laboratory examinations may be useful. A few intoxicants can be directly identified in the blood or urine, especially when information in the history narrows the search. In the more common situation of a comatose patient unable to provide a history, general tests for replacement of anions or osmotic equivalents in the blood (anion gap, osmolar gap) may be useful. A few intoxicants can be identified or strongly suspected on the basis of electrocardiographic or radiologic findings.

1. Osmolar gap

The osmolar gap is the difference between the measured serum osmolarity (measured by the freezing point depression method) and the osmolarity predicted by measured serum concentrations of sodium glucose and BUN:

This gap is normally zero. A significant gap is produced by high serum concentrations of intoxicants of low molecular weight such as ethanol, methanol, and ethylene glycol.

2. Anion gap

The anion gap is the difference between the sum of the measured serum concentrations of the 2 primary cations, sodium and potassium, and the sum of the measured serum concentrations of the 2 primary anions, chloride and bicarbonate:

This gap is normally 12–16 mEq/L. A significant increase can be produced by diabetic ketoacidosis, renal failure, or drug-induced metabolic acidosis. Drugs that cause an anion gap include cyanide, ethanol, ethylene glycol, ibuprofen, isoniazid, iron, methanol, phenelzine, salicylates, tranylcypromine, valproic acid, and verapamil.

3. Serum potassium

Myocardial function is critically dependent on serum potassium level. Drugs that cause hyperkalemia include β-adrenoceptor blockers, digitalis (in overdose), fluoride, lithium, and potassium-sparing diuretics. Drugs associated with hypokalemia include barium, β-adrenoceptor agonists, methylxanthines, most diuretics, and toluene.

C. Decontamination

Decontamination is the removal of any unabsorbed poison from the skin or gastrointestinal tract (Figure 58–1). In the case of topical exposure (insecticides, solvents), the clothing should be removed and the patient washed to remove any chemical still present on the skin. Medical personnel must be careful not to contaminate themselves during this procedure. For most cases of ingested toxins, activated charcoal, given orally or by stomach tube, is very effective in adsorbing any toxin remaining in the gut. Poisons that can be removed by multiple treatments with activated charcoal include amitriptyline, barbiturates, carbamazepine, digitalis glycosides, phencyclidine, propoxyphene, theophylline, tricyclic antidepressants, and valproic acid. Charcoal does not bind iron, lithium, or potassium, and it binds alcohols and cyanide poorly. Less commonly, gastric lavage with a large-bore tube is used to remove noncorrosive drugs from the stomach of an awake patient or from a comatose patient whose airway has been protected with a cuffed endotracheal tube. In the past, decontamination was attempted by inducing vomiting (emesis), mostly by administering syrup of ipecac in a conscious patient. (Fluid extract of ipecac should not be used because it contains cardiotoxic alkaloids.) However, this approach has fallen out of favor because the risks involved, particularly of aspiration, have been shown to outweigh the benefits. Whole bowel irrigation with a balanced polyethylene-glycol electrolyte solution can enhance gut decontamination of iron tablets, enteric-coated pills, and illicit drug-filled packets. Cathartics such as sorbitol can decrease absorption and hasten removal of toxins from the gastrointestinal tract.

D. Enhancement of Elimination

Enhancement of elimination is possible for some toxins (Figure 58–1), including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity caused by fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidification may be useful in toxicity caused by weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to prevent acidosis and renal failure in rhabdomyolysis. Hemodialysis, an extracorporeal circulation procedure in which a patient’s blood is pumped through a column containing a semipermeable membrane that allows the removal of many toxic compounds, is used commonly to remove toxins such as ethylene glycol, lithium, metformin, procainamide, salicylates, and valproic acid, and to correct fluid and electrolyte imbalances.

E. Antidotes

Antidotes exist for several important poisons (Table 58–3). Since the duration of action of some antidotes is shorter than that of the intoxicant, the antidotes may need to be given repeatedly. The use of chelating agents for metal poisoning is discussed in Chapter 57.

Cyanide forms a stable complex with the ferric ion of cytochrome oxidase enzymes and inhibits cellular respiration (See Chapters 11, 12, and 33). What is the connection between the management of cyanide poisoning and the drugs amyl nitrite and nitroprusside? The Skill Keeper Answer appears at the end of the chapter.

Questions 1–3. A 2-year-old girl presented with lethargy, increased respiratory rate, and an elevated temperature that appeared to result from a drug poisoning. Laboratory testing revealed the following serum concentrations: glucose, 36 mg/dL; Na⁺, 148 mEq/L; K⁺, 5 mEq/L; Cl⁻, 111 mEq/L; HCO₃⁻, 12 mEq/L; BUN, 21 mg/dL; osmolality, 300 mOsm/L.

1. The anion gap in this patient is

   • (A) −60 mEq/L

   • (B) −20 mEq/L

   • (C) +5 mEq/L

   • (D) +30 mEq/L

   • (E) +304 mEq/L

2. The osmolar gap in this patient is

   • (A) −40 mOsm/L

   • (B) −5 mOsm/L

   • (C) +15 mOsm/L

   • (D) +60 mOsm/L

   • (E) +305 mOsm/L

3. The patient’s signs, symptoms, and laboratory values are most consistent with an overdose of

   • (A) Acetaminophen

   • (B) Aspirin

   • (C) Ethylene glycol

   • (D) Lead

   • (E) Phencyclidine

4. An 18-month-old boy presented in a semiconscious state with profound hypotension and bradycardia after ingesting a number of his grandmother’s metoprolol tablets. In this case, the most appropriate antidote is

   • (A) Atropine

   • (B) Esmolol

   • (C) Glucagon

   • (D) Naloxone

   • (E) Neostigmine

5. An 81-year-old woman with type 2 diabetes presents to the emergency department in a coma and with tachypnea, tachycardia, hypotension, and severe lactic acidosis approximately 9 h after ingesting a number of her metformin tablets. Her serum glucose concentration is 148 mg/dL. Metformin is a base with a pK_a of 12.4. The procedure that is most likely to improve her condition is

   • (A) Administration of activated charcoal

   • (B) Administration of glucagon

   • (C) Administration of syrup of ipecac

   • (D) Gastric lavage

   • (E) Hemodialysis

6. A 24-year-old female was rushed to the emergency department after she was found in her room hypotensive, with seizures. In the emergency department, the electrocardiogram confirmed ventricular arrhythmias. An overdose of which of the following drugs is the most likely cause of her symptoms?

   • (A) Acetaminophen

   • (B) Amitriptyline

   • (C) Diazepam

   • (D) Ethylene glycol

   • (E) Morphine

7. A patient with heart failure has accidentally taken an overdose of digoxin. The blood concentration of the drug is 8 times the threshold for toxicity. Pharmacokinetic parameters for digoxin in this patient include a clearance of 7 L/h and an elimination half-life of 56 h. If no procedures are instituted to decontaminate this patient, the time taken to reach a safe level of digoxin will be approximately

   • (A) 3.5 d

   • (B) 7 d

   • (C) 14 d

   • (D) 28 d

   • (E) 56 d

   Questions 8–9. A patient is brought to the emergency department having taken an overdose (unknown quantity) of a sustained-release preparation of theophylline by oral administration 2 h previously. He has marked gastrointestinal distress with vomiting, is agitated, and exhibits hyperreflexia and hypotension.

8. The plasma level of theophylline measured immediately upon hospitalization was 80 mg/L. If the oral bioavailability of theophylline is 98%, the clearance is 50 mL/min, volume of distribution is 35 L, and the elimination half-life is 7.5 h, the amount ingested must have been at least

   • (A) 0.3 g

   • (B) 0.6 g

   • (C) 1.6 g

   • (D) 2.8 g

   • (E) 8.0 g

9. A short-acting antidote that can reduce this patient’s tachycardia is

   • (A) Acetylcysteine

   • (B) Deferoxamine

   • (C) Esmolol

   • (D) Fomepizole

   • (E) Pralidoxime

10. A contraindication to the use of gastric lavage for the removal of drugs from the stomach of victim of poisoning is

    • (A) An overdose of iron pills

    • (B) An unconscious patient

    • (C) Ingestion of a corrosive

    • (D) Overdose with a sustained-release formulation

1. Anion gap is calculated by subtracting measured serum anions (bicarbonate plus chloride) from cations (potassium plus sodium). Increases in anion gap above normal are due to the presence of unmeasured anions that accompany acidosis. The gap in this case is 30 mEq/L, a value that is well in excess of the normal gap (12–16 mEq/L). The answer is D.

2. The osmolar gap is the difference between the measured serum osmolality and the osmolarity calculated from the serum sodium, glucose, and BUN concentrations according to the equation above for calculating the osmolar gap. In this case, the measured osmolality is 300 mOsm/L, whereas the calculated osmolality is 305 mOsm/L; the difference is −5 mOsm/L. The answer is B.

3. Of the drugs listed, the 2 that are likely to cause an anion gap are aspirin and ethylene glycol. However, if the child had ingested ethylene glycol, she would be expected to exhibit a significant osmolar gap. The anion gap, lethargy, tachypnea, and hyperthermia all are consistent with aspirin poisoning. The answer is B.

4. Glucagon (Chapter 41) stimulates heart rate and contractility through cardiac glucagon receptors that are coupled to adenylyl cyclase and the cAMP signaling pathway. This ability to increase cardiac cAMP without requiring access to β receptors makes it valuable for β-blocker overdose. The answer is C.

5. In this woman with severe signs of poisoning due to the ingestion of metformin, hemodialysis can be used to accelerate the elimination of both metformin and lactic acid. Since most of the metformin has been absorbed by the time she presented (9 h after drug ingestion), efforts to decontaminate her gastrointestinal tract with activated charcoal, gastric lavage, or syrup of ipecac are unlikely to be beneficial. Furthermore, syrup of ipecac has fallen out of favor and should not be used in unconscious patients. Unlike other drugs used to treat type 2 diabetes, metformin in overdose is unlikely to cause hypoglycemia (see Chapter 41), and this patient’s serum glucose is in the normal range so that glucagon administration is not required. The answer is E.

6. Tricyclic antidepressants such as amitriptyline are extremely toxic in overdose because of their effects in the CNS and cardiovascular system. In addition to hypotension, seizures, and cardiac arrhythmias, the tricyclics have strong antimuscarinic effects. The answer is B.

7. Estimations of the time period required for drug or toxin elimination may be of value in the management of the poisoned patient. If no procedures were used to hasten the elimination of digoxin in this patient, the time taken to reach a safe plasma level of the drug (12.5% of the measured level) is 3 half-lives, or approximately 7 d. The answer is B.

8. Estimations of the quantity of a drug or toxin ingested may be of value in the management of the poisoned patient. Applying toxicokinetic principles, a rough estimate of ingested dose of theophylline could be made by multiplying the peak plasma level of the drug (80 mg/L) by its volume of distribution (35 L) to give a value of 2800 mg, or 2.8 g. Because only about one-fourth of a half-life has passed since ingestion, the amount eliminated since that time will be rather small. The answer is D.

9. The short-acting β blocker esmolol helps reverse the tachycardia and possibly the vasodilation associated with an overdose of theophylline. The answer is C.

10. Neither gastric lavage nor syrup of ipecac should be used in patients who have ingested a corrosive because of the risk of esophageal damage. Gastric lavage can be used in a comatose patient if the airway has been protected with a cuffed endotracheal tube. The answer is C.

The traditional cyanide antidote kit contains amyl nitrite, sodium nitrite, and sodium thiosulfate (See Chapters 11, 12, and 33). The nitrites convert hemoglobin to methemoglobin, which has a higher affinity for the cyanide ion (forming cyanomethemoglobin) than cytochrome oxidase. It is the inhibition by cyanide of cytochrome oxidase that blocks oxidative metabolism and causes much of the toxicity. The sodium thiosulfate reacts with cyanide to form nontoxic thiocyanate ions. A newer cyanide antidote kit contains hydroxocobalamin, a form of vitamin B₁₂ that rapidly reacts with cyanide to form the nontoxic cyanocobalamin. Nitroprusside, a compound with 5 cyanide molecules in addition to nitric oxide complexed to a central iron atom, is often considered the drug of choice in severe hypertension. Prolonged use of nitroprusside may result in toxicity caused by the release of cyanide.

When you complete this chapter, you should be able to:

• ❑ Describe the steps involved in the supportive care of the poisoned patient.

• ❑ Identify toxic syndromes associated with overdose of the major drugs or drug groups frequently involved in poisoning.

• ❑ Outline methods for identifying toxic compounds, including descriptive signs and symptoms and laboratory methods.

• ❑ Describe the methods available for decontamination of poisoned patients and for increasing the elimination of toxic compounds.

• ❑ List the antidotes available for management of the poisoned patient.