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Common antidotes used in the ICU

Griffiths, Carrie L. PharmD, BCCCP, FCCM; Patel, Arzu BS; Hertel, Kristie A MSN, RN, CCRN, ACNP-BC

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doi: 10.1097/01.CCN.0000668560.03626.5c
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According to the 2018 National Poison Data System Annual Report, there were 2,099,751 human exposures to substances ranging from household cleaning products to prescription medications.1 In the critical care setting, patients present with a variety of conditions, including intentional or unintentional poisonings or overdoses. Antidotes are used to counteract the toxicity of poisons. In the US, poison control centers are available 24/7 in every state and the District of Columbia to assist with any type of poisoning. Poison control centers are available in several countries globally.2

This article discusses several common household substances and over-the-counter (OTC) and prescription medications along with the proper use of their respective antidotes. Please note that anticoagulant reversal agents are not discussed, as they were covered in a previous issue of this journal.3

Digoxin and digoxin immune fab (Digibind, DigiFab)

Digoxin is a narrow therapeutic index medication. Clinical benefit is generally seen at serum concentrations ranging from 0.8 to 2 ng/mL; however, clinical benefit may be limited to a lower range of 0.5-0.9 ng/mL in patients with heart failure.4 Due to the narrow therapeutic index of digoxin, unintentional overdose or toxicity is possible. For example, in cases of severe renal insufficiency, the half-life of digoxin can be increased from 36 to 48 hours up to 100 hours; as a result, these patients have an increased risk of accidental overdose.5 Other risk factors for overdose include advanced age, metabolic disorders, and drug interactions.4 Medications such as verapamil, atorvastatin, omeprazole, potassium-depleting diuretics, alprazolam, erythromycin, and tetracycline may lead to increased serum concentrations of digoxin.6,7

Mechanism of toxicity. Digoxin's mechanism of action involves a blockade of sodium-potassium adenosine triphosphatase, especially in myocardial tissue. At therapeutic levels, this results in increased contractility, shortened atrial contraction, and a prolonged atrioventricular (AV) refractory period. However, at supratherapeutic levels, overexcitation of cardiac, gastrointestinal (GI), and central nervous tissues can lead to a variety of toxicity symptoms.4,7

Clinical signs and symptoms. Clinical signs of digitalis toxicity include confusion, loss of appetite, and GI symptoms including nausea, vomiting, and diarrhea. Patients may also experience vision disturbances, which are generally characterized by yellowing or blurry vision, light sensitivity, or seeing “halos” or flashing lights.7 More severe symptoms of overdose include cardiac arrhythmias, such as ventricular fibrillation, ventricular tachycardia, asystole, AV block (first-, second-, and third-degree), ventricular extrasystoles, ventricular ectopic activity, and bradycardia.4

Treatment and monitoring. Digoxin immune fab is an immunoglobulin fragment that possesses a highly specific affinity for digoxin. It has been available for use in digoxin toxicity since 1986.4 This affinity is greater than that of digoxin for its tissue binding sites. That is, digoxin immune fab binds to digoxin, removing it from its tissue binding sites, and the bound drug is then pushed into the extracellular fluid. As a result, it is unable to exert its effect on its target tissues, reversing adverse events associated with overdose.7

Adverse reactions. There have been reported allergic reactions to digoxin immune fab, including urticaria, pruritus, erythema, angioedema, bronchospasm, hypotension, and tachycardia. In addition, infusion-related reactions have been observed, and are related directly to the rate of administration. The infusion should be stopped if either reaction type occurs. Digoxin immune fab may also cause worsening of congestive heart failure, atrial fibrillation, and phlebitis. Overcorrection of the hyperkalemia caused by digoxin toxicity may also lead to hypokalemia.7

Clinical pearls. Obtaining a serum digoxin level before treatment is preferred, as this value can be used to devise a dosing strategy for digoxin immune fab. However, it is important to note that serum digoxin measurements are nonessential for treatment monitoring. Serum concentrations may appear to rise after digoxin immune fab administration, but this can be misleading as this value can be attributed to drug already bound to digoxin immune fab and therefore unable to cause toxicity. Until the bound drug is excreted in the urine, serum levels will not be truly indicative of unbound digoxin.6 In patients with renal impairment, excretion can be delayed by a week or longer. Monitoring measures recommended are ECG changes, temperature, BP, and electrolytes (in particular, potassium levels).7

Beta-blockers/calcium channel blockers and hyperinsulinemia-euglycemia therapy

Two classes of widely used antihypertensive medications, beta-blockers and calcium channel blockers, are associated with high mortality due to overdose and resulting poison-induced cardiogenic shock. In the US, beta-blockers are the fifth most-commonly prescribed class of medication.8 Mortality associated with calcium channel blockers is the highest among cardiovascular medications.9

Mechanism of toxicity. Overdose occurs either intentionally or unintentionally due to low health literacy.9 Beta-blockers work by competitively inhibiting beta-receptors, indirectly decreasing the amount of cyclic adenosine monophosphate produced. This reduces the amount of calcium entering calcium channels. As a result, heart rate and contractility are decreased.10

Calcium channel blockers also affect the entry of calcium by directly blocking calcium channels.11 This leads to relaxation of vascular smooth muscle and vasodilation. Non-dihydropyridine calcium channel blockers such as diltiazem and verapamil also inhibit the sinoatrial and AV nodes.

Clinical signs and symptoms. Overdose can lead to extreme vasodilation with decreased systemic vascular resistance, bradycardia, hypotension, and cardiogenic shock. In addition, excessively limiting calcium influx can cause hyperglycemia, lactic acidosis, metabolic acidosis, altered mental status, dysrhythmias, and seizures.8

Treatment and monitoring. Hyperinsulinemia-euglycemia therapy (HIET) can be used as an antidote for beta-blocker and calcium channel blocker overdose, in addition to supportive care. Advantages of HIET include its wide availability, relatively lower cost, and minimal adverse events.9 There are no irreversible adverse reactions associated with HIET; it may cause hypoglycemia and hypokalemia, both of which can be resolved with relative ease.8 Insulin works to reverse the effects of beta-blockers and calcium channel blockers via several mechanisms; it increases inotropy and intracellular glucose transport, and enhances microvascular perfusion. Overall, this leads to increased cardiac output and elevated BP.9

Although there are no established guidelines for the use of insulin as an antidote, typical dosing includes an I.V. bolus dose, followed by a continuous infusion. It is recommended to titrate the dose based on the patient's glycemic status. In addition, an I.V. dextrose bolus, followed by a continuous dextrose infusion, may be given with the insulin bolus based on the patient's blood glucose. However, it is likely, especially in cases of calcium channel blocker overdose, that the patient will be hyperglycemic, even with insulin.8

Due to the risk of hypokalemia, serum electrolytes should be closely monitored. In addition, continuous cardiac monitoring is recommended.9 During the first hour of insulin infusion, blood glucose should be checked every 20 minutes, then hourly for the duration of the infusion. The onset of action of insulin is generally 15 to 45 minutes; however, it can be delayed, even by several hours. HIET should be continued until the patient's heart rate is greater than 50 beats/minute, and systolic BP remains greater than 100 mm Hg. A dextrose infusion may be required for up to 24 hours after discontinuation of the insulin infusion.8

Acetaminophen and N-acetylcysteine

Acetaminophen is one of the most commonly used OTC medications; its analgesic and antipyretic properties lend itself to being used in many combination products. Because of its ubiquity, it is often viewed as benign, and at therapeutic concentrations, the safety profile of acetaminophen is very good. In addition, acetaminophen is often included in OTC combination cough, cold, and pain medications, increasing the likelihood of accidental overdose. Accidental overdose is exceedingly prevalent and can lead to significant hepatotoxicity that progresses rapidly.12,13 In the US, acetaminophen toxicity is the most common cause of acute liver failure and the primary reason for emergent liver transplants.13

Mechanism of toxicity. Acetaminophen is metabolized by a variety of pathways in the liver, the majority of which produce nontoxic metabolites. However, these pathways can be overwhelmed by excessive intake, resulting in the production and accumulation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which causes severe hepatocyte damage and eventual hepatic failure.13 (See Acetaminophen toxicity pathway.)

Clinical signs and symptoms. Clinical signs of acetaminophen overdose are nonspecific, and a detailed patient history is integral to diagnosis. Most commonly, patients will present with nausea, vomiting, decreased appetite, abdominal pain, confusion, and malaise.13

Treatment and monitoring. N-acetylcysteine (NAC) is the treatment of choice for acetaminophen-induced hepatotoxicity and is effective when administered within 8 hours of overdose. NAC prevents the accumulation of toxic NAPQI through the following mechanisms:

  • It converts existing NAPQI back to acetaminophen or nontoxic cysteine and mercaptate conjugates.
  • It acts as a glutathione precursor, increasing glutathione availability and allowing for safer acetaminophen metabolism.13,14
Figure
Figure:
Acetaminophen toxicity pathway

The necessity for treatment with NAC is determined by the Rumack-Matthew nomogram, which indicates the severity of toxicity based on time after ingestion and serum acetaminophen levels.12 NAC is available in oral and I.V. formulations. Oral NAC is often poorly tolerated due to its unpleasant “rotten egg” or sulfur smell. Oral NAC can be given with high-dose antiemetics to prevent vomiting. In addition, the smell can be “disguised” by administering the oral formulation in a covered cup and straw or with a flavored beverage. The drug should be readministered if vomiting occurs within 1 hour of administration. If vomiting continues, the route of administration should be changed to I.V.13,14 NAC is usually administered based on site-specific protocols. It should be continued until acetaminophen serum levels are no longer measurable and liver transaminases trend toward normal.12,14

Adverse reactions. Adverse reactions of NAC include anaphylaxis related to dose or rate of I.V. infusion. More commonly, patients can experience pruritus, rash, or hives, which respond well to antihistamines and slowing the infusion rate. Life-threatening reactions are rare and are usually caused by too rapid administration of the loading dose, accompanied by risk factors such as underlying airway disease. Recommended monitoring parameters include complete blood cell count, comprehensive metabolic panel, arterial blood gas, blood glucose, serum aminotransferases, and bilirubin. In addition, the patient may require treatment for hypoglycemia, hypophosphatemia, and hypokalemia.14,15

Benzodiazepines and flumazenil (Romazicon)

Toxicity caused by benzodiazepines is frequently seen, either as single or multiple drug overdoses. Although often used for their sedative effects, benzodiazepines can also cause respiratory depression. Prognosis is worsened by concomitant intoxication with alcohol, medications such as anxiolytics, tricyclic antidepressants, opioids, or illicit drugs.16

Mechanism of toxicity. Benzodiazepines act via high-affinity binding to gamma-aminobutyric acid (GABA) receptors in the central nervous system. Due to the long half-life of some benzodiazepines, symptoms of overdose can last for several days. For example, diazepam toxicity may present symptoms for up to 70 hours.17

Clinical signs and symptoms. Generally, clinical presentation of benzodiazepine overdose is loss of consciousness, or difficulty waking accompanied by slow respirations.17

Treatment and monitoring. Flumazenil is often used as an antidote in benzodiazepine overdose and toxicity. It is a 1,4-benzodiazepine derivative. It works to reverse the sedation associated with toxicity by competing for binding of the GABA receptor. Although effective, it is not recommended for use empirically or in situations of coingestion of other toxic substances and benzodiazepine withdrawal, due to seizure risk.18

Serious, but uncommon, adverse reactions associated with flumazenil include seizures, cardiac arrhythmias, unspecified tachycardia, convulsions, and sudden drop in systolic BP; more commonly seen symptoms include mild, transient nausea and vomiting.16 It is important to monitor a patient's vital signs, presence of seizure activity, and mental status while administering flumazenil, as well as 30 to 60 minutes before and 30 to 60 minutes after administration of flumazenil.18

Given that the half-life of benzodiazepines is longer than that of flumazenil, repeat dosing of flumazenil may be warranted if sedation recurs.

Toxic alcohols and fomepizole (Antizol)

In 2015, 12,000 cases of toxic alcohol poisoning were reported in the US. Toxic alcohols are substances containing a hydroxyl group that are not meant for ingestion, including methanol, ethylene glycol, and isopropyl alcohol.19 Toxicity caused by methanol and ethylene glycol has been shown to cause significant morbidity and mortality. Methanol is a typical ingredient found in antifreeze, cleaning solutions, dyes, paint removers, and illegally produced alcoholic beverages. Ethylene glycol can be found in antifreeze and deicing solutions.20 Exposure can occur accidentally, or intentionally, in the case of purposeful inebriation, homicide, or suicide. Additionally, people with altered mental status may ingest substances containing toxic alcohols unknowingly.19 After ingestion, toxic metabolites accumulate within the body, causing a cascade of worsening symptoms. (See Toxic alcohols pathway.)

Mechanism of toxicity. Generally clinical signs and symptoms of toxicity are nonspecific, making diagnosis difficult. Toxic alcohol poisoning should be considered in the differential diagnosis if the patient exhibits any of the following criteria: history of alcohol use disorder/inhalant use, reported ingestion of household cleaners, history of suicidal ideation, or presence of acidemia with altered mental status. It is possible that serum levels will not be available or significant because the process of alcohol metabolism occurs very quickly.19

Treatment and monitoring. Treatment of toxicity is warranted if the patient has one of the following: history of toxic ingestion, levels of methanol or ethylene glycol greater than or equal to 20 mg/dL, or suspected toxic ingestion with large anion gap metabolic acidosis with an arterial pH of less than 7.3, serum bicarbonate of less than 20 mmol/L, or osmolal gap of greater than 10 mOsm/L. Fomepizole combats methanol/ethylene glycol poisoning by competitively inhibiting both substances. Its affinity for alcohol dehydrogenase is 500 times that of ethanol, and 5,000 to 10,000 times that of methanol and ethylene glycol. It is administered as an I.V. infusion. Hemodialysis is indicated if plasma levels of methanol or ethylene glycol are greater than 50 mg/dL, vital signs are deteriorating despite supportive care, metabolic acidosis occurs that is refractory to sodium bicarbonate and supportive care, or renal failure or severe electrolyte abnormalities are present. Fomepizole is more expensive than ethanol, an alternative treatment for ethylene glycol/methanol toxicity, but is associated with fewer adverse reactions, including inebriation, hypoglycemia, hyperosmolarity, vasodilation, and worsened acidosis. Fomepizole therapy should be continued until plasma methanol or ethylene glycol levels are less than 20 mg/dL.20

Figure
Figure:
Toxic alcohols pathway

Opioids (prescription and illicit) and naloxone (Narcan)

Opioids include morphine and medications derived from or structurally like morphine such as hydrocodone, oxycodone, and fentanyl, as well as the illicit drug heroin. Causes of opioid analgesic-related toxicity include medication use errors, prescribing practices, and intentional overdose. Approximately 130 individuals in the US suffer a fatal opioid overdose daily, and in 2018, nearly 70% of drug overdose deaths involved an opioid.21

Mechanism of toxicity. Opioids enact their effects on mu, delta, and kappa opioid receptors, located in the central and peripheral nervous system, as well as peripheral tissues. Each receptor is coupled to multiple cellular mechanisms, which in turn bring about physiologic changes throughout the body. When receptors in the central nervous system are acted on by opioid-containing medications, they can produce profound analgesia, changes in mood, and tolerance. In addition, the release of dopamine caused by opioid use may create a “reward” effect, leading to physical dependence and misuse. When acting upon areas of the peripheral nervous system, particularly in the GI tract, opioid medications can cause severe constipation.22

Clinical signs and symptoms. In cases of opioid analgesic overdose, it is common for the patient to experience somnolence or loss of consciousness. Pupils may be extremely constricted, and the patient's skin may be pale blue and cold to the touch. In addition, opioid overdose is characterized by profound respiratory depression, with respiratory rate decreased to less than 12 breaths/minute.23

Treatment and monitoring. Naloxone has a strong affinity for opioid receptors in the body, and acts as a potent antagonist, quickly reversing the effects of opioid-containing medications. Naloxone is available in intranasal, I.M., and I.V. formulations. Typically, intranasal and I.M. naloxone are prescribed in the outpatient setting; often, patients taking higher-strength opioid analgesics will be prescribed naloxone in conjunction, and family members are often counseled on the importance of identifying and treating accidental overdoses quickly. I.V. naloxone is typically used in hospital settings and is very effective due to its rapid onset of action. Dosing of I.V. naloxone is typically repeated every 2-3 minutes as needed for reversal of respiratory depression.23 Due to the short duration of action of naloxone (half-life 30-81 minutes), patients generally require hospital admission, and additional I.V. naloxone doses or even a continuous I.V. infusion over the course of several hours or days, with the goal of titrating the naloxone to balance the risks of life-threatening respiratory depression and extreme withdrawal.22,23 Opioid withdrawal syndrome is characterized by nausea, vomiting, diarrhea, tachycardia (heart rate greater than 100 beats/minute), aggression, insomnia, hot and cold flashes, diaphoresis, and muscle cramps. Generally, supportive care is indicated in these instances.23

Nursing considerations

Nursing care of a patient suffering from overdose or intoxication of any medication(s) must start with a high suspicion of circulatory and respiratory collapse. Cardiac monitoring along with noninvasive BP and pulse oximetry are the minimal parameters that should be assessed. Physical assessment should be focused on neurologic, cardiac, respiratory, and renal systems. These patients need to be admitted/transferred to a CCU for close observation and monitoring.

Critical care nurses should be prepared to assist the medical team with placement of a central venous catheter and an arterial line. Antidote medications for reversal of overdose can be caustic to peripheral veins necessitating a central line. Hemodynamic monitoring with an arterial line for continuous evaluation of BP is useful for early recognition of hypotension, an indicator of hypoperfusion. For toxic alcohol overdose, placement of a central line for hemodialysis may be required for drug removal. Knowing the treatments for specific drug toxicity and overdose will help a nurse be prepared for the appropriate line placement.

Preparation for placement of invasive monitoring devices must be completed for overdose patients. Digoxin toxicity along with beta-blocker and calcium channel blocker overdose can lead to significant bradycardia and/or arrhythmias that may require placement of a transvenous pacing wire. Nurses must be educated on transvenous pacing with knowledge of ECG confirmation of capture as well as how to adjust the milliamps to obtain capture when the wire has been floated. Cardiogenic shock can be a complication of overdose of these cardiac medications. There is a potential need for a pulmonary artery catheter or noninvasive cardiac monitoring equipment to assess and manage cardiogenic shock.24

Gastric decompression via nasogastric tube insertion may be indicated for a patient who is being treated for an overdose. Gastric decompression decreases the risk of aspiration in patients experiencing altered mental status such as with opioid and benzodiazepine overdoses. Use of a nasogastric tube may help reduce and/or eliminate nausea and vomiting often associated with overdose or as an adverse reaction of the antidote. Critical care nurses must be aware of proper placement techniques and how to evaluate for appropriate placement.

Patients who have overdosed on toxic alcohols, opioids, and benzodiazepines have a high risk of respiratory failure related to bradypnea from sedation as a result of the overdose. Intubation and mechanical ventilation for respiratory support is likely in these patients.25 Nurses should be prepared with appropriate medications and equipment to proceed with intubation. Placement of continuous pulse oximetry and an end-tidal carbon dioxide monitor should be implemented for close respiratory status monitoring of patients who do not immediately require intubation.

Neurologic deterioration is a complication of overdose. Overdose of opioids and benzodiazepines as well as toxic alcohols will result in altered mental status.25 Benzodiazepine, beta-blocker, and calcium channel blocker toxicity can progress to seizures. Frequent neurologic assessments and knowledge of appropriate treatment of seizures are nursing responsibilities with this patient population. If seizures occur, nurses must understand seizure precautions to ensure patient safety. Continuous electroencephalogram monitoring may be required.

Some patients receiving treatment for an overdose or medication toxicity will need to be evaluated by a specialist. Acetaminophen overdose may lead to liver failure and evaluation for transplant may be the only available treatment-focused option. Toxic alcohol overdose requires a nephrologist who can manage hemodialysis for drug removal. A cardiologist or cardiovascular specialist may be needed for arrhythmias or heart failure management associated with digoxin/beta-blocker/calcium channel blocker toxicity.24 If these specialists are not available at a particular institution, nurses should be prepared for transfer to an appropriate tertiary facility.

Conclusion

When evaluating the toxicities mentioned above, important considerations include promptly and accurately identifying which substances are causing toxicity and rapid administration of treatment or supportive care. Therefore, obtaining a thorough patient history is essential. In addition, considering medication-related toxicity in the context of a patient exhibiting nonspecific symptoms could lead to a diagnosis and treatment plan being formed more quickly, resulting in better patient outcomes.

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Keywords:

acetaminophen; antidote; benzodiazepine; beta-blocker; calcium channel blocker; digoxin; digoxin immune fab; flumazenil; fomepizole; hyperinsulinemia-euglycemia therapy (HIET); naloxone; N-acetylcysteine; opioids; toxic alcohols

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