Sodium Channel Blocker Toxicity

Etiology

Sodium channel blocker toxicity results primarily from intentional overdose. However, patients or family members may report an inadvertent increase in medication doses or the addition of a new medication, which might alter the elimination kinetics of the substance and lead to an unsuspected toxic dose. An iatrogenic overdose occurs in the setting of medication errors or unintentional administration of supratherapeutic doses; this can occur when using local anesthetics to facilitate a procedure.[2]

Epidemiology

Most intentional poisonings involve the ingestion of multiple drugs. The number of sodium channel blocker toxicity cases varies depending on the agent involved. According to the 2021 American Association of Poison Centers National Poison Data System, reported exposures included:

• Antihistamines: 14,595 cases, with 101 fatalities
• Beta-adrenergic receptor antagonists: 27,541 cases, with 18 reported fatalities
• Local or topical anesthetics: 5471 cases
• Tricyclic antidepressants: 7781 cases (5.6% of the total number of exposures to all antidepressants), of which 42 fatalities occurred
• Carbamazepine or oxcarbazepine: 6755 cases
• Phenytoin or fosphenytoin: 1374 cases
• Lamotrigine: 10,863 cases [3]

Other literature suggests a hospitalization rate of 78.7% and a mortality rate of 0.73% in TCA overdoses.[4] Literature suggests a generally low incidence of local anesthetic toxicity, ranging from 0.02% to 0.18%.[2][5]

Pathophysiology

No significant effect occurs on the atrioventricular node as it does not depend on fast sodium channels. Instead, sodium channel blockade produces various cardiac effects, as demonstrated by their impact on the myocyte action potential. With varying degrees of potency, class I agents decrease the slope and amplitude of phase 0, reducing the depolarization rate and the conduction velocity through the myocyte. This leads to slower cell depolarization and is important for the desired therapeutic suppression of tachydysrhythmias through reentrant mechanisms. Concomitant anticholinergic effects of many of these drugs can complicate sodium channel effects.[6] Other medications with sodium channel blockade properties, such as TCAs and antihistamines (most prominently diphenhydramine), possess class Ia-like properties. Sodium channel blockers cause metabolic, cardiac, and neurologic symptoms and can lead to hemodynamic compromise and metabolic acidosis-- potentiating the effects of the medications and causing further sodium blockade.[1] Propafenone, in particular, also has β-blocking and calcium-blocking activities, which can worsen toxicity, leading to heart failure by decreased inotropy.[6]

Sodium channel blockers cross the blood-brain barrier and function by multiple mechanisms. They inhibit the gamma-aminobutyric acid (GABA) system (primarily lidocaine), activate the sodium ouabain-sensitive current, stimulate serotonin (5-HT)2C receptors, antagonize histamine H1 receptors, and block all noradrenaline activating effects. Through these actions, adrenergic stimulation occurs. These medications are also pro-convulsant in large doses through the above mechanisms.[6] Combining other drugs can alter the elimination kinetics. A recent case report describes how propafenone delayed metoprolol metabolism by inhibiting the cytochrome P450 2D6 enzyme. The interaction of the 2 medications led to more profound toxicity and, in this case, cardiovascular collapse.[7] TCAs are well known for their anticholinergic effects. However, they may also cause potassium channel blockade, peripheral alpha blockade, and norepinephrine reuptake blockade, which could complicate the clinical presentation.[8]

Toxicokinetics

The toxicokinetics of sodium channel blockers depends on the agent involved and the route of administration. Like other xenobiotics, a drug's typical kinetics are changed in supratherapeutic dosing. Medications such as TCAs and antihistamines possess anticholinergic properties, which may lead to slowed gut motility and cause delayed or prolonged absorption of ingested pills.[9][10] Additionally, the first-pass metabolism of TCAs is saturable. As a result, bioavailability increases in overdose. Free TCA concentration increases with acidic serum pH due to decreased protein binding. 

Carbamazepine is primarily metabolized by CYP3A4 to carbamazepine 10-11-epoxide, with zero order kinetics observed in large overdoses.[11] Lamotrigine is primarily metabolized via glucuronidation to lamotrigine-2-N-glucuronide.[12] Local anesthetics, such as lidocaine or bupivacaine, cause vasodilation and increase systemic uptake. The addition of epinephrine can counteract this vasodilation and reduce systemic uptake.

History and Physical

Patients with sodium channel blocker toxicity will usually present with a complaint of overdose or a report of iatrogenic overdose due to a medication error. For patients presenting with reported overdose, obtaining information about all potential medications ingested is critical for case management. A high index of suspicion for co-ingestion of over-the-counter medications, such as acetaminophen and aspirin, should be maintained. The potential use of other substances, such as ethanol, cocaine, or opioids, should also be questioned. Medication lists, medication reconciliation via the electronic medical record, or direct contact with a pharmacy can help facilitate the process.

A thorough physical exam is indicated. Specific exam findings may identify a toxidrome, such as anticholinergic, and help determine the extent of toxicity or identify potential drugs involved in the overdose. This includes evaluation for:

• Patient mental status
• Pupillary size
• Presence of diaphoresis
• Absence of axillary sweat, eg the "toxicologist handshake"
• Absence of bowel sounds
• Muscle rigidity
• Skin flushing
• Tremor

Patients presenting with TCA or antihistamine toxicity are lethargic, confused, or potentially agitated on physical exam. They are usually tachycardic and have other symptoms of anticholinergic toxicity, such as mydriatic pupils, decreased perspiration, and elevated core temperature. Patients presenting with cocaine toxicity are agitated with symptoms of sympathetic upregulation, including tachycardia, diaphoresis, hypertension, and complaints of chest pain.

Patients presenting with iatrogenic toxicity, such as from local anesthetics, will typically develop symptoms rapidly after administration of the local anesthetic. Patients may complain of perioral paresthesias initially before developing dizziness, altered mentation, coma, seizure, and subsequent respiratory or cardiac arrest due to dysrhythmia. More potent local anesthetics, such as bupivacaine, may lead to cardiotoxicity without the preceding central nervous system toxicity.

Evaluation

No pathognomonic findings or toxidromes are typical in the setting of sodium channel blocker toxicity. Physical exam findings vary by the substance ingested. Patients who have ingested TCAs present with tachycardia, whereas those with ingestion of 'pure' sodium channel-blocking medications can present with significant bradycardia.[13] Patients with potential sodium channel blocker toxicity require an immediate electrocardiogram (ECG). Toxicity of sodium channel blockers leads to widening the QRS complex, lengthening the QT interval, a new right axis deviation, bradydysrhythmias, ventricular tachycardia, ventricular fibrillation, or torsades des pointes.[13] Brugada phenocopy, a sodium channelopathy disorder, is also seen during acute toxicity.[14] Obtaining electrolyte, renal, and hepatic profiles, acetaminophen and salicylate levels, arterial or venous blood gas, a drug screen, and a complete blood count should be considered for co-ingestions.

Treatment / Management

Immediate initial management begins with assessing the airway, breathing, and circulation. Many patients present with hypotension, bradycardia, or tachycardia and altered mental status. An endotracheal tube or other advanced airway should be placed in patients who are unable to protect their airway, develop respiratory failure, or deteriorate into cardiac arrest. In a patient presenting early, activated charcoal should be administered in large overdoses where severe toxicity or death is possible. Careful consideration is provided for patients who may have contraindications to activated charcoal, such as depressed mental status or vomiting, as these patients are at high risk of aspiration.

The cornerstone of treatment for sodium channel blocker toxicity is the administration of sodium bicarbonate; it is indicated for patients with an electrocardiogram demonstrating a QRS duration >100 ms or any suspicious QT prolongation or dysrhythmia.[13] Sodium bicarbonate is beneficial in raising the serum pH and increasing the extracellular sodium. Alkalinization increases the electrochemical gradient across cell membranes, helping to offload sodium channels; this might also increase the protein binding of the offending agent. Patients should be given 1 to 2 mEq/kg as a bolus dose.[1] Bolus doses can be administered until the QRS duration is less than 100 ms. The doses can be followed with a continuous infusion of sodium bicarbonate at 1.5 to 2 times maintenance with a pH goal of no greater than 7.55. The infusion is made by adding 2 to 3 ampules (50 mEq) in 1 liter of 5% dextrose injection, D5W.[13] 

Hypertonic saline is considered in refractory cases when patients remain unstable after optimizing fluids, vasopressors, and sodium bicarbonate (ie, the patient's pH is 7.55).[15] This remains an option in dire circumstances, as reported in a case of flecainide overdose.[16] Lidocaine, a class Ib antidysrhythmic, is also used for refractory dysrhythmia due to sodium channel blockade. Lidocaine has favorable kinetics, with fast on and fast off binding of sodium channels, competing for binding sites. The result is increased periods with no drug bound, leading to restoration of sodium channel function.(B3)

Management of hypotension requires a combination of volume resuscitation, vasopressor, and inotropic support. Norepinephrine is generally considered the first line for hypotension unresponsive to fluids.[17] Additional agents, such as epinephrine or vasopressin, are added if additional support is needed. Patients with local anesthetic toxicity have benefitted from the administration of 20% lipid emulsion in severe toxicity.[18] The mechanism of action of lipid emulsion is unclear; however, it is hypothesized that the emulsion acts as a lipid sink, with an electrochemical gradient drawing the lidocaine into the lipid. (B3)

Patients should be given a 1.5 mL/kg bolus followed by a 0.25 mL/kg infusion.[19] Much of the data supporting the use of lipid emulsion is from case reports of bupivacaine toxicity.[20][21][22] The use of lipid emulsion is extended to other local anesthetics. Few studies exist on lipid emulsion for other agents with sodium channel toxicities. Extracorporeal membrane oxygenation (ECMO) has been used in a refractory case with reported survival.[16] In general, the drugs that cause sodium channel blockade toxicity are highly lipophilic, have a comprehensive volume of distribution, and are not dialyzable. Seizure management is accomplished with benzodiazepine medications, such as lorazepam and midazolam. Phenytoin and its derivatives are avoided as they are sodium channel blockers (class Ia) and will likely lead to clinical deterioration. Intubation and sedation with propofol should be considered for seizures refractory to other management. Patients who continue to have hemodynamic instability despite optimization of sodium bicarbonate and vasopressors should be evaluated for ECMO. Successful resuscitation is reported in overdoses of local anesthetics,[23] TCAs,[24] and diphenhydramine.[25][26](A1)

Differential Diagnosis

Patients presenting with ventricular dysrhythmias have a broad differential. This may include the following:

• Acute coronary syndrome
• Electrolyte abnormalities (eg, hypomagnesemia, hyperkalemia)
• Congenital cardiac disease
• Structural heart disease 

The differential for sodium channel blockade toxicity includes medications such as:

• Antihistamines
• Antipsychotics
• Antispasmodics
• Chloroquine
• Class Ia and Ic antiarrhythmics
• Cocaine
• Local Anesthetics
• Phenothiazines
• Venlafaxine toxicity

Prognosis

The high mortality rate of TCA overdose is well known. Class I antiarrhythmic toxicity is associated with a significantly higher mortality rate (22.5%) compared with other drugs (1%).[14] Prompt recognition and treatment are vital to minimize morbidity and mortality. Patients can fully recover from sodium channel blocker toxicity with early identification and appropriate treatment. 

Complications

Complications of sodium channel blocker toxicity include hypotension, bradycardia or tachycardia, cardiogenic shock, cardiovascular collapse, respiratory depression, encephalopathy, status epilepticus, and death.