A “Dirty” Medication

Author: Frank Marowitz, DO Emergency Medicine Resident, PGY II

Fellow: Richard Chen, MD, Medical Toxicology / Emergency Medicine Attending

Faculty: James Krueger, MD, Medical Toxicology / Emergency Medicine Attending

You are a junior resident at a prestigious EM residency in North Philadelphia working a busy Monday morning shift in the ED when you get an EMS call overhead: “Medic 54 en-route to your facility with a 26-year-old male found unresponsive, CPR in progress. ETA of 5 minutes.”

You assemble with your attending, senior resident, two nurses and a respiratory therapist in the resuscitation bay awaiting your patient’s arrival.  The medic unit enters the ED with compressions ongoing via the LUCAS device and the patient is being bagged through an in-place ET tube. 

As the patient is transferred from the stretcher to the ED bed the paramedic gives report:

“We were called to a private residence for Peter, a 26-year-old male who was found down and unresponsive in his bedroom by his brother who called 9-1-1 and then started compression-only CPR after being coached by the dispatcher.  The patient had no pulse or breathing, we continued CPR with our LUCAS device and intubated the patient with a 7.0 ET tube that is 23 cm at the lip.  He was found to be in PEA with no shockable rhythm.  We have given 1 L NS through an 18 g IV in the right hand and 5 rounds of epinephrine.  He is still in PEA arrest.  The brother did not indicate any other medical history and he followed us to the hospital.”

The team goes to work with respiratory taking over bagging, the nursing staff quickly working to get 2 more IVs and labs, and the senior resident performs an assessment.  You quickly insert a central line in the right femoral vein and then get to work on a POCUS assessment of the heart and lungs, which shows no pericardial effusion and good lung sliding. Now 2 more liters of NS are hanging in pressure bags. You note that the patient’s mucous membranes are dry.

The patient’s brother arrives and mentions that patient just went through a bad breakup and lost his job.  He wasn’t sure if it is important, but he also found an empty prescription pill bottle in the trash this morning with the label ripped off. He is not sure what medications his brother is on.

You begin to go through reversible causes of cardiac arrest using the classic ACLS “H’s and T’s”

Learning Point 1: H’s and T’s of PEA arrest

  • H’s
    • Hypovolemia
      • Unlikely given no response to 3L of NSS
    • Hypoxemia
      • Unlikely as this patient has a definitive airway in place with good position and has a SpO2 of 95%
    • Hyperkalemia / Hypokalemia
      • Unlikely as this patient has an i-STAT potassium of 4.8
    • H+ ion excess (acidosis)
      • Possible, as patient pH is 7.15
    • Hypothermia
      • Unlikely as this patient has a temp of 36.6°C on arrival
  • T’s
    • Tension Pneumothorax
      • Unlikely as this patient has no tracheal deviation, equal breath sounds bilaterally, and good lung sliding on POCUS bilaterally
    • Tamponade
      • Unlikely as there is no sign of pericardial effusion on POCUS
    • Thrombosis MI vs PE
      • Less likely as this patient has no risk factors for MI, no obvious ST elevation on Zoll Monitor and he has no risk factors for PE
    • Toxins
      • Definite possibility given the history provided by the brother

Learning Point 2: Common Toxicologic causes of cardiac arrest

  • Beta blockers
    • Mechanism of Action
      • Beta blockers inhibit both beta-1 and beta-2 activity at toxic levels
    • Presentation with toxicity
      • Patient may present with primarily cardiotoxicity including hypotension and dysrhythmias
        • Sotalol also inhibits potassium channels
      • Patient may present with normoglycemia or hypoglycemia
      • Seizures, altered mental status, or bronchospasm also occur
        • CNS toxicity is most common with more lipophilic agents, such as propranolol
    • Diagnosis / Workup
      • Diagnosis is based on clinical presentation and history
      • Hypoglycemia or normoglycemia can be seen
      • ECG findings in beta blocker overdose may include sinus bradycardia, AV nodal blockade, ventricular dysrhythmias, and asystole
      • Decreased cardiac contractility may be seen on POCUS
    • Antidotal therapy for beta blockers includes:
      • Benzodiazepines for seizures
      • Vasopressors (titratable)
        • Epinephrine – 1mg pushes or 0.1-1 mcg/kg/min infusion
        • Norepinephrine – 0.2 mcg/kg/min infusion, titrate as needed
      • Glucagon (inotropic and chronotropic effects)
        • IV bolus of 3 to 10 mg (0.05 mg/kg then:
        • IV infusion at rate of 1 to 5 mg/h
      • High Dose Insulin Euglycemia Treatment
        • IV Bolus 1 U/kg followed
        • IV infusion start at 1U/kg and can increase to response
          • Goal of infusion is to decrease vasopressor requirements
          • Will require frequent glucose checks and dextrose infusion
  • Calcium channel blockers (CCBs)
    • Mechanism of Action
      • CCBs antagonize L-type (long-acting) voltage-gated Ca2+ Channels
    • Presentation with toxicity
      • Cardiotoxicity is more common with non-dihydropyridines (e.g. verapamil and diltiazem) than with dihydropyridines (e.g. amlodipine, nicardipine).
        • Cardiotoxicity effects include sinus bradycardia, atrioventricular block, hypotension
        • Dihydropyridines mainly cause vasodilatory shock, but can be cardiotoxic in larger ingestions
        • Hyperglycemia occurs due to inhibition of insulin release in the pancreas via blockade of L-type calcium channels
    • Diagnosis / Workup
      • Diagnosis is based on clinical presentation and history suggesting CCB ingestion
      • Hyperglycemia is a poor prognostic factor
    • ECG findings include bradycardia, ventricular dysrhythmia and AV block
      • Antidotal therapy for CCBs include:
        • Calcium gluconate (3g) or calcium chloride 10% (1g)
        • Atropine + epinephrine for bradyarrhythmia
        • Vasopressors (titratable)
          • Epinephrine – 1mg pushes or 0.1-1 mcg/kg/min infusion
          • Norepinephrine – 0.2 mcg/kg/min infusion, titrate as needed
        • Glucagon (inotropic and chronotropic effects)
          • IV bolus of 3 to 10 mg (0.05 mg/kg then:
          • IV infusion at rate of 1 to 5 mg/h
      • High Dose Insulin Euglycemia Treatment
        • IV Bolus 1 U/kg followed
        • IV infusion start at 1U/kg and can increase to response
          • Goal of infusion is to decrease vasopressor requirements
          • Will require frequent glucose checks and dextrose infusion
  • Cocaine
    • Mechanism of Action
      • Cocaine has neurotransmitter effects that include blocking reuptake of biogenic amines (dopamine, norepinephrine, and epinephrine) which results in sympathetic toxicity
      • Cardiovascular effects including hypertension, tachycardia, and vasospasm
    • Presentation with toxicity
      • Patients with cocaine toxicity will present with a sympathomimetic toxidrome
      • Patients may also have agitation, rhabdomyolysis, acute kidney injury, hyperthermia
    • Diagnosis / Workup
      • Largely a clinical diagnosis with the appropriate history
        • Common ECG Changes found with cocaine toxicity are tachyarrhythmias and STEMI
    • Therapy for cocaine and other sympathomimetics
      • Lorazepam 2 mg IV (0.1 mg/kg)
      • Diltiazem 20 mg IV
      • Beta Blockers are contraindicated
        • Potential for unopposed alpha stimulation leading to further vasoconstriction
  • Digoxin
    • Mechanism of Action
      • Digoxin inhibits Na+/K+ ATPase leading to an increase in intracellular calcium and results in a resting membrane potential closer to zero and increased myocardial irritability
    • Presentation with toxicity
      • Patient with digoxin toxicity may present with nausea and vomiting, headache, dizziness, confusion, altered mental status, bradydysrhythmias and ventricular dysrhythmias
    • Diagnosis / Workup
      • Diagnosis is made by history and digoxin serum levels
        • Digoxin levels > 2ng/ml concerning for toxicity
      • Hyperkalemia is a common finding, with potassium > 5.0 indicating severe toxicity in acute ingestions
      • Pathognomonic ECG Changes in digoxin toxicity is bidirectional ventricular tacycardia
    • Antidotal therapy for Digoxin
      • Digoxin Immune Fab (Digibind/Digifab)
      • Use of phenytoin, lidocaine, or magnesium can also be considered
  • Tricyclic antidepressants (TCAs)
    • Mechanism of Action
      • TCAs have a wide array of receptor effects, which can lead to both a number of beneficial and unwanted effects. They act to inhibit reuptake of norepinephrine and serotonin, block sodium channels in conducting cells, and antagonize postsynaptic serotonin receptors. They also have K+ channel blockade, antihistaminic, and antimuscarinic effects
    • Presentation with toxicity
      • Patients will present with likely altered mental status which may be attributed to antimuscarinic and antihistaminic toxidromes
      • Patient may have altered mental status, seizures, cardiac conduction or rhythm disturbances, hypotension, and/or respiratory depression
    • Diagnosis / Workup
      • Diagnosis is clinical with history suggestive of ingestion
      • Characteristic ECG Changes:
        • Right axis deviation of the terminal 40 ms of QRS which means:
          • Terminal R wave seen in aVR and/or a S wave seen in I/aVL
          • The presence of tall R waves in aVR that are >3 mm is most specific for poor outcomes in TCA overdose
        • Common but not specific findings include sinus tachycardia or PR, QRS, and QT interval prolongation
        • Right bundle branch block, A-V blocks, and Brugada patterns are also seen
    • Antidotal therapy for TCAs
      • Sodium bicarbonate
        • IV bolus of 1 to 2 mEq/kg, repeated until QRS narrowing
        • IV infusion (150 mEq/L in D5 water) at rate of 2 to 3 mL/kg/h with pH goal 7.50-7.55
          • Overcomes sodium channel blockade by increasing available sodium
          • TCA binding to cardiac sodium channels decreased in more alkalotic environments
        • If in Torsades de Pointes
          • 2 g of IV magnesium sulfate

Back to the case:

At the next pulse check, the team achieves return of spontaneous circulation (ROSC).  You ask for a 12-lead ECG and the ED Tech hands you this:

Your interpretation is as follows

  • Rate – 100’s
    • Rhythm – regular, possibly sinus, but p-waves visible only in V2
    • Axis – hard to tell as most of the leads look isoelectric
    • Intervals – QRS is wide at 160 ms, QT is prolonged, PR appears normal
    • ST changes / waveform morphology – no clear ST changes, large R wave in aVR, abnormal appearing T-waves

You summarize this ECG to the attending as a “wide complex tachycardia with no obvious ST changes but the QRS morphology has a tall terminal R wave in aVR and a prominent terminal S wave in I and aVL”.  The team agrees that the ECG has findings concerning for sodium channel blockade.

Knowing that you may now have a way to treat this patient and hopefully avoid another cardiac arrest, you order a bag of 150 mEq sodium bicarbonate in 1 liter D5W. While that is made by pharmacy you start pushing amps of sodium bicarb (50 mEq per 50 ml ampule).  After the 5th amp of sodium bicarbonate you notice a rhythm change on the Zoll monitor so you request the tech to run another 12-lead ECG which looks like this:

You summarize this ECG to the team as a “narrow complex sinus tachycardia without ST changes but with generally flattened t waves”. You recheck vitals and the patient now has a strong femoral pulse with a blood pressure of 113/72 with a SpO2 of 97%.

Learning Point 3: Utility of ECG in TCA overdose

Prior to the current opioid epidemic, TCA’s led the list of pharmaceutical agents involved in fatal poisonings, often secondary to seizures and ventricular arrhythmias. Given the common causes of mortality in TCA overdose, waiting for laboratory TCA levels is too slow to be useful in acute TCA poisonings.  When overdosed, TCA’s have a significant sodium channel blockade, affecting the depolarization of the cardiac myocytes.  This manifests as a widening of the QRS on ECG.  ECG changes due to TCA overdose provide a predictive tool for the severity of toxicity from an overdose, making it an important tool for the ED clinician. 

Boehnert, Et al. describe that in TCA overdose a QRS interval greater than 100 milliseconds is associated with a 34% chance of seizures and a 14% chance of developing a life-threatening cardiac arrhythmia, but ventricular arrhythmias did not occur until the QRS was greater than 160 milliseconds, after which the chance increased to 50%.  The only problem with using QRS interval as an assessment of TCA toxicity is that QRS prolongation is seen with many medications that cause sodium channel blockade.

In another study, Liebelt et al. compared the value of lead aVR and QRS-interval duration in the prediction of seizures or ventricular arrhythmias in acute TCA toxicity. Their work concluded that RaVR > 3mm was the only parameter that significantly predicted seizures or arrhythmias. The sensitivity and specificity of RaVR > 3mm predicting seizures or arrythmias is 81% and 73% respectively.

Figure 1 illustrates how to measure RaVR

References:

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