Pharmacotherapy of Cardiac Arrest

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Vasopressors in the Setting of Cardiac Arrest

Vasopressors play a vital role in the management of cardiac arrest by increasing systemic vascular resistance and maintaining adequate perfusion pressure. The use of vasopressors aims to improve hemodynamic stability and enhance coronary and cerebral blood flow, ultimately increasing the chances of successful resuscitation. Here, we will delve deeper into the purpose and multiple considerations of vasopressors in the setting of cardiac arrest.

Purpose:

The main purpose of vasopressors during cardiac arrest is to generate vasoconstriction and increase arterial blood pressure. This helps restore organ perfusion and improve the chances of restoring spontaneous circulation. Vasopressors act on different receptors to achieve their hemodynamic effects. The most commonly used vasopressor in cardiac arrest is epinephrine.

Epinephrine:

Epinephrine, an alpha-1 agonist, exerts its effects by causing vasoconstriction and increasing cardiac contractility. It is considered the first-line vasopressor in cardiac arrest. The administration of epinephrine during resuscitation helps elevate systemic blood pressure, augment myocardial and cerebral blood flow, and improve the chance of achieving return of spontaneous circulation (ROSC).

Considerations:

While administering vasopressors during cardiac arrest, several important considerations should be kept in mind:

Alternative to Epinephrine: Vasopressin: In certain cases, vasopressin may be considered as an alternative to epinephrine. Vasopressin acts as a V1 receptor agonist and causes vasoconstriction. It has been shown to be as effective as epinephrine in cardiac arrest and may be particularly useful in refractory cases.
Administration Route: In the absence of intravenous (IV) or intraosseous (IO) access, endotracheal tube administration of vasopressors may be used. Epinephrine can be diluted and given through the endotracheal tube at a dose two to two-and-a-half times higher than the IV dose. However, IV or IO access is preferred whenever possible.
Timing and Repeated Dosing: Vasopressors, especially epinephrine, should be administered consistently and repeatedly during CPR. The recommended dosing interval is every 3 to 5 minutes. This helps maintain the desired hemodynamic effects continuously throughout resuscitation efforts

Epinephrine
- Mechanism: Alpha-1 agonist → vasoconstriction, inotropy
- Dose:
  - Adult: 1 mg IV/IO push every 3-5 minutes
  - Pediatric: 0.01 mg/kg (0.1 ml/kg of 0.1 mg/ml concentration) IV/IO push every 3-5 minutes
Considerations:
- First-line vasopressor
- Titrate to perfusion/hemodynamic goals
- Use ET tube if no IV/IO access (2-2.5 x IV dose diluted in 10 ml NS)

Vasopressin:
- Mechanism of Action: Vasopressin exerts its effects primarily via V1 receptors on vascular smooth muscle cells, resulting in vasoconstriction and increased peripheral vascular resistance. Unlike catecholamines such as epinephrine, vasopressin does not exert inotropic effects on the heart. It has a unique mechanism compared to other vasopressors, as it does not work through adrenergic receptors and does not significantly affect heart rate or contractility.
- Pharmacokinetics: Vasopressin has a half-life of about 10 to 20 minutes and is metabolized in the liver and kidneys. The drug can be administered through IV/IO routes and typically requires no dilution.
- Indications and Clinical Scenarios: Vasopressin has been considered as an alternative or adjunct to epinephrine in certain situations. It may be particularly useful in cases of acidosis, as vasopressin’s vasoconstrictive effects are less pH-dependent compared to catecholamines. Additionally, it has shown to be effective in refractory or prolonged cardiac arrest cases and in instances where epinephrine has shown to be ineffective.
- Dose: The typical dose of vasopressin in adult cardiac arrest is 40 units IV/IO push, which can be repeated every 3-5 minutes, similar to the dosing interval of epinephrine.

Considerations:
- Drug Availability: Vasopressin may not always be readily available in emergency code carts and often requires refrigeration, which can limit its immediate utility.
- pH-Independent Action: Its effects are less influenced by the acidic environment that commonly exists during cardiac arrest, potentially providing an advantage over catecholamines in certain scenarios.
- No Beta-Adrenergic Effects: Vasopressin does not have the beta-adrenergic effects such as increased heart rate and myocardial oxygen demand.
- Renal Effects: Vasopressin may cause water retention and should be used cautiously in patients with renal impairment.
- Side Effects: Common side effects include decreased cardiac output due to increased afterload, hyponatremia, and abdominal cramping. Therefore, patient response should be closely monitored.
Conclusion on Vasopressin: While vasopressin has unique pharmacological advantages that make it a valuable alternative to catecholamines like epinephrine, its application comes with its own set of considerations including availability, dosing, and side-effect profile. Tailoring the choice of vasopressor to the individual clinical situation and understanding the pharmacological nuances can help optimize outcomes in cardiac arrest management.

Conclusion:

Vasopressors, particularly epinephrine, are an essential component of the pharmacological interventions used during cardiac arrest. Their use aims to increase systemic vascular resistance and maintain adequate perfusion pressure, ultimately improving the chances of successful resuscitation. Proper dosing, titration, and consideration of alternative options are crucial in achieving optimal outcomes and maximizing the chances of achieving ROSC.

Antiarrhythmics

Amiodarone

Mechanism of Action:
- Amiodarone is a unique antiarrhythmic agent that acts on multiple ion channels, including sodium (Na+), calcium (Ca++), and potassium (K+), resulting in a complex antiarrhythmic profile. This drug is classified under Vaughan-Williams Class III but exhibits properties of all four classes of antiarrhythmics. By blocking these ion channels, amiodarone prolongs action potentials and refractory periods in cardiac myocytes. The net result is suppression of arrhythmias and restoration of normal cardiac rhythm.
Pharmacokinetics:
- Amiodarone is highly lipid-soluble and has a very long half-life, ranging from 25 to 100 days. It’s primarily metabolized in the liver to its active metabolite, desethylamiodarone. Due to its long half-life, it can accumulate in tissues, and side effects may persist long after the drug is discontinued.
Indications and Clinical Scenarios:
- Amiodarone is commonly used for refractory ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) that have not responded to initial resuscitative measures, including defibrillation and administration of other antiarrhythmic agents. It’s also used in other tachyarrhythmias where other treatments have failed.
Dose:
- Adults: The initial dose is 300 mg IV/IO bolus, administered over 3-5 minutes. An additional bolus of 150 mg can be given if the arrhythmia persists or recurs.
- Pediatrics: The initial pediatric dose is 5 mg/kg IV/IO, infused over 20-60 minutes. This dose can be repeated up to a maximum of 15 mg/kg/day.
Considerations:
- Utilized for Refractory VF/VT: Amiodarone is the drug of choice for shock-resistant VF/VT, generally administered after multiple unsuccessful defibrillation attempts.
- Hypotension: Amiodarone can induce hypotension, particularly when administered as a rapid bolus. It’s essential to monitor blood pressure closely and consider reducing the rate of infusion or discontinuing the drug if severe hypotension occurs.
- Bradycardia: The drug can also cause bradycardia, which may necessitate the initiation of pacing or administration of a chronotropic agent.
- QT Prolongation: Amiodarone has the potential to prolong the QT interval, increasing the risk for torsades de pointes. This is particularly important in patients who already have a prolonged QT or who are on other medications that can prolong the QT interval.
- Drug Interactions: Amiodarone has a wide range of drug interactions, including with other antiarrhythmics, anticoagulants, and thyroid medications. Consideration should be given to potential interactions when administered.
- Pulmonary Toxicity: Although not an immediate concern during cardiac arrest, providers should be aware that amiodarone has a black box warning for pulmonary toxicity, which can manifest as acute respiratory distress syndrome (ARDS) or chronic interstitial pneumonitis.

Lidocaine
Mechanism of Action:
- Lidocaine primarily acts as a sodium (Na+) channel blocker, inhibiting the fast sodium channels in the myocardial cell membrane during phase 0 of the action potential. This reduces cellular excitability and automaticity, thereby stabilizing the myocardial membrane and controlling arrhythmias such as ventricular fibrillation (VF) and ventricular tachycardia (VT).
Pharmacokinetics:
- Lidocaine has a half-life of approximately 1.5 to 2 hours and is metabolized primarily in the liver. It is highly protein-bound and distributes well into tissues. Given its hepatic metabolism, care must be taken when administering lidocaine to patients with liver dysfunction.
Indications and Clinical Scenarios:
- Lidocaine is most often considered for use in cardiac arrest cases involving refractory VF or VT, particularly in place of amiodarone is not available, ineffective, or contraindicated. It can also be used in other ventricular arrhythmias and sometimes for local anesthesia during certain procedures.
Dose:
- Adults: The initial dose is usually 1-1.5 mg/kg IV/IO bolus. This is followed by an infusion at 1-4 mg/min to maintain therapeutic levels and antiarrhythmic effects.
- Pediatrics: The initial pediatric dose is 1 mg/kg IV/IO bolus, followed by an infusion at 20-50 mcg/kg/min.
Considerations:
- Alternative for VF/VT: Amiodarone is no longer preferred for refractory VF/VT over lidocaine in the most recent guidelines, lidocaine serves as a valuable alternative.
- CNS Toxicity: Excessive levels of lidocaine can lead to central nervous system (CNS) symptoms, such as confusion, seizures, and even coma. Therefore, monitoring for signs of toxicity is crucial.
- Cardiovascular Effects: High doses of lidocaine can also affect cardiac function, potentially causing bradycardia, hypotension, and various arrhythmias. Close monitoring is essential, especially when administered with other cardiovascular-active medications.

Magnesium

Mechanism of Action:
- Magnesium acts as a membrane stabilizer and serves as a calcium (Ca++) antagonist. By blocking calcium influx into the cell, magnesium helps to regulate cellular excitability and stabilizes the electrical activity of myocardial cells. This is particularly crucial for rhythm control in conditions like torsades de pointes and ventricular arrhythmias associated with hypomagnesemia.
Pharmacokinetics:
- Magnesium has a half-life of about 3.5–4 hours in patients with normal renal function and is primarily excreted unchanged by the kidneys. Renal impairment necessitates close monitoring and dose adjustments. The drug has a wide distribution and can cross the blood-brain barrier as well as the placenta.
Indications and Clinical Scenarios:
- The primary indications for magnesium in a cardiac setting are torsades de pointes and significant hypomagnesemia. Magnesium is also often considered in cases of ventricular arrhythmias when other antiarrhythmics are contraindicated or ineffective. In some instances, it may be used in the treatment of severe asthma exacerbations, eclampsia, or pre-eclampsia.
Dose:
- Adults: An initial dose of 1-2 g IV/IO is administered as a bolus. The dose may be repeated if ventricular arrhythmias persist or recur.
- Pediatrics: The initial pediatric dose is 25-50 mg/kg IV/IO, given as a bolus. The maximum dose should not exceed 2 g.
Considerations:
- Indicated for Torsades de Pointes: Magnesium is the first-line treatment for torsades de pointes, irrespective of the patient’s magnesium levels. It is particularly effective in terminating this polymorphic ventricular tachycardia and preventing recurrence.
- Hypomagnesemia: In cases of ventricular arrhythmias associated with hypomagnesemia, magnesium can be both diagnostic and therapeutic. Normalization of magnesium levels can often correct the underlying arrhythmia.
- Renal Function: Given its renal excretion, caution should be exercised when administering magnesium in patients with renal impairment. Serum levels must be closely monitored in these situations to prevent hypermagnesemia.
- Potential Side Effects: At higher doses, magnesium can cause hypotension, bradycardia, and respiratory depression. These require immediate attention and possibly the administration of calcium gluconate as an antidote.

Calcium
- Mechanism of Action:
  - Calcium ions are essential for multiple cellular processes, including muscle contraction, neurotransmission, and enzyme activity. In the cardiovascular context, calcium is crucial for cardiac muscle contraction and electrical stability. Calcium salts, like calcium chloride and calcium gluconate, are the available forms of calcium used to treat various conditions.
- Indications and Clinical Scenarios:
  - Hyperkalemia: Calcium is administered in cases of severe hyperkalemia to stabilize the myocardial cell membrane and mitigate arrhythmogenic effects, although it doesn’t lower potassium levels.
  - Hypocalcemia: Calcium is used to correct acute symptomatic hypocalcemia, often seen in conditions like sepsis, acute pancreatitis, and massive transfusions.
  - Calcium Channel Blocker Overdose: In the event of an overdose, calcium can be effective in counteracting the negative inotropic and vasodilatory effects of calcium channel blockers.
- Dose:
  - Adults: Typically, 1-3 g of calcium (either as calcium chloride or gluconate) is administered IV over 5-10 minutes. Calcium chloride has a higher elemental calcium content than calcium gluconate, so it is more potent but also more irritating to veins.
  - Pediatrics: A dose of 20 mg/kg IV (which translates to 0.2 ml/kg of a 10% calcium chloride solution) is given over 5-10 minutes.
- Considerations:
  - Form of Calcium: Calcium chloride has three times as much elemental calcium as calcium gluconate but is more caustic to the veins. The choice between the two often depends on venous access and the severity of the condition being treated.
  - Incompatibile with sodium bicarbonate

Sodium bicarbonate

Mechanism of Action:
- Sodium bicarbonate acts as a buffer to neutralize excess acids in the blood, thereby raising the pH and alleviating metabolic acidosis. Also, it counteracts its sodium channel blocking effects on the myocardium of hyperkalemia and TCA overdose
Indication: Severe acidosis, hyperkalemia, TCA overdose
Dose:
- Adult: 1 mEq/kg IV bolus initially, can repeat every 10 minutes
- Pediatric: 1 mEq/kg IV bolus initially, can repeat every 10 minutes
Consideration
- AHA ACLS guidelines do not recommend the routine use of sodium bicarbonate outside of hyperkalemia and TCA overdose

Dextrose
- Indication: Hypoglycemia
- Dose:
  - Adult: 25-50 g (50 ml D50W or 100 ml D25W) IV push
  - Pediatric: 0.5-1 g/kg (2-4 ml/kg D25W) IV push

Naloxone
- Indication: Opioid overdose
- Dose:
  - Adult: 0.4-2 mg IV/IM/IO/intranasal, can repeat every 2-3 minutes
  - Pediatric: 0.1 mg/kg IV/IM/IO/intranasal, maximum 2 mg per dose

Alteplase/ Tenecteplase
- Indication: Suspected massive pulmonary embolism or myocardial infarction
Mechanism of Action:
- Alteplase is a fibrin-specific plasminogen activator that converts plasminogen to plasmin, leading to clot lysis. This can be vital in cases of cardiac arrest precipitated by a massive pulmonary embolism or acute myocardial infarction by restoring blood flow to compromised tissues.
Indications in Cardiac Arrest:
- Massive Pulmonary Embolism: Alteplase is considered in cases of cardiac arrest where a massive pulmonary embolism is suspected, and conventional resuscitation efforts are unsuccessful.
- Myocardial Infarction: Though less common, alteplase may also be considered in certain cases of cardiac arrest attributed to acute myocardial infarction, especially if percutaneous coronary intervention is not immediately available.
Alteplase Dosing Recommendations:
- Adults: An initial dose of 50 mg is administered IV over 2 minutes. If no return of spontaneous circulation (ROSC) is achieved, an additional 50 mg bolus may be considered after 15 minutes. Resuscitative efforts, including CPR, should continue for at least 15 minutes after administration to allow the drug to circulate. If ROSC is achieved after only the initial 50 mg dose, an additional 50 mg over 2 hours could be considered.
- Pediatrics: A dose of 0.6 mg/kg is administered IV over 2-5 minutes, with a maximum dose of 50 mg. There’s no strong data to guide pediatric dosing in this setting.
Tenecteplase Dosing Recommendations
- Adults: The dosing for tenecteplase is generally weight-based, with a single IV bolus usually ranging from 30 to 50 mg depending on the patient’s weight. It’s administered as a one-time rapid intravenous push over 5 seconds.
  - For example, patients weighing less than 60 kg might receive 30 mg, 60-69 kg might receive 35 mg, 70-79 kg might receive 40 mg, 80-89 kg might receive 45 mg, and 90 kg or more might receive 50 mg.
- Pediatrics: There is limited data on the pediatric dosing of tenecteplase in the setting of cardiac arrest, and it’s generally not recommended due to insufficient evidence. If considered, consult expert opinion and consider weight-based dosing similar to adult recommendations, with appropriate adjustments for age and size.
- Single-Dose Administration: Unlike alteplase, tenecteplase is administered as a single bolus, which may be advantageous in a resuscitation setting where ongoing infusions could be challenging to manage.
Considerations:
- Timing: It’s crucial to administer alteplase as early as possible after confirming the suspected etiology, as delayed treatment can significantly decrease its efficacy.
- Contraindications: Risk factors for bleeding, recent surgery, or known bleeding disorders need to be assessed due to the thrombolytic nature of alteplase.
- Monitoring: Hemodynamic and coagulation parameters should be closely monitored after administration. Any signs of bleeding or allergic reactions must be promptly addressed.
- Subsequent Treatment: If ROSC is achieved, additional diagnostic and therapeutic steps (like advanced imaging or anticoagulant therapy) may be necessary to further address the underlying issue.
- Data Scarcity: There’s limited evidence for the use of alteplase in cardiac arrest settings, particularly in children. Clinical judgment must guide the decision to administer the drug.
- Advanced Diagnostic Tools: If available, point-of-care ultrasound or other advanced imaging modalities can be beneficial in confirming the diagnosis before administration.
Conclusion on Alteplase in Cardiac Arrest:
- The use of alteplase in the setting of cardiac arrest is primarily guided by clinical suspicion of massive pulmonary embolism or myocardial infarction as the underlying cause. Though used less frequently than other resuscitative measures, alteplase can be a life-saving intervention when used judiciously and in the appropriate clinical context. However, its use necessitates careful monitoring and comes with its own set of risks and considerations.

Special Considerations

Pediatrics:

Use pediatric PALS algorithms
Use weight-based dosing for all medications
Lower defibrillation energy (2 J/kg, maximum 50-75 J)
Intubation often required early

Pregnancy:

Left lateral uterine displacement during CPR
Consider the impact of medications on the fetus (role of magnesium?)
Prepare for emergency cesarean delivery if no ROSC in 5 minutes

Toxicology:

Identify potential causative agents based on history
Administer antidotes early (naloxone for opioids, calcium for CCB)
Consult poison control for guidance on specific toxicologies

Medication	Mechanism	Adult Dose	Pediatric Dose	Key Considerations
Epinephrine	α1 agonist	1 mg IV/IO push q3-5min	0.01 mg/kg (0.1 mL/kg of 0.1 mg/mL) IV/IO push q3-5min	First-line vasopressor
Vasopressin	V1 agonist	40 units IV/IO push, can repeat q3-5min	IV: 0.4 units/kg	Alternative to epinephrine
Amiodarone	Multichannel blocker	300 mg IV/IO bolus, can give additional 150 mg	5 mg/kg IV/IO over 20-60 min, can repeat up to 15 mg/kg/day	Refractory VF/VT
Lidocaine	Na+ channel blocker	1-1.5 mg/kg IV/IO bolus, then 0.5-.75 mg/kg as second dose	1-1.5 mg/kg IV/IO bolus, 1-1.5 mg/kg IV/IO bolus, then 0.5-.75 mg/kg as second dose	Refractory VF/VT
Magnesium	Membrane stabilization	1-2 g IV/IO over 5-20 min	25-50 mg/kg IV/IO over 5-20 min, max 2 g	Torsades de pointes
Calcium	Stabilize cardiac membrane in Hyperkalemia	1-2 g IV over 5-10 min	20 mg/kg IV over 5-10 min	Hyperkalemia, hypocalcemia
Sodium bicarbonate	Severe acidosis	1 mEq/kg IV bolus, can repeat q10min	1 mEq/kg IV bolus, can repeat q10min	Severe acidosis
Dextrose	Hypoglycemia	25-50 g IV push	0.5-1 g/kg IV push	Hypoglycemia
Naloxone	Opioid antagonist	0.4-2 mg IV/IM/IO/IN, can repeat q2-3min	0.1 mg/kg IV/IM/IO/IN, max 2 mg/dose	Opioid overdose
Alteplase	Thrombolytic	50 mg IV over 2 min	Limited data, max 50 mg	Pulmonary embolism, STEMI
Tenecteplase	Thrombolytic	ranging from 30 to 50 mg depending on the patient’s weight	Limited data, max 50 mg	Pulmonary embolism, STEMI

Emergency Medicine 201

Quizzes

Participants 396

Pharmacotherapy of Cardiac Arrest

Antiarrhythmics

Special Considerations