Sudden cardiac death and cardiac arrest remain one of the leading causes of mortality in the United States, with more than 900 occurrences daily.1 The rate of survival in cases of out-of-hospital arrest is estimated to be less than 20%.2,3 Pharmacotherapy for a pulseless cardiac arrest has changed dramatically over the past decade; however, studies have failed to show consistent evidence supporting medications leading to an improvement in survival to hospital discharge. Efforts such as cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) have improved survival and remain the focus of the American Heart Association's (AHA's) recommendations.
The chain of survival focuses on 4 key elements that are associated with increased likelihood of survival during a sudden cardiac arrest.4 Those elements include early access, early CPR, early defibrillation, and early advanced cardiac life support (ACLS).5 Several other factors may affect the chances of survival, most notably physical location of the cardiac arrest, initial rhythm of the arrest, and presence of any preexisting medical conditions. The addition of automatic external defibrillators to community locations is supported by the AHA and is suggested to be a vital step in improving the chain of survival.6,7 It has been reported that a witnessed ventricular fibrillation arrest in the community where an automatic external defibrillator is available has increased survival to 49% to 74%.8,9
Pharmacologic therapy for a cardiac arrest should always be accompanied by the appropriate nonpharmacologic treatment with CPR, and defibrillation is of primary importance. Since the revision of the 2005 AHA guidelines for CPR and ECC, efforts have been made to encourage all healthcare practitioners to focus on effective CPR.5 These recommended changes have been widely based on current literature supporting a higher compression-per-minute rate, with recommendations for 100 compressions per minute. Additional changes have focused on changes to defibrillation in recommending only a single shock and minimizing interruptions to CPR during intubation, line placement, and medication administration. Whereas most ACLS therapies such as placement of an endotracheal tube or medication administration have not been shown to improve survival to hospital discharge, they remain recommended practices.5 This review will focus on the medications used in ACLS, with an emphasis on a pulseless cardiac arrest. Additional information will be provided on agents commonly used for treatment of electrolyte abnormalities that lead to a cardiac arrest.
Route of Medication Administration
When drug therapy is administered, it is important to note that the route of administration will affect the onset of action. For example, if an intravenous (IV) medication is given peripherally, it will take 1 to 2 minutes longer to reach the central circulation than if it had been administered via a central line. The onset of effect for a peripherally administered medication can be aided by a bolus of 20 to 30 mL of flush following administration of a medication with elevation of the extremity.10 Additional routes of administration, including intraosseous (IO) and endotracheal (ET), have been used if the patient does not have IV access; however, IO administration is preferred over ET administration because of a more predictable pharmacologic effect for the former.11 Medications that may be administered intraosseously include epinephrine, vasopressin, amiodarone, magnesium, adenosine, blood, and fluids.5 Optimal ET dosing for medications is unknown, but is suggested to be 2 to 2.5 times the recommended IV dose. Medications that may be safely administered via an ET route may be easily remembered by the acronym NAVEL: naloxone, atropine, vasopressin, epinephrine, and lidocaine. Combining medications administered via an ET route with 5 to 10 mL of water or sodium chloride solution is recommended and may enhance drug absorption (Table 1).
Timing of Drug Therapy
In the 2000 AHA guidelines, the recommendation was to give drugs immediately after a postshock rhythm check. It was also recommended in the 2000 guidelines to check a rhythm every 2 minutes, thus resulting in frequent chest compression interruptions. The 2005 AHA guidelines5 recommend that medications should be administered during CPR as soon as possible after a rhythm check. Medications should be prepared in anticipation of the next probable rhythm. The selection of drug therapy should be made reflective of a rhythm check to ensure that the drug is specifically indicated for the rhythm observed. The emphasis should remain on minimizing interruptions in chest compressions. It is also recommended that institutions keep a time clock on the code cart or have a specified timekeeper present during a cardiac arrest.
Vasoactive Agents
Vasoactive agents such as epinephrine and vasopressin are used to enhance organ perfusion. These agents are recommended by the AHA for pulseless ventricular fibrillation (VF) or ventricular tachycardia (VT), asystole, or pulseless electrical activity (PEA) (Figure 1). While the vasoactive agents have been shown to increase the return of spontaneous circulation (ROSC), placebo-controlled trials have failed to show that administration of vasopressors in any pulseless arrest have led to neurologically intact survival to hospital discharge.12
Epinephrine is a mixed [alpha]-adrenergic and [beta]-adrenergic receptor stimulator (inotrope) that increases coronary and cerebral perfusion pressure during CPR. The recommended dosage of epinephrine for a pulseless arrest is 1 mg IV/IO every 3 to 5 minutes. Higher doses of epinephrine have failed to provide substantial evidence of improved survival to hospital discharge, but may be needed for calcium channel blocker or [beta]-blocker overdoses. It is important to note that myocardial workload may be increased because of the [beta]-adrenergic effects of epinephrine. An increase in myocardial workload could be detrimental during an acute myocardial infarction but should not change the recommendations for epinephrine in a pulseless arrest.
Vasopressin causes vasoconstriction by nonadrenergic peripheral vasoconstriction through both the vasopressin1 and vasopressin2 receptors. This vasoconstriction increases coronary perfusion pressure and may increase ROSC.13 Vasopressin is theorized to preserve blood flow to vital organs such as the heart and brain while producing selective vasoconstriction of resistance vessels. Several trials have been recently conducted to evaluate the efficacy of vasopressin during a pulseless cardiac arrest. The trials have identified the largest benefit in those patients given a single dose of vasopressin 40 units IV during an asystolic arrest when compared to epinephrine 1 mg IV given every 3 minutes.14 Limited improvement in survival is seen in nonasystolic arrest when vasopressin is compared to epinephrine. While these trials have had varying results, the AHA now recommends that 1 dose of vasopressin 40 units IV/IO replace either the first or second dose of epinephrine. Of note, there are currently more trials ongoing comparing vasopressin and epinephrine in patients with cardiac arrest.15 Vasopressin has a half-life of 10 to 20 minutes, and, therefore, repeat doses are not generally necessary. If a patient fails to respond after administration of vasopressin, additional doses of epinephrine may be given after allowing sufficient time for the absorption of vasopressin (usually 3 to 4 min).
Adjunct Therapy for a Pulseless Arrest
Atropine produces cholinergic-mediated Increases in heart rate, blood pressure, and systemic vascular resistance. While atropine is recommended by the AHA for patients with symptomatic bradycardia, PEA with bradycardia, and asystole, limited research exists to support its use for asystole and slow PEA. Atropine has limited adverse effects, is easy to administer, and is of minimal cost, and therefore it continues to be recommended. The dosage of atropine for asystole or PEA is 1 mg IV/IO repeated every 3 to 5 minutes until a maximum of 3 mg has been reached. Dosages of 0.5 mg IV up to a maximum of 3 mg are recommended for symptomatic bradycardia (Figure 2). For patients who have had a cardiac transplantation, atropine may be ineffective because of lack of vagal innervation. Alternative therapies for cardiac transplant patients include isoproterenol (Isuprel), theophylline, or terbutaline (Brethine).
Antiarrhythmics
Antiarrhythmic therapy is recommended either before or after the third shock for a VF/VT arrest (Figure 3). Both lidocaine and amiodarone remain in the ACLS algorithm for VF/VT, while magnesium is recommended only for torsades de pointes. There is a lack of evidence to show that antiarrhythmic therapy increases survival to hospital discharge.
Since its approval by the US Food and Drug Administration in 1985, amiodarone (Cordarone) has become one of the most commonly prescribed antiarrhthymics on the market. Its use in cardiac arrest and life-threatening arrhythmias was first studied in 1983, and since that time, amiodarone has been shown to increase short-term survival to hospital admission when given for an out-of-hospital cardiac arrest in comparison with lidocaine16,17 or placebo.6 It is an antiarrhythmic agent that affects the sodium, potassium, and calcium channels, thereby prolonging the action potential duration and refractory period. Amiodarone, additionally, has [alpha]- and [beta]-blocking properties. Amiodarone should be given as a 300-mg IV/IO bolus over 1 to 2 minutes for a pulseless arrest. The dose may be repeated with a 150-mg dose for patients with refractory VF/VT. A continuous infusion should be started after a successful resuscitation with a dose of 1 mg per minute for 6 hours followed by 0.5 mg per minute for 18 additional hours. The most commonly seen adverse effect is hypotension: an adverse effect that may be reduced by the administration of a vasopressor prior to the bolus or by slowing the rate of administration. In addition, there are long-term adverse effects of amiodarone associated with continuous administration, which require that physicians are diligent in monitoring the thyroid, liver, eyes, lungs, and skin.
Lidocaine is a class IB antiarrhythmic agent that acts via sodium channels, leading to a membrane-stabilizing effect. It has long been used for cardiac arrest secondary to a pulseless ventricular tachycardia or fibrillation but without literature to support an improvement in survival. As mentioned previously, trials have shown amiodarone to be superior to lidocaine in both short-term survival and ROSC. The AHA therefore lists lidocaine as an alternative antiarrhythmic agent. The dosage of lidocaine is 1 to 1.5 mg/kg bolus IV/IO and can be repeated with 0.5 to 0.75 mg/kg IV/IO in 5 to 10 minutes with a maximum dose of 3 mg/kg. After a successful resuscitation, an infusion of lidocaine at 1 to 4 mg/min is recommended. Serious adverse effects include hypotension, confusion, seizures, and arrhythmias.
Magnesium is recommended for a pulseless ventricular tachycardia or fibrillation that resembles torsades de pointes. The mechanism of action for magnesium for torsades de pointes is not clearly established but thought to shorten the action potential through myocardial potassium channels. A dosage of 1 to 2 g diluted in 10 mL of 5% dextrose in water given over 5 to 20 minutes is recommended. Rapid administration is associated with hypotension, which is frequently reversible by administration of calcium.
Electrolyte Abnormalities as a Cause of Cardiac Arrest
Electrolyte disturbances are frequently associated with causing cardiac arrest. Rapid reversal of electrolyte imbalance in a nonemergent situation has been associated with severe complications, including seizures, coma, and death. For most electrolyte abnormalities, an underlying cause can be identified and treated to prevent worsening of the abnormality.
Potassium is one of the most frequently reported electrolyte disturbances leading to cardiac arrest owing to its notable effects on the heart.18 The first step in treating a hyperkalemic emergency is to stop any exogenous potassium sources (ie, IV fluids and supplements). A thorough evaluation of additional medications that may cause hyperkalemia should be performed immediately (Table 2).19 Medications such as calcium chloride, sodium bicarbonate, insulin and 50% dextrose, and nebulized albuterol are frequently used to treat hyperkalemia. Once the patient is stabilized, medications such as sodium polystyrene (Kayexalate) and furosemide (Lasix) may be used to assist with the elimination of potassium. For severely hyperkalemic patients, emergent dialysis may be needed.
The role of calcium chloride in the treatment of hyperkalemia is to stabilize the myocardial cell membrane and reduce the risk of VF. In addition, higher doses of IV calcium during a cardiac arrest may be recommended in a calcium channel blocker toxicity or overdose. Calcium is not used to lower the serum potassium levels. Calcium chloride is preferred over calcium gluconate for a patient experiencing a cardiac arrest because the chloride formulation has approximately 3 times the amount of elemental calcium compared with the gluconate formulation.18 Usual dosages of calcium chloride are 0.5 to 1 g IV over 2 to 5 minutes. Calcium should be diluted and is preferably given intravenously via a central or a large peripheral line to avoid any potentially harmful effects should extravasation occur.
Promoting intracellular distribution of potassium is achieved by the use of 10 to 20 mg of nebulized albuterol, 10 units of IV insulin (in combination with 50% dextrose unless the patient is hyperglycemic), and/or sodium bicarbonate. The use of sodium bicarbonate in the treatment of acidosis is controversial and has not shown any evidence of improving survival. In addition, sodium bicarbonate has been shown to decrease systemic vascular resistance, increase CO2, and may even inactivate catecholamines by exacerbating central venous acidosis. Whereas there are disadvantages in certain situations, sodium bicarbonate has proven beneficial in the treatment of prearrest acidosis, tricyclic overdoses, and hyperkalemia. Rapid identification and treatment of hyperkalemia is essential and should in many cases be considered a life-threatening emergency.
Conclusion
The AHA recommendations come from an extensive evidence-based medicine evaluation process in collaboration with the International Liaison Committee on Resuscitation. The evidence is difficult to interpret because of insufficient power in the clinical trials for resuscitation, leading to failure to show an improvement in survival to hospital discharge. Therefore, the subject experts have made recommendations on the basis of nonrandomized or retrospective observation studies. The treatment of a pulseless arrest with medications remains a recommended practice by these groups despite a lack of evidence to support an increase in survival to hospital discharge. In the treatment of a pulseless arrest, appropriate and effective basic life support is essential and should be the focus of therapy. It is suggested that full details of treatment be reviewed in the 2005 AHA guidelines for CPR and ECC.
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