Pharmacotherapy Considerations for Inpatient Advanced Cardiac Life Support

Cardiac arrest, defined as the cessation of cardiac mechanical activity and confirmed by the absence of signs of circulation, is arguably the most serious emergency in the field of medicine.1 Despite significant research, survival to hospital discharge remains at 9.1% for patients with out-of-hospital cardiac arrest; the survival rate is slightly higher at 18.8% for patients with in-hospital cardiac arrest.1 Survival with good functional status at hospital discharge is even lower, at 7.1% for patients with out-of-hospital cardiac arrest and 12.9% for patients with in-hospital cardiac arrest.1 Factors thought to contribute to this notable difference in survival rates include cause of the arrest, time to initiation of basic life support, and increased availability of treatment modalities and personnel for patients with in-hospital cardiac arrest.2High-quality cardiopulmonary resuscitation and early defibrillation of shockable rhythms are the most effective interventions for improving survival rates and long-term clinical outcomes.3 Additional interventions, including establishing intravenous (IV) access for medication administration, should not delay or impede cardiopulmonary resuscitation or defibrillation. Nevertheless, medications remain a fundamental component of advanced cardiac life support (ACLS) and are the focus of this review.Before discussing medication management and special considerations in cardiac arrest, it is important to highlight the goal of resuscitation. Although return of spontaneous circulation would appear to be the most intuitive target outcome of ACLS, in recent years the focus has shifted toward outcomes that are deemed more patient centered and meaningful. In 2018, a group of survivors of cardiac arrest, their family members, clinicians, researchers, and the International Liaison Committee on Resuscitation convened to develop a core outcome set for cardiac arrest.4 After reaching consensus, the group identified survival, neurologic function, and health-related quality of life as the core outcomes for future studies of cardiac arrest.4 This recommendation is notable because no drug has ever been shown to improve survival with favorable neurologic outcome.3 However, given the impact of drug therapy on short-term survival and the potential for a time-dependent benefit in patients who have experienced minimal downtime, the American Heart Association (AHA) continues to recommend medication therapy in ACLS.5Epinephrine, amiodarone, and lidocaine are the only 3 medications currently recommended within the AHA’s adult cardiac arrest algorithm. A historical summary of guideline changes and landmark studies of these 3 agents is represented in the Figure. Unlike amiodarone and lidocaine, epinephrine has a place in the algorithm both for shockable rhythms (ventricular fibrillation [VF] and pulseless ventricular tachycardia [VT]) and for nonshockable rhythms (asystole and pulseless electrical activity).3Epinephrine is the only medication that has been recommended in every publication of the AHA guidelines for ACLS. Its mechanistic benefit is through α-adrenergic vasoconstriction leading to increased coronary and cerebral perfusion pressure during cardiopulmonary resuscitation.5 In contrast, the β-adrenergic effects of epinephrine may be detrimental given the propensity to increase myocardial oxygen demand, decrease cerebral microvascular blood flow, and be proarrhythmic.5Despite the prolonged historical use of epinephrine in patients with cardiac arrest, little evidence clearly defines its appropriate use, optimal dose, and timing of administration. However, the PARAMEDIC-2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest) trial, the largest medication-focused cardiac arrest trial to date, provided pivotal evidence for the use of epinephrine in cardiac arrest.12 This study, a multicenter, double-blind, placebo-controlled trial of 8007 patients with out-of-hospital cardiac arrest, compared the use of epinephrine 1 mg IV every 3 to 5 minutes with placebo. The use of epinephrine significantly improved survival at 30 days compared with placebo (3.2% vs 2.4%, P = .02). Unfortunately, the study showed no significant difference between groups in the rate of survival to hospital discharge with favorable neurologic outcome, and the percentage of patients classified as having severe neurologic impairment at discharge was higher in the epinephrine group than in the placebo group (31% vs 17.8%).The PARAMEDIC-2 trial also elucidated information regarding the use of epinephrine in rhythm-specific subgroups. For the primary outcome of survival at 30 days, epinephrine had a significant benefit only in patients with a nonshockable initial rhythm.12 For this reason and in alignment with AHA recommendations, it is reasonable to delay epinephrine administration in patients with shockable rhythms until initial defibrillation attempts have failed.5 The European Resuscitation Council 2021 guidelines for adult advanced life support specifically recommend that epinephrine be used in patients with shockable rhythms only after 3 defibrillation attempts.13 For patients with nonshockable rhythms, both the AHA and the European Resuscitation Council recommend that epinephrine be given as soon as feasible.11Another consideration is whether the total number of epinephrine administrations should be limited during prolonged resuscitation attempts. The physiologic rationale for this theory is that epinephrine may have detrimental β-adrenergic effects. The high dose of epinephrine used in cardiac arrest has been associated with postresuscitation myocardial dysfunction and subsequent postresuscitation syndrome. Javaudin et al14 found a cumulative epinephrine dose of 5 mg or greater to be independently associated with an increased risk of early cardiocirculatory death in the intensive care unit after nonshockable out-of-hospital cardiac arrest.14 The study findings suggest that although numerous repeated doses of epinephrine may increase the chance of return of spontaneous circulation, the beneficial impact on overall survival is likely lost and repeated doses only delay death until the time of postresuscitation care in the intensive care unit. Due to the observational study design, the results should be interpreted cautiously; prolonged resuscitation, resulting in more epinephrine doses, is also associated with a worse prognosis.14 Fortunately, the Epi-DOSE (Epinephrine Dose: Optimal Versus Standard Evaluation) trial is recruiting participants at the time of this writing. This study will compare the effectiveness of a low cumulative dose of epinephrine (up to 2 mg total) with that of a standard epinephrine dose (up to 6 mg total) in patients with out-of-hospital cardiac arrest.15 Although a maximum cumulative epinephrine dose is not currently included in recommendations from the AHA or the European Resuscitation Council, capping the total number of epinephrine administrations to 3 to 5 doses is common in clinical practice.Bedside dilution of epinephrine is a practical consideration that is critical for health care professionals to understand. Epinephrine is commonly administered during ACLS using syringes prefilled with epinephrine 1 mg/10 mL. During prolonged resuscitation attempts, depleting the supply of prefilled epinephrine syringes in ACLS carts is not uncommon. When the supply is depleted, a member of the team must be able to prepare additional 1 mg/10 mL epinephrine syringes. The 2 most common strategies are to use 0.9% sodium chloride either in an IV solution bag or in a flush syringe. To dilute epinephrine with an IV solution bag, 10 mg of concentrated epinephrine must be injected into a 100-mL bag of 0.9% sodium chloride, creating a 1 mg/10 mL concentration from which 1-mg doses can be withdrawn into 10-mL syringes. Another option is to waste 1 mL from a 0.9% sodium chloride flush syringe and then add 1 mg of concentrated epinephrine to the flush that now contains 9 mL of 0.9% sodium chloride. Regardless of the strategy used, it is paramount that all diluted products are prominently labeled and that clear closed-loop communication is used to avoid inadvertent administration of epinephrine.Patients with initial shockable rhythms (VF or pulseless VT) have significantly higher survival rates than do those with initial nonshockable rhythms. For patients with in-hospital cardiac arrest, the chance of survival to discharge is nearly 5 times as high for those with shockable rhythms as for those with nonshockable rhythms.16 This finding is likely owing to the effectiveness of defibrillation, which is most successful when administered as early as possible.3 Unfortunately, greater than 20% of patients may have VF or pulseless VT that is unresponsive to defibrillation alone, so additional interventions, including antiarrhythmic therapy, may be needed.17 Antiarrhythmics are used not necessarily for direct pharmacologic conversion but rather to help restore and maintain a spontaneous perfusing rhythm in combination with defibrillation.The 2 antiarrhythmic agents currently recommended for treatment of shockable rhythms are lidocaine and amiodarone. Both are considered first-line options. Lidocaine is a class IB antiarrhythmic that works by inactivating sodium channels, raising the depolarization threshold, and reducing arrhythmogenesis.8 Amiodarone is a class III antiarrhythmic that blocks potassium rectifier currents, prolonging the action potential and refractory period.8Unlike recommendations for epinephrine, guideline recommendations for antiarrhythmics have changed substantially over the years, as depicted in the Figure. Before the first landmark trial of antiarrhythmic therapy for cardiac arrest in 1999, the AHA recommended lidocaine solely on the basis of animal studies and rational conjecture.8 In 1999, the ARREST (Amiodarone for Resuscitation After Out-of-Hospital Cardiac Arrest due to Ventricular Fibrillation) trial randomized 504 patients with out-of-hospital cardiac arrest and shock-refractory VF or pulseless VT to receive either amiodarone or placebo.7 The study showed increased rates of survival to hospital admission with the use of amiodarone compared with placebo (44% vs 34%, P = .03). Although this result was promising and prompted the guideline recommendation for amiodarone that persisted for 18 years, only 13% of patients in the study survived to discharge, a finding with no significant difference between groups.7 In the 2002 ALIVE (Amiodarone Versus Lidocaine in Prehospital Ventricular Fibrillation Evaluation) trial, amiodarone and lidocaine were directly compared in 347 patients with out-of-hospital cardiac arrest and shock-refractory VF or pulseless VT. The study showed improved survival to hospital admission with the use of amiodarone compared with lidocaine (22.8% vs 12%, P = .009) but no difference in survival to hospital discharge between the 2 agents (5% vs 3%, P = .34).9 In the ROC-ALPS (Resuscitation Outcomes Consortium–Amiodarone, Lidocaine or Placebo Study) trial, the largest and most recent trial of antiarrhythmic therapy in cardiac arrest to date, 3026 patients with out-of-hospital cardiac arrest and shock-refractory VF or pulseless VT were randomized to receive amiodarone, lidocaine, or placebo.10 The study found no significant differences between either agent and placebo in survival to hospital discharge except in a subgroup of patients with witnessed arrest, for whom both lidocaine and amiodarone had a benefit over placebo.10 This finding led to the AHA’s 2018 updated recommendation to use either lidocaine or amiodarone as a first-line option for VF or pulseless VT.11 To further investigate this unique finding in a subset of patients with witnessed arrest, Wagner et al18 retrospectively reviewed 14 630 patients with in-hospital cardiac arrest and VF or pulseless VT who received amiodarone (n = 10 058) or lidocaine (n = 4572). They found a significant increase in 24-hour survival, survival to hospital discharge, and favorable neurologic outcome at discharge for patients who received lidocaine compared with those who received amiodarone.18 Although the study was observational and thus had significant limitations compared with the other randomized controlled trials, its findings raised the question of whether lidocaine should be preferentially used in the inpatient setting.Although current guideline recommendations provide equal support for amiodarone and lidocaine, some logistical concerns are worth considering. Lidocaine is supplied in a prefilled syringe, allowing for more rapid administration compared with amiodarone, which must be drawn from a vial. In contrast, the fixed dose of amiodarone (300 mg with an option for a second dose of 150 mg) may be preferred over the weight-based dosing recommended for lidocaine. However, in practice it is common to administer the entire 100-mg prefilled lidocaine injector because for most patients the 100-mg dose falls within the dosing range of 1 to 1.5 mg/kg. For patients known to weigh less than 70 kg, a reduced dose of lidocaine can be considered and prepared by wasting the excess from the 100 mg/5 mL dose injector.Previous iterations of ACLS guidelines have included various other medications that have since been removed from the cardiac arrest algorithm. Many of these medications continue to be used regularly despite a lack of guideline recommendations or robust supporting evidence.During cardiac arrest a shift toward anaerobic metabolism results in a buildup of byproducts and ineffective removal of carbon dioxide, which can lead to systemic acidosis. This acidosis can result in arrhythmias, vasodilation, and diminished vasopressor response.13 For this reason, sodium bicarbonate is commonly used for its ability to increase pH and correct metabolic acidosis through the bicarbonate buffer system. Sodium bicarbonate was a recommended medication in the original 1974 AHA guidelines for cardiac arrest. However, the evidence does not support its use and may even suggest harm.6,19 In a meta-analysis of 28 000 patients across 14 studies (4 randomized controlled trials and 10 observational trials), sodium bicarbonate was associated with poorer rates of return of spontaneous circulation and worse neurologic status at discharge.19 Since 2010, the AHA has recommended against the routine use of sodium bicarbonate given a lack of proven benefit except in patients with hyperkalemia or drug overdose.20As with sodium bicarbonate, calcium was an essential medication recommended in the 1974 AHA guidelines for cardiac arrest.6 The physiologic rationale for calcium use is that calcium is required for all muscle contractility, including cardiac contractility, so increasing calcium availability may have a beneficial effect in arrhythmia termination with defibrillation.20 The literature supporting the use of calcium in cardiac arrest is extensive but shows mixed outcomes. A recent multicenter, double-blind randomized controlled trial by Vallentin et al21 examined whether empiric calcium administration after the first dose of epinephrine improved outcomes in patients with out-of-hospital cardiac arrest. The trial was terminated early during the interim analysis due to concerns for harm within the calcium group. After early trial termination, the analysis included 391 patients and showed no difference between calcium and placebo in the achievement of sustained return of spontaneous circulation (19% vs 27%, P = .09). Thirty-day survival and survival with favorable neurologic outcome were worse within the calcium group.21 As a result, the recently updated 2023 AHA guidelines now recommend against the routine use of calcium for patients with cardiac arrest.5Magnesium is a vasodilator that serves as an important cofactor in regulating sodium, potassium, and calcium flow across membranes.20 Literature examining the use of magnesium for patients with cardiac arrest is limited, but 4 small randomized controlled trials failed to show a beneficial effect on return of spontaneous circulation or survival to hospital discharge.20 Magnesium is commonly used in the management of torsades de pointes. However, it primarily functions to prevent reinitiation of torsades rather than to terminate the rhythm itself. Although data to support the use of magnesium for patients with torsades de pointes are scarce, considering its use in this patient population is reasonable given the limited risk associated with magnesium administration.Patients with cardiac arrest can have high levels of circulating catecholamines of both endogenous and exogenous (epinephrine administration) origin. The β-adrenergic effect of epinephrine may be proarrhythmic and worsen cardiac ischemia, potentially contributing to prolonged refractory arrhythmias. Esmolol, a parenteral selective β1-adrenergic receptor antagonist, may counteract these unwanted effects.22 In a single-center retrospective study, Driver et al23 compared patients with refractory VF who received esmolol (n = 6) with those who did not (n = 19). Esmolol improved rates of sustained return of spontaneous circulation, survival to hospital discharge, and survival with good neurologic function. Similarly, Lee et al24 compared patients with refractory VF who received esmolol (n = 16) with those who did not (n = 25). Esmolol was associated with a significantly increased rate of sustained return of spontaneous circulation but no difference in long-term outcomes. In both studies, esmolol was given as a 500 µg/kg loading dose followed by continuous infusion, and refractory VF was defined as VF resistant to 3 or more defibrillations, 300 mg of amiodarone, and at least 3 doses of epinephrine. Although esmolol is not yet recommended within current guidelines, it may be considered a potential option in this unique patient population.22Despite limited evidence for improving longterm outcomes, drug therapy continues to play an integral role in ACLS. Although medications used in ACLS may seem to pose no harm given these patients’ condition, the evidence for use of these agents and their true appropriateness must be considered. Furthermore, as we enter an era focused on personalized medicine, we may soon see recommendations for more patient-specific cardiac arrest algorithms or an individualized approach based on cause, setting, and unique circumstances of the cardiac arrest rather than a one-size-fits-all algorithm. In this scenario, a high level of medication expertise will become even more paramount.