The first reported use of epinephrine in the treatment of cardiac arrest was by George Crile in 1903, where he reported to the New York Times that he had “maintained life for ten and a half hours in a dog whose head had been cut off… primarily by the injection… of [epinephrine]”. The full report of these experiments by Crile and Dolley were published in 1906, which showed that the addition of epinephrine to their resuscitation procedures improved rates of return of spontaneous circulation (ROSC) in asphyxiated dogs compared to those who did not receive epinephrine. More than half a century later, experiments performed by Redding and Pearson further established the role of epinephrine in both asphyxia and electrically induced ventricular fibrillation (VF) in dogs. ^,, Even in these early reports, the authors emphasized the importance of chest compressions to circulate the drug, as well as the timeliness of epinephrine administration, which at the time, was often most rapidly achieved by intracardiac injection.

Physiologically, epinephrine is a non-selective alpha-adrenergic and beta-adrenergic receptor agonist, though peripheral vasoconstriction via the stimulation of alpha-1 receptors is thought to be the primary mechanism of action during CPR. By increasing peripheral vascular resistance, venous return and DBP are increased, which in turn raise coronary artery perfusion pressure (CoPP), augmenting myocardial oxygen delivery. In children with non-pulseless bradycardia requiring CPR, enhanced chronotropy via beta-receptor agonism may also be a contributing mechanism.

Despite little more than anecdotal evidence in human cardiac arrest, epinephrine was the only vasopressor included in the original ECC guidelines in 1974. In this report, a dose of 0.5 mg of epinephrine every 5 min was recommended—the same total dose used in the original Pearson and Redding dog experiments. Yet, because the animals in these experiments likely weighed about 10 kg, the weight-based dosing was reduced nearly 7-fold to 10-fold in humans. Since that time, epinephrine has been a cornerstone of resuscitation efforts and is the only medication uniformly recommended for cardiac arrest in both ACLS and PALS. ^,

Despite its longstanding predominance as the primary medical intervention during CPR, the use of epinephrine for cardiac arrest remains controversial. Concerns for potential deleterious effects of epinephrine include increased myocardial oxygen demand and arrhythmogenicity ^,,, and decreased pulmonary and cerebral blood flow. Until recently, no randomized controlled trials (RCTs) had compared epinephrine with placebo during CPR, leading to ongoing debates about efficacy in humans. However, in 2018, Perkins and colleagues published a randomized double-blind clinical trial of 8014 adult patients with out-of-hospital cardiac arrest (OHCA) comparing 1 mg doses of epinephrine every 3 to 5 min versus placebo for the duration of the pre-hospital resuscitation. Their findings showed that use of epinephrine resulted in increased survival to hospital admission, 30-d survival and survival to hospital discharge, but did not show a significant increase in discharge with favorable neurologic outcome (though the study was not powered for this endpoint). A subsequent meta-analysis, which included this trial found that epinephrine increased ROSC, survival to hospital discharge and 3-mo survival in adult OHCA. These data ultimately led to the AHA strengthening their recommendation for epinephrine administration in adult cardiac arrest from a Class 2b to Class 1. While similar RCTs continue to be lacking for adult and pediatric in-hospital cardiac arrest (IHCA), observational data in these populations suggest improved outcomes when epinephrine is given earlier in the resuscitation. ^,,

Current ACLS and PALS guidelines follow an algorithmic approach, recommending standard epinephrine dosing (1 mg in adults or 0.01 mg/kg in children) at standard dosing intervals (every 3– 5 min) during CPR. ^, However, thoughtful titration of vasopressor administration based on patient-specific physiology is an exciting area for investigation. For example, recent data in children experiencing IHCA show that only about half of patients had an adequate response to the initial epinephrine dose, defined as an increase in DBP of ≥5 mm Hg. In this study by Morgan and colleagues, greater DBP response to epinephrine was associated with higher adjusted risk of ROSC, survival to discharge, and survival with favorable neurologic outcome. This raises the question of whether alterations in vasopressor administration—in both epinephrine responders and non-responders—may further augment DBP and CoPP and ultimately improve outcomes.

While the AHA endorses the use of DBP for CPR quality monitoring, evidence supporting potential modifications to vasopressor management is lacking. ^, One such alteration requiring further investigation is dose of epinephrine itself. While some studies comparing “high-dose” epinephrine (0.2 mg/kg) with standard dosing of 1 mg suggested improved augmentation of CoPP, RCTs in adults ^,, and children with varying “high-dose” regimens showed no survival benefit. However, as the physiologic response to epinephrine was not available in these trials, the question remains as to whether a subgroup of epinephrine non-responders may still benefit from higher dosing.

A second aspect of vasopressor management that warrants further exploration is the frequency of epinephrine administration. For example, a patient who experiences an initial robust DBP response to epinephrine which then quickly declines may justify more frequent administration. On the other hand, in a patient already meeting DBP goals during CPR, continued frequent epinephrine administration may introduce further detrimental effects without substantial gains in CoPP. This may be especially relevant for patients undergoing extracorporeal-CPR, during which repeated epinephrine doses over a prolonged resuscitation are thought to lead to excessive vasoconstriction with subsequent difficulty in achieving adequate assisted circulation after cannulation. ^,

Finally, the selection of vasopressors based on patient physiology is another area of interest. Because genetic variation and other factors involved in adrenergic receptor expression likely explain at least some of the variability in epinephrine responsiveness, ^, drugs which target alternative mechanisms, such as vasopressin, may be beneficial in certain populations. These may include patients with poor response to initial epinephrine administration or patients with certain underlying dysrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (VT), which may be worsened by epinephrine.

While epinephrine remains a mainstay in the management of cardiac arrest, much is left to be explored as to how this and other vasopressors can be tailored to optimize individual physiology and ultimately improve outcomes. The variability in patient response to epinephrine underscores the necessity for rigorous study of physiologic-based alterations to epinephrine dosage and frequency and the use of alternative vasoactive agents.

Vasopressin is a hormone with a differential dose-dependent mechanism of action. It is commonly recognized for its antidiuretic effect on the V2 receptors in the renal distal tubule and collecting ducts, which is useful in the treatment of diabetes insipidus. However, at high doses, vasopressin is primarily a non-adrenergic vasoconstrictor through its action on the V1 receptors of vascular smooth muscle. ^, During CPR, this vasoconstrictive effect increases aortic DBP and, in turn, can increase CoPP with resultant ROSC. ^,, In addition, the concomitant increase in mean arterial pressure and consequent increase in cerebral perfusion can improve the likelihood of favorable neurologic outcomes.

Translational animal studies in the 1990s established that intravenous vasopressin during CPR increased CoPP and increased rates of ROSC. ^,,, A small RCT subsequently demonstrated higher rates of survival to hospital admission in adults with OHCA treated with vasopressin compared to epinephrine. Following this work, vasopressin was first incorporated into the AHA Guidelines in 2000 as an alternative to epinephrine. For pediatric cardiac arrest, vasopressin was suggested as a potential vasoconstrictor during CPR in the 2005 update of the AHA guidelines for pediatric and neonatal resuscitation. However, no formal recommendation for or against its use was provided, owing to lack of pediatric-specific data.

Since that time, several RCTs of vasopressin compared to epinephrine demonstrate similar outcomes without establishing a clear benefit for the use of vasopressin over epinephrine. ^,, Though, most of these studies have focused on adult patients experiencing OHCA. For adult IHCA, a single center double-blinded RCT demonstrated that the combination vasopressin, steroids, and epinephrine (VSE) resulted in higher rates of ROSC and survival to hospital discharge compared with epinephrine alone. These investigators then expanded to a multi-center RCT using the same protocol, which again showed higher rates of ROSC and survival to hospital discharge with favorable neurologic status for patients in the VSE arm. Similarly, a more recent and larger multi-center trial randomizing 512 patients also showed a higher rate of ROSC with VSE compared to epinephrine alone; however, there was no difference in rates of 30-d survival or survival with favorable neurologic outcome between groups. ^, Overall, these generally favorable findings underscore the need for further research to validate and optimize the VSE protocol for adult IHCA and explore its application in pediatric patients.

Data on vasopressin for pediatric patients remain largely observational. ^, In one small pediatric IHCA interventional trial, epinephrine plus vasopressin did not improve outcomes compared with epinephrine plus placebo. In contrast, a 10-patient, non-randomized pilot trial using historic matched controls found increased 24-h survival when children were treated with a “rescue” dose of vasopressin instead of repeating epinephrine among patients without ROSC after an initial dose of epinephrine.

Ultimately, vasopressin was removed from the AHA algorithms for adult cardiac arrest in 2015 primarily to simplify the management algorithm, as vasopressin was not shown to improve outcomes. ^,, Consequently, epinephrine remains the sole vasopressor recommended during cardiac arrest, although its superiority over vasopressin was also not demonstrated. Despite its removal from the guidelines, large national registries studies continue to report the use of vasopressin in a small proportion of IHCA patients, suggesting that some physicians still find a role for it in specific cases of cardiac arrest. ^,

From a physiologic perspective and considering the available data, it is possible that certain patient populations could benefit from vasopressin during cardiac arrest management. As we move toward a more personalized, physiology-directed approach to resuscitation, the role of vasopressin may become clearer. While its action on the V1 receptors of vascular smooth muscle provides systemic vasoconstriction, vasopressin’s effect on the V1 receptors in the pulmonary vasculature stimulates nitric oxide release, leading to pulmonary vasodilation. This dual effect may be beneficial during CPR for patients with underlying pulmonary hypertension, who may have lower rates of ROSC with our current IHCA management compared to the general population. ^,, Additionally, in contrast to epinephrine, vasopressin does not cause cerebral vasoconstriction as the cerebral vessels do not have V1 receptors and thus has the potential for less neurologic injury. As many critically ill patients are already receiving catecholamines via vasoactive infusions before their cardiac arrest, they may benefit from an alternative mechanism for increasing aortic DBP that does not rely on adrenergic receptors. This may be especially beneficial for patients with pre-arrest catecholamine-refractory vasodilatory shock. As above, Morgan and colleagues established that some children have minimal or no increase in DBP responses following epinephrine administration, and these non-responders have worse outcomes compared to children with an adequate DBP response. Translational animal studies have similarly established that some animals are non-responders to epinephrine doses. A personalized resuscitation approach may include a trial of vasopressin “rescue” for patients with arterial blood pressure monitoring at the time of cardiac arrest who fail to achieve an adequate DBP response after an initial dose of epinephrine. Additional opportunities for a tailored approach may include early use of vasopressin in patients with pulmonary hypertension or those on pre-arrest epinephrine infusions.

Future investigations should focus on understanding the physiologic response to vasopressin during cardiac arrest and assessing its effectiveness when integrated into a physiology-directed resuscitation strategy. Laboratory data from large animals have shown increased CoPP response to vasopressin in cases where there was a poor response to epinephrine in a cardiac arrest model. Well-designed, large, multi-center observational studies may provide additional insight into the physiologic response to vasopressin in patients who have already received at least 1 dose of epinephrine to support a more definitive RCT protocol.

Acidosis is commonly observed during cardiac arrest, either as an inciting etiology, ^, or as the result of the no flow/low flow circulatory state that occurs during cardiac arrest regardless of the cause. This occurs because hypoxia and ischemia during cardiac arrest necessitate reliance on anaerobic glucose metabolism, producing a lactic acid byproduct. The acidosis is then worsened by the inability of liver and kidneys to clear excess lactic acid in the no/low flow state. Acidosis reduces the efficacy of catecholamines, ^, blunts myocardial contractility, ^, impairs the immune response, and causes arterial vasodilation and irreversible neurologic damage. ^, In keeping with these physiologic concepts, treating intra-arrest acidosis with a buffer solution, such as sodium bicarbonate, could theoretically mitigate these effects and improve patient outcomes.

Based on this rationale, early animal trials showed higher rates of ROSC when sodium bicarbonate was added to the resuscitation protocol compared to no sodium bicarbonate in electrically induced VF in dogs ^,,, and hyperkalemic arrest in pigs. Intra-arrest bicarbonate also improved cerebral reperfusion in a porcine cardiac arrest model and lessened myocardial dysfunction in a rat model after successful resuscitation. ^, Other animal studies, however, failed to find improvements with intra-arrest sodium bicarbonate, ^,,, and some even found lower rates of ROSC with its use. ^, Other work demonstrated possible risks of bicarbonate use during cardiac arrest, including shifts toward intracellular acidosis, metabolic alkalosis resulting in impaired tissue oxygen delivery, hyperosmolarity, and acute shifts in potassium or calcium levels leading to impaired cardiac function. ^,

In humans, two large RCTs examined intra-arrest bicarbonate for adults with OHCA in the 1990’s. ^, The outcomes from these trials showed an equivocal effect of sodium bicarbonate overall, ^, with the exception of a subgroup analysis in one study, which showed a significant survival benefit in patients with pre-hospital arrest greater than 15 min. A smaller trial from 2018 was not powered to detect differences in patient outcomes but showed improvement in metabolic acidemia with bicarbonate. No RCTs have been performed in children or adult IHCA. Observational studies in both pediatrics and adults have revealed mixed results but often report associations between intra-arrest bicarbonate and worse outcomes. ^,,,, However, these studies suffer from confounding by indication and resuscitation time bias (e.g. “hail Mary” after prolonged CPR).

These data have led the AHA to recommend against the routine use of sodium bicarbonate during cardiac arrest in both adults and children except in special circumstances. ^, Unfortunately, the existing data provide little evidence as to which subpopulations may benefit from intra-arrest sodium bicarbonate. For example, the preclinical experiments employed varying models of inducing cardiac arrest and varied resuscitation protocols, rendering them difficult to translate to the bedside. Even the human clinical trials are difficult to extrapolate across all cardiac arrest victims given that these studies were limited to adults with prolonged OHCA, the largest of which included only those with shockable rhythm refractory to defibrillation. While observational work has attempted to address other cardiac arrest populations, such as children and adult IHCA, they are inherently limited by critical risk of bias, and the question remains as to whether these populations may be helped or harmed by intra-arrest bicarbonate. Even the AHA guideline-specified circumstances of hyperkalemia and sodium channel blocker toxicity have little supporting evidence ^,, ; though, new clinical data may be difficult to generate due to lack of equipoise for this recommended treatment and the relative rarity of cardiac arrests from hyperkalemia or sodium channel blocker toxicity. Notably, a recent animal trial showed that bicarbonate improved rates of ROSC in pigs with hyperkalemia-induced cardiac arrest.

Given these murky data, intra-arrest sodium bicarbonate remains one of the most longstanding controversies in cardiac arrest management. In fact, despite the AHA’s relatively restrictive recommendations, bicarbonate is used in about half of pediatric and adult IHCA, far more than what would be expected from only arrests involving hyperkalemia or sodium channel blocker toxicity. ^, A recent survey showed that many clinicians identified pre-arrest acidosis, pulmonary hypertensive crisis or shock or a prolonged arrest time as circumstances for which they would consider using bicarbonate. While little to no data exist for use of buffer therapy in these conditions, the unique physiology and theoretic benefit of bicarbonate in these scenarios is appealing and warrants further exploration.

Overall, the evidence surrounding intra-arrest sodium bicarbonate in cardiac arrest remains inconclusive, and experts continue to contend the theoretic risks and benefits of the practice. The lack of robust direct evidence, promising potential physiologic benefits, and continued frequent use of intra-arrest bicarbonate all point to the need for rigorous clinical trials to identify which populations, if any, might benefit from this intervention and to clarify its role in cardiac arrest management. Clinical trials with personalized approaches based on individual patient characteristics and specific underlying conditions are most likely to elucidate the optimal use of bicarbonate during cardiac arrest.

The first documented use of calcium in cardiac arrest in humans was by Kay and Blalock in 1951 when they reported 4 cases of pediatric cardiac arrest during cardiac surgery in which intracardiac administration of calcium chloride, among other resuscitative efforts, resulted in ROSC. Given its crucial role in excitation-contraction coupling in myocytes, calcium was thought to improve myocardial contractility and defibrillation success. Based on these theoretic benefits, the initial 1974 ECC guidelines recommended routine calcium administration in cardiac arrest, citing its potential to prolong systole and increase ventricular excitability. However, intra-arrest calcium may also have detrimental effects. During cardiac arrest, myocardial cell injury causes a significant increase in intracellular calcium level, which is further exacerbated by calcium administration, leading to worsening cellular injury and mitochondrial dysfunction. ^, Additionally, calcium overload could lead to hypercontraction and myocardial stunning, ^,, as well as increased risk of dangerous arrhythmias. ^, Excessive calcium can also induce oxidative stress, exacerbating ischemia-reperfusion injury and further worsening myocardial recovery. ^, Due to these concerns, some have even advocated for the use of calcium channel blocker during cardiac arrest.

A recent meta-analysis by Hsu and colleagues identified 3 RCTs which evaluated calcium versus placebo in cardiac arrest, all in adult OHCA. ^,,, The first 2 were conducted in 1982 to 1983 by Stueven and colleagues in which investigators compared calcium versus placebo in asystole and pulseless electrical activity, respectively. ^, Both trials showed absolute increases in rates of survival to hospital admission with calcium that were not statistically significant (7.7% vs 2.9%, P =.37; and 16.7% vs 4.8%, P =.07; respectively). Notably, only 1 of the total 165 patients across the 2 trials survived to hospital discharge. A subgroup analysis of patients with widened-QRS or ischemic changes in electrocardiogram showed higher survival to hospital admission with calcium compared to placebo (20.5% vs 3.2%, P <.028). Based on the lack of clear survival benefit, the AHA removed the recommendation for routine calcium administration in 1992, with exceptions for hyperkalemia, hypocalcemia, and calcium channel blocker toxicity.

More recently, a landmark RCT comparing calcium administration with placebo for adult OHCA conducted in Denmark by Vallentin and colleagues was terminated early due to concerns for harm in a pre-planned interim analysis of 383 patients. The primary outcome of sustained ROSC was 19% in the calcium group compared to 27% in the placebo group (risk ratio: 0.72; 95% CI, 0.49–1.03; P =.09). Additionally, at 30-d follow-up, only 10 patients (5.2%) in the calcium group versus 18 patients (9.1%) in the saline group were still alive (risk ratio, 0.57; 95% CI, 0.27–1.18; P =.17).

While informative, these trials were again limited to only adult OHCA, and do not provide direct evidence for other important populations, such as adult IHCA and pediatric cardiac arrest, in any setting. Furthermore, as the median time from arrest to intervention in the Valentin trial was 18 min (Interquartile range, 14–23 min), these findings may not be generalizable for use earlier in CPR. For other cardiac arrest populations, Hsu and colleagues also identified observational studies that included adult IHCA, which have yielded mixed results. ^,,, Observational studies in pediatric IHCA consistently report that calcium administration is associated with worse outcomes. ^,,,, However, as with sodium bicarbonate, the associations with worse outcomes in all these studies are confounded by indication bias and resuscitation time bias, as calcium is often provided as a last-ditch effort late in the resuscitation when outcomes are poor.

The current AHA guidelines for both adults and children recommend against the routine use of calcium during cardiac arrest. ^, However, there may still be special circumstances where intra-arrest calcium administration is beneficial, and opportunities for a tailored approach should be further investigated. For example, calcium is recommended for cardiac arrest in the setting of hyperkalemia in order to stabilize the cardiac cell membrane, though more recent research suggests an alternative mechanism of restored conduction through calcium-dependent propagation. While physiologically sound, the evidence supporting calcium administration in hyperkalemic arrest is limited. A meta-analysis, which included 1 adult and 1 pediatric observational cardiac arrest study concluded that there was no evidence supporting the clinical effect of calcium in acute hyperkalemia. Recent animal work has also shown no benefit in resuscitation of pigs with hyperkalemic arrest. Additional circumstances for calcium endorsed by the AHA include hypermagnesemia (Class 2b, C-EO), β-blocker overdose with refractory shock (Class 2b, C-LD), and calcium channel blocker overdose (Class 2a, C-LD), though evidence for each of these recommendations is also limited. ^,

Given the recent signal for potential harm in the Vallentin trial, further exploration of intra-arrest calcium should carefully consider the potential study population to target physiologic conditions that could potentially benefit from calcium.

Lidocaine was initially used as an anesthetic agent in the 1940s and was later used as an anti-arrhythmic agent in the 1950s. Lidocaine has been classified as a Vaughan-Williams class Ib anti-arrhythmic that blocks voltage and pH-dependent sodium channels. Lidocaine was first explored in animal models of shockable cardiac arrest after the initial experiments with procaine failed to restore a perfusing rhythm in dogs. In 1956, Carden and Steinhaus published a series of experiments in dogs with VF induced by coronary occlusion in which they reported that CPR with lidocaine ( without electrical defibrillation) was able to convert these animals to an organized rhythm. Subsequently, lidocaine has been recommended for VF and VT since the original 1974 ECC guidelines. This recommendation persisted for decades despite limited evidence in humans. ^,

Amiodarone first became available as an antiarrhythmic compound in the 1970s with intravenous amiodarone becoming available in 1995. Amiodarone is classified as a Vaughan-Williams class III anti-arrhythmic given that it prolongs the action potential by inhibition of the outward potassium channels. It also has class I activity with inhibition of the sodium channels, as well as some class II, beta blocking effects. ^, Amiodarone was initially used for the control and prevention of ventricular arrhythmias and sudden death. Its use increased significantly after the Cardiac Arrhythmia Suppression Trial showed that there was an increase mortality from arrhythmic deaths in patients receiving Class I drugs (encainide or flecainide) for prevention of ventricular arrhythmias post-myocardial infarction. With the availability of intravenous amiodarone, several multi-center studies looked at its effectiveness in the treatment of recurrent VT or VF with all of them showing that amiodarone was safe and effective in the treatment of life-threatening ventricular arrhythmias. ^,,

In 1999, Kudenchuk and colleagues performed a randomized, double-blinded placebo-controlled study in adult OHCA with shock-refractory VF and pulseless VT (pVT) and demonstrated that amiodarone resulted in a higher rate of survival to hospital admission compared to placebo (44% vs 34%, P =.03). With pre-planned population of 500 patients, the study was powered to address differences in rates of survival to hospital admission. Although the study was underpowered to meaningfully address differences in survival to hospital discharge, the actual rates of survival to hospital discharge were essentially the same in both groups (13.4% vs 13.2%). As this was the highest quality evidence supporting any antiarrhythmic at the time, amiodarone was introduced in the 2000 AHA guidelines for both adult and pediatric resuscitation as a potential first-line agent. ^,

In a subsequent RCT of adults with OHCA and shock-resistant VF, Dorian and colleagues demonstrated that patients treated with amiodarone had higher rates of survival to hospital admission compared with those treated with lidocaine (22.8% vs 12.0%, OR 2.17; 95%CI, 1.21–3.83). Though again, this study was underpowered to evaluate rates of survival to hospital discharge (5% vs 3.8%, respectively). Notably, both the Kudenchuk and Dorian RCTs were criticized for the use of the additive polysorbate 80 in both study arms, which is a typical diluent for amiodarone, but was added to the control arm (placebo arm in the Kudenchuk study and lidocaine arm in the Dorian study) for blinding purposes. Because polysorbate 80 has been shown to cause hypotension and bradycardia, concerns arose that the additive may have introduced harm in the conrol groups and falsely favored amiodarone.

Given the limitations of these 2 trials, Kudenchuk and colleagues embarked on the large multi-center double-blind Amiodarone versus Lidocaine versus Placebo for Shock (ALPS)-Refractory VF/pVT study. In addition to targeting a larger sample size powered for survival to hospital discharge, the ALPS investigators also attempted to facilitate more prompt anti-arrhythmic therapy by providing extensive training and equipment for intra-osseous access. This was felt to be important, as the median time to intervention in the previous trials were 21 min and 24 min, respectively. Despite these efforts, however, the median time from emergency services call to drug administrations in ALPS was still greater than 19 min. For the 3026 adults with OHCA and shock refractory VF/pVT in ALPS, they were unable to demonstrate a difference in survival to hospital discharge between amiodarone, lidocaine, or placebo (24.4% vs 23.7% vs 21.0%, respectively). Interestingly, in patients with a witnessed cardiac arrest, both drugs were associated with higher rates of survival compared to placebo (27.7% vs 27.8% vs 22.7%, respectively). In addition, post-hoc Bayesian analyses of the overall ALPS trial results by many of the original authors demonstrated that the probability of survival from amiodarone was 83% (strong prior) to 95% (strong prior) and from lidocaine was 78% (strong prior) to 90% (strong prior), each compared to placebo. Notably, while this trial eliminated polysorbate 80 from both arms, the additive is still commonly used in amiodarone formulations in the United States, and therefore, its real-world effectiveness compared to lidocaine may be different when using that formulation.

Importantly, the aforementioned trials were limited to adult OHCA. For adult IHCA, a large observational study using AHA’s Get With the Guidelines-Resuscitation (GWTG-R) registry showed that among patients with IHCA from VF/pVT, lidocaine was associated with higher rates of ROSC, 24-h survival, survival to hospital discharge and favorable neurologic outcomes compared to amiodarone.

In children, the data comparing amiodarone and lidocaine in VF/pVT are limited to 2 retrospective observational studies in IHCA at AHA GWTG-R participating hospitals. In 2014, Valdés and colleagues showed that lidocaine administration was associated with increased rates of ROSC and 24-h survival compared to amiodarone or no drug. However, they were unable to demonstrate differences in rates of survival to hospital discharge. In 2020, Holmberg and colleagues again compared lidocaine to amiodarone in a later cohort of children in the GWTG-R database, this time using propensity score matching to adjust for potential confounders. In this study, the authors showed no differences between amiodarone and lidocaine for ROSC, 24-h survival, and survival to hospital discharge. They concluded that amiodarone and lidocaine appeared to be equally effective, though patients who received neither drug were not included, and medication timing was not accounted for in the study.

Current ACLS and PALS guidelines recommend that amiodarone or lidocaine may be considered for VF/pVT that is unresponsive electrical defibrillation. ^, Given that the existing evidence does not suggest superiority of one drug over the other, the choice of which drug to use in a cardiac arrest is often based on personal preference and comfort with each drug. However, the differing mechanisms of action of these drugs offer theoretic benefits in certain patients, which require further exploration in clinical research. For example, if the dysrhythmia is thought to be related to prolonged QTc (congenital or acquired), lidocaine may be more efficacious given that amiodarone can further prolong repolarization (i.e. QTc). On the other hand, if the cardiac arrest is preceded by a supraventricular arrhythmia, amiodarone may have benefits over lidocaine given the latter has minimal effect on the supraventricular tissues. Another consideration that may be explored in different clinical scenarios is the half-life of each drug. Because lidocaine has a significantly shorter half-life than amiodarone, ^, it has a more rapid onset of action whereas the longer half-life of amiodarone might provide longer anti-arrhythmic coverage. Finally, given the potential for detrimental cardiovascular effects in children, particularly in infants less than 3 mo and when administered as a rapid bolus (<20 min), some pediatric cardiologists discourage its use for infants. Yet definitive data to address the risks and benefits for this population are needed.

Future research comparing the use of either drug in cardiac arrest patients should focus on identifying populations, which might benefit best from one drug or the other. Additionally, given that in the majority of studies the anti-arrhythmic drugs were administered late in resuscitation after 3 failed shocks, it would be of interest in future studies to see if earlier administration of an anti-arrhythmic (e.g. after initial failed shock or prior to initial epinephrine), would improve outcomes.