Adjunctive Therapeutics in the Management of Cardiopulmonary Resuscitation: A Narrative Literature Review

Nearly 565,000 patients will suffer from prehospital and inpatient cardiac arrest in the United States per annum. Cardiopulmonary resuscitation and all associated interventions used to achieve it remain an essential focus of emergency medicine. Current ACLS guidelines give clear instructions regarding mainstay medications such as epinephrine and antiarrhythmics; however, the literature remains somewhat controversial regarding the application of adjunctive therapeutics such as calcium, magnesium, sodium bicarbonate, and corticosteroids. The available data acquired in this field over the past three decades offer mixed pictures for each of these medications on the effects of core metrics of cardiopulmonary resuscitation (e.g., rate of return of spontaneous circulation, survival-to-hospitalization and discharge, 24 h and 30 d mortality, neurological outcome), as well as case-specific applications for each of these interventions (e.g., polymorphic ventricular tachycardia, electrolyte derangements, acidosis, post-arrest shock). This narrative literature review provides a comprehensive summary of current guidelines and published data available for these four agents and their use in clinical practice.


Introduction
In the United States, 356,000 patients suffer from out-of-hospital cardiac arrest (OHCA) each year, presenting to the emergency department (ED) with an often-undifferentiated cause of arrest [1].An additional 209,000 patients will then sustain in-hospital cardiac arrest (IHCA) after admission irrespective of their original diagnosis or involvement of cardiac arrest (CA) prior [2].For the former, the challenge for emergency physicians is to attempt to reverse the underlying cause of arrest to restore circulation.For the latter, valuable data can still be derived for application in the ED.
A critical component of cardiac arrest management involves electrolyte shifts and related pathologic mechanisms.This can occur both as the possible cause of the initial arrest, as well as an insult acquired during the course of resuscitation, primarily due to acidosis, medication administration, and underlying comorbidities.Aside from standard medications such as epinephrine and antiarrhythmics, other adjunctive therapeutics, including calcium, magnesium, sodium bicarbonate, and corticosteroids, have been investigated to address this concern.Historically, these medications have been utilized due to theoretical benefits in reversing or mitigating physiological changes in cardiac arrest, yet the empiric and case-specific administration of each remains highly debated [1].
This review discusses the current clinical guidelines and available literature associated with each of these therapeutic interventions.Both general and specific outcomes have been examined by various researchers, including potential benefits in improving the achievement of return of spontaneous circulation (ROSC), effects on patient mortality, survival-to-hospitalization  Magnesium and valium may need to be given as early as possible to be truly neuroprotective agents.

Magnesium
Magnesium administration in cardiac arrest has been evaluated in terms of both safety and efficacy for its use in cardiac arrest.The original 2015 American Heart Association (AHA) guidelines (and a recent 2018 update) recommend against its empiric use in cardiac arrest, although it does consider its potential efficacy specifically for QTc prolongation and resultant polymorphic ventricular tachycardia, otherwise known as torsades de pointes (TdP).Further research has also been conducted regarding its effects in refractory ventricular fibrillation (v-fib) arrest, broader applications of this electrolyte continue to be debated [18].
Magnesium was originally evaluated in a pilot study by Miller et al. [13] for safety as an ancillary therapy in cardiac arrest.They demonstrated no significant increase in patient harm and showed comparable rates of survival-to-discharge, as well as a temporal relationship between magnesium administration and ROSC [13].Two early studies initially evaluated the potential efficacy of magnesium sulfate in both the prehospital and inpatient settings.The first was achieved through the Magnesium in Cardiac Arrest (MAGIC) Trial (1997) by Fatovich et al. [14] (n = 67), which determined early administration of MgSO 4 (5 g IV) vs. placebo generated no significant difference in achievement of ROSC (23% vs. 22%) [19].For inpatient arrest, Thel et al. [15] reported similar results, namely equivalent rates of ROSC (54% vs. 60%, p = 0.44), survival to 24 h (43% vs. 50%, p = 0.41), and survival-to-discharge (21% vs. 21%, p = 0.98) [15].
Despite this, magnesium still serves an important role in pre-arrest and intra-arrest management as the treatment of choice for QTc prolongation and its subsequent degeneration into torsades des pointes [22].The mechanism behind its utility in this instance is the theorized reduction in early after-depolarizations in cardiac myocytes to help terminate underlying dysrhythmias.Because of the same underlying mechanism of effect, it may be safely administered specifically in ventricular fibrillation arrest with profound electrolyte abnormalities (i.e., hypomagnesemia, hypokalemia) likely causing the arrest itself [23].Although there are not many randomized controlled trials demonstrating this, it has been well-demonstrated in case reports and practice [24].Per the updated 2018 European Resuscitation Council (and related) guidelines, magnesium sulfate is recommended in this specific instance, but not advised for empiric use in all cardiac arrests [25].
Conclusion: Magnesium should be given as a first-line agent in the management of torsades des pointes.Evidence has not shown benefit in other causes of cardiac arrest; however, there has been no harm demonstrated from administration (see Table 1).

Sodium Bicarbonate
Sodium bicarbonate (NaHCO 3 ), considered to be a mainstay adjunct in resuscitative management, remains rather controversial.Typically administered as a buffer against systemic acidosis sustained during cardiac arrest, its empiric administration has remained a focus of discussion for decades.However, guidelines from the European Resuscitation Council from 2015 recommend against routine sodium bicarbonate use, except in cases of "life-threatening hyperkalemia, cardiac arrest associated with hyperkalemia," and "cardio-vascular toxicity (hypotension, cardiac arrhythmias) caused by tricyclic antidepressants and other fast sodium channel blockers" [26].The American Heart Association (AHA) recommendations from the same year echo this, citing their original stipulation from 2010 that "routine use of sodium bicarbonate is not recommended for patients in cardiac arrest" despite the emergence of new research on the matter [27].
The literature indicates inherent potential in sodium bicarbonate in specific CA patient cohorts, although any reported benefits are largely drawn from retrospective data analyses and observational trials.Bar-Joseph et al. [28,29] performed a post hoc analysis of data derived from the Brain Resuscitation Clinical Trial III (BRCT III).In their first analysis (n = 2915, 54.5% NaHCO 3 ), they noted a linear correlation between sodium bicarbonate and longer advanced cardiovascular life support (ACLS) duration [28].Their second investigation examined 2122 OHCA patients with pre-ACLS downtime less than 30 min.In this case, the authors categorized treatment sites as "high users" or "low users" based on sodium bicarbonate administration.Here, "high user" locations sustained higher rates of ROSC (33.5% vs. 25.7%,aOR 1.36, 95% CI [1.08-1.70]),higher average rates of discharge (5.3% vs. 3.0%), and more favorable neurological outcomes (5.3% vs. 2.1%, aOR 2.18, 95% CI [1.23-3.86]).More interestingly, however, the authors note "high user" centers also more critically ill patients, including less "favorable" presenting rhythms (e.g., ventricular fibrillation, pulseless ventricular tachycardia), less patients with "short" time periods between collapse and arrest, and less bystander cardiopulmonary resuscitation (CPR).Despite this, such centers experienced better outcomes when these factors should have otherwise diminished or reversed such trends [29].Contrary to this, a recent meta-analysis by Wu et al. [30] including six observational studies comprising 18,406 adult CA patients in Asia and North America determined no significant difference in ROSC (OR 1.185, 95% CI [0.680-2.065])or survival-to-discharge (OR 0.296, 95% CI [0.066-1.323])[30].
In the inpatient setting, a single-center, retrospective, observational study by Wang et al. [34] assessed both sodium bicarbonate and calcium in cardiac arrest implicated by hyperkalemia and found similarly promising results.Their study cohort was small (n = 109 patients) and primarily focused on in-hospital cardiac arrests (IHCA) with confirmed hyperkalemia (K > 6.5 mEq/L).Here, they found 36.7% of patients regained spontaneous circulation and 3.7% survived to discharge.In the sodium bicarbonate treatment arm, ROSC was again significantly increased, particularly when serum potassium levels did not exceed 7.9 mEq/L (OR 10.51; 95% CI [1.50-112.89];p = 0.03).The same could be said of those receiving calcium with potassium below 9.4 mEq/L (OR 51.11; 95% CI [3.12-1639.16];p = 0.01) [34].Contrary to this, a more recent retrospective cohort (n = 1060 patients) assessed by the same group only found improved neurological outcomes after treatment in sustained IHCA greater than 20 min.(OR 6.16, 95% CI [1.42-26.75]).Furthermore, greatest survival-to-discharge was seen in those without acidemia and not treated with sodium bicarbonate (OR 1.56; 95% CI [1.01-2.4];p = 0.05).The authors therefore recommend against empiric administration and favor a case-specific approach (e.g., prolonged arrest) [35].
The evidence therefore remains unclear as to whether sodium bicarbonate should be broadly employed for OHCA and IHCA.Yet as previously mentioned, the consideration of actual duration of arrest in the use of sodium bicarbonate remains open to debate.First proposed by Vukmir et al. [37] in a robust prospective, double-blinded, randomized clinical trial in 874 OHCA patients over 4 years, initial analysis did not demonstrate a significant difference in patient survival between the sodium bicarbonate (median 100.2 mEq/L, IQR 66.8-104.4)or placebo treatment subgroups (7.4% vs. 6.7%, p = 0.88).However, upon further evaluation, the authors demonstrated a near two-fold increase in survival in those who received treatment after prolonged cardiac arrest exceeding 15 min (32.8% vs. 15.4%,p = 0.007), thus raising the question of the utility of sodium bicarbonate in cardiac arrest of variable duration [37].A subsequent retrospective study by Weng et al. [38] redemonstrated this association of sodium bicarbonate and extended cardiac arrest (>15 min), although the achievement of ROSC was similar between the treatment and control arms after standard (40.0%vs. 32.3%,p = 0.465) and multivariate (aOR 1.270; 95% CI [0.501-3.219];p = 0.615) analysis.Moreover, only 6.7% of patients who received sodium bicarbonate sustained ROSC and none survived to hospital discharge [38].Vukmir et al. [37] note these poor outcomes may be partially attributed to the adverse side effects of sodium bicarbonate itself (e.g., hypernatremia, metabolic alkalosis, central venous acidosis with reduced exogenous pressor efficacy), although they warn of significant selection bias after eliminating all patients with shorter arrest times (<15 min), and therefore those with higher likelihood of positive outcomes [37,38].
The impact of sodium bicarbonate on patient outcomes such as the achievement of sustained ROSC and positive neurological outcome thus remain unclear.The current literature is highly retrospective in nature with few clinical trials available, although some do exist.
Conclusion: Evidence remains inconclusive, but does support the use of sodium bicarbonate in cases of severe acidosis or prolonged downtime without evidence of harm (see Table 2).

Corticosteroids
Steroids serve as yet another potential adjunctive therapeutic in cardiopulmonary resuscitation.Their utilization is based upon the premise that the hypothalamic-pituitaryadrenal (HPA) endocrine axis acts as a "self-defense" mechanism against stressors to homeostatic physiology, including myocardial infarction, sepsis, shock, surgical insult, and most severely, cardiac arrest itself.This results in endogenous release of HPA-controlled hormones including arginine vasopressin (ADH), adrenocorticotropic hormone (ACTH), and cortisol.One study by Ito et al. [39] comprising 36 cardiac arrest patients (nine survivors vs. 27 non-survivors) revealed globally elevated plasma levels of all three of these in both groups, presumably due to stress induced during arrest and subsequent resuscitation attempts.More interestingly, serum cortisol was significantly increased in survivors (p = 0.029), which allowed for derivation of an ROC curve (cutoff of cortisol 16.7 µg/mL) for predicting non-survival in this cohort (Sn 100%, Sp 100%, NPV 0.519) [39].Since then, exogenous corticosteroids and vasopressin have been extensively utilized to replicate this physiological response in hopes of improving absolute mortality in cardiac arrest, as well as secondary post-arrest outcomes after initial ROSC is achieved.
Conclusion: Steroids may provide an improvement in the achievement of ROSC, without clear benefit to overall mortality or survival to discharge.There has not been found to be evidence of harm, so corticosteroids may be considered as a safe adjunct therapy (see Table 3).Significant improvement in shock reversal with hydrocortisone in patients with significant adrenal insufficiency was seen in this study and should be further investigated.
Authors comment that increased post-CA IL-6 levels are associated with worse morbidity/mortality, here reduced after hydrocortisone, but without improvement in secondary outcomes (may be a correlative, rather than a causative).

Discussion
In this review, we examine the literature surrounding four adjunct therapies and their roles in the management of cardiac arrest: calcium, sodium bicarbonate, magnesium, and steroids.These adjunct therapies are not included in the current ACLS algorithms but have been widely used by emergency physicians during cardiac arrest, and it is important to determine when they might be of benefit to selected patients and when they ought to be withheld.
Calcium chloride is typically supplied in code carts as an intravenous push dose for use in cardiac arrest, as an adjunct to epinephrine to improve myocardial contractility.However, the evidence presented in this review does not support its use except in cases of severe hyperkalemia.Several studies have actually shown risk of harm with empiric calcium administration in both pediatric and adult populations, including decreased rate of ROSC and hospital discharge.The one exception to this has been improvement in the rates of ROSC in cases of severe hyperkalemia, as calcium can stabilize the cardiac membrane in these patients (Table 1).Based on this evidence, it is not recommended to administer calcium routinely in cardiac arrest, unless hyperkalemia is confirmed as a cause using bedside electrolyte panels, or if the clinical history strongly supports this as a cause, such as in the case of patients who have missed hemodialysis sessions.
Magnesium is recommended as a first-line medication for polymorphic ventricular tachycardia, or torsades des pointes.It has also been studied as an adjunct therapy in cases of refractory ventricular fibrillation.Although shown to be of benefit in TdP, there has not been evidence to support its routine use for management of refractory ventricular fibrillation.However, unlike empiric calcium administration, there has been no evidence of harm in magnesium administration, and so this may be considered for use in cases with electrolyte abnormalities or undifferentiated cause of arrest without concern for harm to the patient (Table 1).
Sodium bicarbonate is commonly given as an adjunct therapy in cardiac arrest for its benefit in correcting severe acidosis, which decreases cardiac contractility, peripheral vascular tone, and beta receptor sensitivity to vasopressor medications.Although studied widely, the literature remains mixed.Sodium bicarbonate is notoriously difficult to study, in part due to its aforementioned status as a "last ditch effort" intervention for patients with more severe acidosis on presentation and prolonged resuscitation time, often the same patients who have worse outcomes due to underlying pathology at baseline.The evidence presented in this review (Table 2) remains inconclusive; however, the literature supports its use for patients with severe acidosis or prolonged cardiopulmonary resuscitation without evidence of harm.
Steroids have been given in cardiac arrest in order to support the physiologic stress response, with evidence showing higher levels of cortisol in survivors of cardiac arrest.Several large trials have suggested an improvement in ROSC in patients who receive steroids during cardiac arrest, with the largest improvements seen when steroids are given early in the resuscitation.The data to support whether steroids improve overall survival and mortality remains mixed, with some trials showing improvement in ROSC without improved survival to hospital discharge.None of the large trials have shown any evidence of harm with steroid administration, and it may be considered as a useful adjunct in resuscitation (Table 3).

Limitations
There are several limitations in our review.First, our review examines four adjunct therapies which are known to have mixed or inconclusive data despite being studied extensively.Although the purpose of this review is to provide better context for this mixed data, it will also make the review inherently prone to differences in conclusions and interpretation.Second, the nature of a narrative review carries an inherent risk of errors of objectivity and interpretation.We have, however, attempted to minimize this by providing as much objective data as possible to demonstrate how our conclusions and recommendations were drawn.

Conclusions
Based on our review, we recommend against the routine use of calcium in cardiac arrest, except in cases of severe hyperkalemia.Magnesium administration also does not seem to have clear benefit when administered, although it has not been found to cause harm and thus may be given empirically in certain patient subsets (i.e., electrolyte derangements, TdP).The literature regarding sodium bicarbonate remains unclear with current guidelines still recommending against its empiric use.It should still be considered, however, in those with severe acidosis and/or prolonged arrest.Intravenous corticosteroids and combination therapies (e.g., VSE) have been shown to have some benefit in cardiac arrest, with several large trials showing improvement in rates of ROSC, although this may not ultimately translate into improvement in overall survival.Their use in cardiac arrest and post-arrest shock may therefore be considered as safe and potentially advantageous.

Table 1 .
Summary of available clinical data regarding the use of magnesium sulfate and calcium chloride in cardiopulmonary resuscitation.

Table 2 .
Summary of available clinical data regarding the use of sodium bicarbonate as an adjunctive therapeutic in cardiopulmonary resuscitation of in-hospital and/or out-of-hospital cardiac arrest.

Table 3 .
Summary of available clinical data for sole corticosteroid and combined regimen use in cardiopulmonary resuscitation and post-resuscitation shock.