INTRODUCTION

Sudden cardiac arrest (CA) syndrome is a life threatening and life altering event for surviving patients.  According to the American Heart Association, over 350,000 out-of-hospital cardiac arrest events occur in the United States each year (American Heart Association [AHA], 2015).  Healthcare providers are faced with the challenge of maximizing prognoses in the surviving, post-resuscitated patient population.  Patients with a history of CA face many immediate as well as long term complications.  Of these long-term complications, perhaps the most impactful sequela of CA is irreversible neurological damage.   It is therefore imperative that all measures be taken to help preserve neurological function throughout the traumatic event and post-resuscitative therapeutic processes.  For this reason, practitioners and medical researchers are currently investigating new methods to mitigate detrimental long-term effects.  One such method currently being employed is targeted temperature management (TTM), [also known as iatrogenically-induced hypothermia].  Neurological function preservation of some CA patients has been observed following TTM.  However, there are several drawbacks associated with TTM therapy, which include potentially detrimental effects of treatment such as immune system depression and increased bleeding potential, as well as a considerable cost of therapy application.  In addition, the post-cardiac arrest patient population is not monolithic. This population can be further segregated into categories depending upon the initial rhythm and location at onset, presence or absence of witness of the event as well as other factors.  Several of these factors have varying prognoses associated with them.  Subsequently, further exploration into which forms of CA respond to TTM and which patient populations and accompanying comorbidities benefit from TTM therapy application is warranted.

In 2015, the American Heart Association published an update to its 2010 guidelines.   Among its updates was the inclusion of non-shockable post resuscitation cardiac patients to its recommendation of mild therapeutic hypothermia treatment applications (Callaway, 2015).  Prior to the update, mild therapeutic hypothermia had been recommended therapy for shockable CA resuscitation (Callaway, 2015).  Currently, there is minimal and conflicting data regarding therapeutic benefits of TTM for non-shockable CA patient.

Shockable rhythm CA patients, including both in-hospital CA (IHCA) and out-of-hospital CA (OHCA), who successfully achieve ROSC and undergo TTM show an increased proportion in favorable neurological outcomes compared to those who do not.  The effectiveness of TTM for non-shockable CA rhythms patients’ neurological outcomes, however, is inconclusive due to low number of studies and subsequent insufficient data.  Nonetheless, the American Heart Associates 2015 Guidelines update now recommends TTM as post ROSC therapeutic intervention for patients with initial non-shockable CA rhythms.  Given the current insufficiencies in evidence supporting the benefits of TTM for non-shockable CA, paired with the known therapeutic risks, a careful analysis of current available evidence to aid clinicians in evaluating TTM as a prospective treatment option is prudent.  It is incumbent upon physicians to perform risk benefit analyses of exposing patients, particularly in the presence of comorbidities, in addition to considerable cost to patients and families, to additional harm with minimal evidence of therapeutic effect of the intervention being applied.

In this article, six studies were reviewed for comparative analysis of neurological outcomes of shockable and non-shockable cardiac arrest patients, after restoration of spontaneous circulation.

CARDIAC ARREST

Cardiac Arrest: Mechanism and Precipitation of Neurologic Deficiencies

Cardiac arrest is an event in which akinesis of cardiac myocytes leads to impaired ventricular contractility (Kasper et al., 2015).  This cardioplegic event leads to a decrease in brain perfusion and subsequent anoxic neurologic state (Kasper, 2015).  During this period of decreased perfusion or “downtime,” the brains metabolic requirements go unfulfilled which precipitates neurologic tissue damage.

Cardiac Arrest Classifications: Shockable vs Non-shockable

Non-traumatic CA is generally classified into two categories, shockable and non-shockable.  These categories are determined by the initial cardiac rhythm of the arresting event and its ability to be remedied by defibrillation (shock) or not (Kasper, 2015).  Shockable CA syndrome, which includes pulseless ventricular tachycardia (pVT) and ventricular fibrillation (VF), exhibit better responsiveness to defibrillation intervention than non-shockable CA events, which includes asystole, bradyarrythmia and pulseless electrical activity (PEA) (Kasper, 2015).  Non-shockable rhythm CAs, are generally associated with adequate pace-making electrical activity and subsequently don’t benefit from defibrillation.  They are found as secondarily precipitated complications of hemodynamically unstable patient populations (Kasper, 2015).  The pathology lies in the cardiac myocytes inability to complete the contraction-relaxation cycle.  These two rhythms subsequently require conversion to a shockable rhythm and/or rapid identification and treatment of the underlying cause(s) (Kasper, 2015).  Successful achievement to and maintenance of return of spontaneous circulation (ROSC) in this patient population often requires close management of hemodynamic instability and dysfunction (Kasper, 2015).

Cardiac Arrest: Out-of-Hospital vs In-Hospital

Currently, total (TTM and non-TTM) adult IHCA patients have better survival to hospital discharge (25.6%) and favorable NOs (20.0%) than total OHCA patients with survival to discharge (10.4%) and favorable NOs (8.4%) (Benjamin, 2019).         

NEUROLOGICAL OUTCOMES

Neurological Outcomes: Methodologies and Analysis Metrics– CPC Scale

Currently, there are several metrics used to assess neurological outcomes of post-cardiac arrest patients treated with targeted temperature management (TTM).  The most common international assessment scale used by practitioners is the cerebral performance category (CPC) scale.  This is a five-point semiqualitative scoring system used to assess patient neurological function and outcomes.  The five category designations were utilized as outlined by Kiehl et al. (2017) as follows: cerebral performance category 1 (CPC1)- good cerebral performance; cerebral performance category 2 (CPC2)- moderate cerebral disability; cerebral performance category 3 (CPC3)- severe cerebral disability; cerebral performance category 4 (CPC4)- coma or vegetative state; and cerebral performance category 5 (CPC5)- brain dead (Kiehl, 2017).  A binary grading metric was constructed to stratify patient neurological assessments, in which a CPC score of 1-2 would be classified as a “favorable” NO, while scores of 3-5 would be classified as an “unfavorable” NO (Hsu, 2014).

Neurological Outcomes: Methodologies and Analysis Metrics- Other Prognostic Indicators

Five of the six studies explored and identified prognostic indicators which provided some correlation between the metric(s) or assay, survival to discharge, patient NOs at discharge and/or patient prognosis.  The CPC, investigated by Hsu et al. (2014), is currently widely utilized as an assessment tool for post-CA survivors.  It has been criticized as a crude metric owing to the level of inherent subjectivity in its scoring as well as questions as to its reliability (Hsu, 2014).  Comparatively, it is still a better scoring system than both the C-GRApH, APACHE2 and SOFA (Kiehl, 2015; Yoon, 2017).   Although statistically significant correlations were observed in the investigations of each of these assessment tools, none were in our opinion sufficient as stand-alone prognostic indicators.  In addition to assessing the validity of assessment tools, clinicians must also take into consideration its degree of accessibility, ability to conduct/collect/administer, convenience of use, reproducibility, and costs of administration, as well (Kiehl, 2017).  For these reasons, Kim et al.’s (2017) retrospective analysis on lactate and NOs and Kiehl et al.’s (2017) exploration of blood lactate and C-GRApH tests were of keen interest (Kim, 2017; Kiehl, 2017).  Blood lactate levels are relatively low cost and can be obtained through point of care instrumentation in a matter of minutes.  However, the positive correlation found between increased post admission blood lactate levels and unfavorable post-TTM NOs may be of minimal use considering the many different effectors of increased lactate levels.  Other studies exploring more tissue specific markers such as NSE are currently showing promise and may be more suited for prognostic purposes of NOs in the future (Vondrakova et al., 2017).  Each metric and/or assay discussed may be quite useful if employed in various combinations to aid clinicians in obtaining a more comprehensive clinical picture and inform patient care strategies.

Neurological Outcomes post-TTM: Shockable vs Non-shockable Cardiac Arrest

Hsu et al. (2014), Kim et al. (2015), Perman et al. (2015), Kim et al. (2017), Kiehl et al (2017) and Yoon et al. (2018) all observed clinically significant difference in NOs in patients experiencing initial shockable CA rhythms compared to initial non-shockable rhythms undergoing the same treatment protocols for their respective studies (Hsu, 2014; Kim, 2015; Perman, 2015; Kim, 2017; Kiehl, 2017 & Yoon, 2018).  Hsu et al. (2014), Kim et al. (2015), Perman et al. (2015), Kim et al. (2017), Kiehl et al (2017) and Yoon et al. (2018) reported cardiac arrest patients experiencing initial shockable rhythms had favorable NOs percentages of 84, 62, 51, 62, 39 and 47, respectively, while those treated with TTM after a non-shockable CA events had favorable NOs percentages of 52, 16, 21, 20, 3 and 16 respectively.

Neurological Outcomes post-TTM: Out-of-Hospital vs In-Hospital Cardiac Arrest

Hsu et al. (2014), Perman et al. (2015), Kim et al. (2017) studies provided comparative data on post-TTM NOs for patients by initial arrest event location.  All three studies reported an increase in favorable NOs for OHCA patients.  Perman et al. (2015) and Kim et al. (2017) both reported an one percent and three percent respective difference in patients treated with TTM after experiencing OHCA event versus an IHCA event undergoing the same treatment protocol.  Hsu et al. (2014) however, observed OHCA patients experienced a higher percentage of favorable NOs with a difference of 17 percent. Hsu et al.

DISCUSSION

Considering the relative lack of performance of TTM in non-shockable CA patient NOs compared to shockable CA patients, therapeutic benefit measured against potential patient harm should be considered when clinicians are devising treatment strategies.  Furthermore, physicians carry a fiduciary responsibility when prescribing treatment protocols that carries considerable financial cost to patients (Kalra et al. 2018; Gajarski et al., 2015).  The benefits of TTM for shockable rhythm patients has been clearly established with favorable numbers-needed-to-treat (NNT) of 6 patients for favorable NOs and an NNT=7 for avoidance of mortality (NEJM, 2002; Bernard et al., 2002; Muengtaweepongsa et al., 2017).  However, as stated in the introduction to this study, there is currently minimal and conflicting data investigating the therapeutic effects of TTM on non-shockable CA patients.  The studies that have been conducted to date, as does this one, fail to provide clear, clinically significant evidence demonstrating the benefits of TTM intervention for non-shockable CA patient with ROSC.  Perhaps the 2015 AHAs Guideline Update will address this issue by increasing the amount of data on the topic for evaluation.  One such study, the 2015 HYPERION trial, a multicenter (22 French ICUs) randomized, controlled assessor blind superiority trial which has yet to be published, we anticipate will deliver a large dataset (n=584) to help address this lack of evidence and provide more substantial insights on NNT, numbers-needed-to-harm (NNH) as well as additional pertinent statistics (Lascarrou, 2015).  As noted in the introduction to this study, it is incumbent upon clinicians to perform risk benefit analyses of exposing patients, particularly in the presence of comorbidities, to additional harm with minimal evidence of therapeutic effect of the intervention being applied.  To this end, further evaluation is warranted.

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