American Journal of Emergency Medicine 36 (2018) 498-523

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Correspondence

More questions than answers – ALS interventions for out of hospital cardiac arrest

In this issue of the journal, the investigators studied a prospective, observational, cohort of patients that were defibrillated by only Emer- gency Medical Services (EMS) with witnessed out of hospital arrest (OHCA) [1]. They analyzed the correlation of Advanced life support -level care (as defined by placement of an advanced airway and/ or epinephrine administration) to patients who did not receive ALS- level care with outcomes defined as survival at one month and minimal neurological disability at one month. After propensity-matching, the au- thors report a negative correlation between ALS-level care and favor- able outcomes. The objective of this editorial is to outline several limitations of the study design, summarize current evidence, and sug- gest avenues for further research.

Any study which is observational is subject to uncontrolled and po- tentially unknown confounding variables [2]. This is evident by the fact that all baseline characteristics were different between the two groups. This is not surprising as it was at the discretion of the EMS providers to administer ALS-level care. Using propensity matching can help two sim- ilar groups become more similar [3]. However, in this case, two very dif- ferent groups were matched resulting in skewed data and interpretation.

A significant limitation of this study is the effect of propensity matching. We argue that in this case the use of statistical modeling does not remove confounding variables, but rather it adds them. For in- stance, the propensity matching resulted in significantly earlier cases within the time frame studied. In a consecutive fashion, 2005 was the most represented year and 2013 was the least represented. Prior to matching, the number of cases per year were more uniform. This differ- ence is important because public access to defibrillators increased over this time period in Japan – with it highly likely there was less access in 2005 versus 2013 [4]. This can crucially change the characteristics of the population over time, as more OHCA victims respond to earlier de- fibrillation. The authors do not discuss to what degree, if any, this or other temporal trends may have confounded their results. An additional limitation of the matching is that beyond age and sex, there is no other demographic information of the patient including comorbidities and pre-existing cardiac disease. Therefore, it is plausible that important dif- ferences in baseline medical conditions exist between the groups.

Another striking consequence of the propensity matching is that all patients in the ALS group with successful intravenous (IV) line access were excluded from the propensity-matched cohort. It is likely that a significant number of those unable to receive an IV despite receiving ALS was secondary to a confounding variable that correlates with a greater severity of illness such as severe hypovolemia, morbid obesity, or end-stage renal disease. The lack of IV access is likely what caused a huge percentage of patients receiving epinephrine to be excluded from the propensity-matched cohort (8897/9208, 96.6%). Another

result of this matching was that most patients who achieved return of spontaneous circulation (ROSC) in the ALS group were excluded (1916/1994, 96.1%). This further supports the idea that unknown con- founding variables contributed to the difference in outcomes reported. After ALS care is divided by ability to obtain IV access, so did the out- comes of ROSC, one month survival, and Cerebral Performance Category 1 or 2. The match-excluded patients contain 98.7% of the ALS pa- tients with IV access and 96.6% epinephrine administration. By compar- ing the ALS match-excluded to the ALS match-included patients, there is an associated increased in one month survival and CPC 1 or 2 favoring the match-excluded group (12.2% vs 8.92% 1-month survival and 5.05% vs 2.87% CPC 1 or 2).

It is unclear if, and when, intraosseous lines (IO) were introduced into the Japanese EMS system. The ubiquity of the IO has resulted in increased rates of successful access in a significantly shorter time [5]. IO placement is less likely to select against comorbid illness and al- lows a provider to quickly resume other critical tasks involved in car- diac arrest care. Because the current study was largely limited by the ability to obtain IV access for epinephrine administration, future studies should investigate the utility of IO line as rescue, or first line, access.

In addition to the concerns with matching, the overall inclusion criteria may make it challenging to apply these results in other situa- tions. 6204 patients were excluded because of missing defibrillation data and 3223 patients were missing intubation or epinephrine data. It should not be assumed that the missing data occurred at random. More concerning is the 25,541 patients that were excluded because they received epinephrine after ROSC, presumably because they re- quired additional blood-pressure support as part of their usual and ap- propriate post-arrest care. By precluding a large number of patients with ROSC, the investigators narrowed their patient cohort to include only those that have poorer outcomes. Despite studying the efficacy of interventions during cardiac arrest, the investigators removed a subset of patients based on interventions and outcomes after cardiac arrest. This further limits the applicability of this study to clinicians on-scene as the study data cannot be applied without knowing, a priori, which cardiac arrest patient will achieve ROSC and later require epinephrine. The authors acknowledge that the overall low incidence of ROSC limits the external validity of their study. What is not addressed is that this data has been statistically manipulated to no longer have internal validity ei- ther. A review of the previously published data by Kitamura et al. [4] on OHCA and EMS defibrillation, using the same national Japanese data reg- istry from January 1, 2005 to December 31, 2007, demonstrated a one month survival of 24% and CPC 1 or 2 of 14% [4]. Relative to Kitamura’s study, the rate of favorable outcomes in this month’s publication is re- duced by over 50%. It should be noted that this month’s article includes a broader range of dates but January 2005 to December 2007 encom- passes 33.5% of the total data and 43.7% of the patients that were propen- sity matched. It is possible that the differences in achieving ROSC between the two studies is secondary to the differences in inclusion criteria (specif-

ically, the use of epinephrine for post-arrest care).

0735-6757/(C) 2017

Correspondence / American Journal of Emergency Medicine 36 (2018) 498–523 499

We propose several variables that were likely contributory but not accounted for. While ALS in the study is defined as epinephrine admin- istration or intubation, until recently, neither aspect has been part of the Japanese EMS OHCA algorithm. According to the methods cited, epi- nephrine was not available to EMS providers until April 2006. Thus, ALS care can only be defined as intubation prior to April 2006. Addition- ally, tracheal intubations were not performed by EMS until July 2004. A recent study demonstrated the rate of First-pass success in OHCA by EMS is dependent on the provider’s level of experience [6]. The relative- ly new implementation of EMS intubation may have biased the Negative outcomes suggested in this paper. Moreover, a variety of airway devices were used in this study and the correlation between subglottic versus supraglottic devices was not discussed. Relatedly, the critical impor- tance to the success of endotracheal intubation is the presence of the en- dotracheal tube in the trachea. Now considered a gold-standard, the authors do not discuss the use of confirmatory analysis such as capnography or colorimetric EtCO₂ to ensure proper location [7]. Addi- tionally, minimizing interruptions is of vital importance during cardiac arrest. It is unclear to what degree compressions were compromised during attempts to place a more definitive airway. Lastly, another unre- ported variable is the use of vasopressin, amiodarone, lidocaine, atro- pine, or bicarbonate – all of which have been part of cardiac arrest care in recent years. Collectively, this raises the concern that the obser- vational data collected is much more heterogeneous than previously ap- preciated. It is possible that following current cardiac arrest guidelines with Early defibrillation, epinephrine administration, adequate uninter- rupted compressions, and successful, properly confirmed, first pass in- tubation results in improved OHCA outcomes.

The multiple papers published on epinephrine administration and intubation in OHCA have revealed mixed results and there is a need for additional research. Current ACLS guidelines do not provide specific recommendations on the timing of intubation. The proposed benefits include improved oxygenation and ventilation, the ability to provide Continuous chest compressions (improve coronary perfusion pressure), and the ability to assess the adequacy of chest compressions using EtCO₂. Perhaps there is a J-curve phenomenon with ideal timing for in- tubation. A recent observational study of in-hospital cardiac arrest (ICHA) demonstrated worse outcomes with intubation b 15 min into the arrest [8]. Prioritizing airway management in early cardiac arrest does not appear to be helpful. However, its usefulness in prolonged ar- rest cannot be ignored. Another component of airway management is the success rate of the procedure itself. A US-based study found a dose-dependent negative correlation with the number of intubation at- tempts and favorable outcomes [9]. A recent systematic review and meta-analysis showed non-physician out-of-hospital intubations have lower success ratesand higher rates of complications when compared to physician out-of-hospital intubation attempts [10]. Likely this reflects the limited training paramedics received and need for continual skill re- finement throughout their career. There has been a call for educators and researchers to develop a strategy that improves EMS procedural skills in hopes of improving patient outcomes. Given the lack of clear correlation (and reasonable arguments for both their benefits and harms), a randomized controlled study would better elucidate the caus- al relationship between airway management and long-term outcomes. The use of epinephrine in cardiac arrest has been central to the ACLS algorithm for decades; however, its efficacy has never been proven. The American Heart Association provides a Class IIb level recommendation for epinephrine which is considered “weak” and is the lowest Level of evidence for which any therapy would be recommended [11]. While initial animal models proposed a benefit, few human RCTs have been performed – only one of which was double blind placebo [12]. In the only RCT double blind placebo study of 1 mg epinephrine for OHCA, epi- nephrine increased the rate of ROSC but did not significantly improve survival to hospital discharge or rate of good neurological function [13]. While this study was highly selective for its inclusion criteria and underpowered to detect differences in survival and neurological

outcomes, it demonstrated that an unmet need continues to exist with regards to the utility of epinephrine in cardiac arrest. This data largely mirrored the conclusions of a similar study that included a non-blinded control [14].

The dosing of epinephrine has been partially investigated. In an RCT, “high-dose” epinephrine (7 mg) vs “standard-dose” (1 mg) has been shown to have no positive effect on any outcome for patients with OHCA or IHCA [15]. Additional observational studies have shown a dose-dependent deterioration in clinical outcomes for cumulative epi- nephrine dose in OHCA [16]. The same study group as this month’s sub- mission have previously reported that pre-hospital epinephrine administration was associated with improved ROSC, but decrease sur- vival and neurological outcomes [17]. The association with poorer neu- rologic outcomes is supported by multiple animal models correlating the pathophysiology with decreased cerebral cortical microcirculatory blood flow [18]. This challenges the benefit of epinephrine dosing and compels researchers to investigate the utility of “low-dose” vs “no- dose” epinephrine. A dose selection design with smaller and smaller epinephrine doses in randomized arms could assess whether any dose of epinephrine is effective by failing to find any evidence of dose re- sponse. This could be accomplished by blinded studies with smaller and smaller amounts of epinephrine in vials – as an example – in one arm all study epinephrine would have 1 mg per vial but in another each vial would have 0.1 mg and in another arm each vial would have 0.05 mg (with intermediate dose tiers potentially included). This could address the problem of sicker patients “requiring” larger doses of epinephrine and would perhaps be more feasible than a fully placebo controlled trial. Randomization to the very low dose arms could only occur after it was clear that the intermediate doses were not more beneficial than the low doses [19]. The timing of epinephrine has been called into question. There are conflicting observational studies, one showing that early epinephrine adminis- tration in OHCA had improved outcomes relative to late epinephrine (with a cutoff at 10 min) [20].

However, another study demonstrated the association of worse out- comes (ROSC, Survival and neurological outcomes) for patients with IHCA that received epinephrine less than 2 min into their cardiac arrest resuscitation [21]. The timing of OHCA epinephrine can be difficult to study as down-times are unreliable and EMS-Response times are unavoidable and introduce potential bias. Including only cases of witnessed cardiac arrest may improve the reliability of the study.

Finally, an OHCA presents EMS with an austere environment and transportation further exacerbates this crisis by restricting a provider to driving. Future studies should investigate the utility of the “stay- and-play” approach versus “load-and-go” in ALS trained and equipped teams. This strategy will also have to be balanced with ongoing ECPR studies and the critical time to cannulation.

In summary, the authors attempted to evaluate the efficacy of intu- bation and epinephrine in patients who received EMS defibrillation with out of hospital cardiac arrest. Unfortunately, as with all observa- tional studies, no causal relationship can be determined. Regardless of this limitation, there are other biases in this publication that make their application to clinical medicine challenging such as excluding ROSC patients that later require epinephrine. Admittedly, this is a diffi- cult patient population to study as cardiac arrest is a syndrome, not a disease. The heterogeneity of the population and the inability to acquire substantial information prior to necessary action makes proving the ef- ficacy of any intervention challenging. We commend the authors for in- vestigating Clinically meaningful outcomes such as 1 month survival and good neurological function at 1 month. In previous studies, ROSC is a frequently reported outcome which, in isolation, has no significance to patient-centered care. We would continue to encourage future re- searchers to investigate primary outcomes such as survival (at least one month) and good neurological status.

Future research should control for the patient baseline health char- acteristics, paramedic experience, and implement a single current

500 Correspondence / American Journal of Emergency Medicine 36 (2018) 498–523

resuscitation algorithm. Additional variables which may affect Cardiac arrest outcomes include the type of advanced airway used, the use of IO for difficult access, the utility of transport, and the use of EtCO₂ for ad- equate compressions in intubated patients.

Ryan E. Tsuchida, MD

Department of Emergency Medicine, University of Michigan, Ann Arbor, MI,

United States E-mail address: tsuchida@med.umich.edu.

William J. Meurer, MD, MS

Department of Emergency Medicine, University of Michigan, Ann Arbor, MI,

United States Department of Neurology, University of Michigan, Ann Arbor, MI,

United States Stroke Program, University of Michigan, Ann Arbor, MI, United States Michigan Center for Integrative Research on Critical Care, University of

Michigan, Ann Arbor, MI, United States Frankel Cardiovascular Center, University of Michigan, United States Corresponding author at: Department of Emergency Medicine, TC B1- 354 1500 E. Medical Center Drive, Ann Arbor, MI 48109, United States.

E-mail address: wmeurer@med.umich.edu.

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3. Ristagno G, Tang W, Huang L, Fymat A, Chang YT, Sun S, Castillo C, Weil MH. Epi- nephrine reduces cerebral perfusion during cardiopulmonary resuscitation. Crit Care Med 2009;37(4):1408-15.
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“Reply to letter, More questions than answers

– advanced life support interventions for out of hospital cardiac arrest”

To the Readers:

https://doi.org/10.1016/j.ajem.2017.11.064

References

30 October 2017

Thank you for your interest, thoughts and comments regarding our study investigating “Effects of advanced life support on patients who suffered cardiac arrest outside of hospital and were defibrillated” [1]. We appreciate the time you took to comment on our research and the important insights you have provided.

According to the Japanese Resuscitation guidelines for patients with out-of-hospital cardiac arrest (OHCA), the administration of advanced airway management and epinephrine are recommended after defibril-

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3. d’Agostino RB. Tutorial in biostatistics: propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17(19):2265-81.
4. Kitamura T, Iwami T, Kawamura T, Nagao K, Tanaka H, Hiraide A. Nationwide public- access defibrillation in Japan. N Engl J Med 2010;362(11):994-1004.
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6. Dyson K, Bray JE, Smith K, Bernard S, Straney L, Nair R, et al. Paramedic intubation experience is associated with successful tube placement but not cardiac arrest sur- vival. Ann Emerg Med 2017;70(3):382-390.e381.
7. Cook TM, Nolan JP. Use of capnography to confirm correct tracheal intubation during cardiac arrest. Anaesthesia 2011;66(12):1183-4.
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sequence intubation success and adverse events: a systemic review and meta anal- ysis. Ann Emerg Med 2017;70(4):449-59.

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lation to patients with OHCA whose initial rhythms are shockable. Al- though the efficacy of early defibrillation has been established [2], we know very little about the effects of advanced airway management and/or epinephrine on defibrillated patients with OHCA. In addition, the optimal response intervals for advanced airway management and epinephrine administration are also less clear than that of defibrillation [2]. We also do not know whether advanced airway management and epinephrine interact. Thus, using national data from the whole sample of OHCAs occurring between 2005 and 2013 in Japan, we conducted the study [1].

As the correspondence authors admit, any observational study is subject to potential confounding [3]. The publicly-available data is Utstein formatted, and has limited information. Although sophisticated statistical methods, such as time-dependent propensity matching, were used, we could not be free from the problems of confounding and lack of information in the study. As we noted in our paper, typical limitations are as follows. (1) Data on In-hospital CPR after hospital arrival were not included in the analysis. (2) Allocation to the ALS and control groups was not random. Although we performed a propensity analysis, we could only partially control and adjust for factors actually measured, and could not control for unknown confounding factors. (3) We did not have information about the process of advanced airway manage- ment. (4) In Japan, it is reported that advanced airway devices should be considered only when the patient cannot be adequately ventilated by a bag-valve-mask or a long transportation time is expected [4]. Thus, this practice may represent a substantial confounder and can be a limitation to the study. (5) We did not have information on the skill levels of individual EMS personnel or the integrity and validity of the na- tional registry data.

Almost all problems raised in the correspondence seem to be related to these limitations of our study. As is true for all epidemiological stud- ies, it is difficult to collect all necessary information and control these factors. Here again, we would like to emphasize that there are many limitations to our study, and the external validity of the findings might