Treatment Outcomes of Epinephrine for Traumatic Out-of-hospital Cardiac Arrest: A Systematic Review and Meta-analysis.

INTRODUCTION: Despite the standard guidelines stating that giving epinephrine for patients with cardiac arrest is recommended, the clinical benefits of epinephrine for patients with traumatic out-of-hospital cardiac arrest (OHCA) are still limited. This study aims to evaluate the benefits of epinephrine administration in traumatic OHCA patients.
METHODS: We searched four electronic databases up to June 30, 2020, without any language restriction in research sources. Studies comparing epinephrine administration for traumatic OHCA patients were included. Two independent authors performed the selection of relevant studies, data extraction, and assessment of the risk of bias. The primary outcome was inhospital survival rate. Secondary outcomes included prehospital return of spontaneous circulation (ROSC), short-term survival, and favorable neurological outcome. We calculated the odds ratios (ORs) of those outcomes using the Mantel-Haenszel model and assessed the heterogeneity using the I2 statistic.
RESULTS: Four studies were included. The risk of bias of the included studies was low, except for one study in which the risk of bias was fair. All included studies reported the inhospital survival rate. Epinephrine administration during traumatic OHCA might not demonstrate a benefit for inhospital survival (OR: 0.61, 95% confidence interval [CI]: 0.11-3.37). Epinephrine showed no significant improvement in prehospital ROSC (OR: 4.67, 95% CI: 0.66-32.81). In addition, epinephrine might not increase the chance of short-term survival (OR: 1.41, 95% CI: 0.53-3.79).
CONCLUSION: The use of epinephrine for traumatic OHCA may not improve either inhospital survival or prehospital ROSC and short-term survival. Epinephrine administration as indicated in standard advanced life support algorithms might not be routinely used in traumatic OHCA. Copyright:

INTRODUCTION

Trauma remains a leading cause of death and disability worldwide. According to the World Health Organization status report on road safety in 2018, over 1.35 million people die each year due to road traffic injury (RTI).[1] RTI is also the leading killer of children and young adults (5–29 years of age).[1] Traumatic cardiac arrest (TCA) is known to have the worse outcome.[2] Still, the overall survival from TCA (5.6%) is equivalent to that of non-TCA events.[234] The causes of TCA differed from non-TCAs; therefore, a different approach to managing the situation is needed.[567] The most common causes of TCA included severe traumatic brain injury and hypovolemia from hemorrhage.[34] Most deaths from TCA occurred in the first 5 min following the traumatic event and most of these deaths cannot be prevented.[8] Priorities in TCA mainly focused on (1) hemorrhagic control, (2) restoration of circulatory blood volume, (3) airway management, and (4) relieving of tension pneumothoraxes, over conventional cardiopulmonary resuscitation (CPR).[2]

Currently, according to the latest CPR guidelines,[9] epinephrine is recommended for use in adults with cardiac arrest. In spite of the recommendation, the therapeutic effects of epinephrine on TCA are still controversial.[2] A large randomized-controlled trial (RCT) demonstrated that the use of epinephrine resulted in a significantly higher rate of 30-day survival in adults with out-of-hospital cardiac arrest (OHCA). However, in this study, the percentage of TCA patients was only 1.5%.[10] Epinephrine, also known as adrenaline, has direct actions on adrenergic receptors which results in an increased cardiac force of contraction, increased cardiac output, and enhanced peripheral vasoconstriction.[11] Nevertheless, cardiac arrest from TCA patients due to hypovolemia did not occur immediately after traumatic events. TCA patients will experience maximal catecholamine release and vasoconstriction for a short period after the onset of cardiac arrest.[2] Thus, epinephrine administration may worsen tissue perfusion.[2] However, in 2015, a study conducted by Chiang et al. demonstrated that epinephrine administration increased short-term survival, especially for those with a longer prehospital time.[12] Together with the study conducted by Aoki et al., in 2019, prehospital epinephrine administration was associated with prehospital return of spontaneous circulation (ROSC) but not associated with 1-month survival.[13] As a result of these issues, the treatment outcomes for the use of epinephrine in traumatic OHCA patients are still limited. Hence, we performed an up-to-date systematic review and meta-analysis to evaluate the benefits of epinephrine administration in traumatic OHCA patients.

METHODS

We prepared this manuscript based on the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines for systematic reviews.[14] Our review was prospectively registered with PROSPERO international prospective register of systematic reviews in health and social care (id: CRD42020199195).

Search strategy and criteria

Two authors (W. W./T. T.) independently searched on multiple standard databases, including PubMed, Scopus, Web of Science, and Cochrane CENTRAL. Each database was searched from its beginning to June 30, 2020, without language restriction. We used Medical Subject Headings terms included the combination of search terms with various spellings and endings: “trauma,” “traumatic,” “out-of-hospital,” “adrenaline,” “epinephrine,” “cardiac arrest,” “TCA,” “CPR,” “heart arrest,” “cardiopulmonary arrest,” and “sudden cardiac death.” We also searched all of the relevant meta-analyses and their references to identify additional studies. Moreover, we searched and identified any unpublished trial registered on the website “clinicaltrial.gov.”

Included studies were selected based on the following criteria: (a) a study involved a traumatic OHCA; (b) at least one arm of participants received epinephrine during OHCA; and (c) reported at least one of the following outcomes: prehospital ROSC or ROSC on arrival at the hospital, survival to hospital admission, 7- or 30-day inhospital survival, survival to hospital discharge, and neurological outcome at discharge. We limited included studies to original articles on humans. No restriction was made concerning study design. We excluded the studies lacking either a control group (i.e., case report, case series) or a review article. Three authors (T. T./C. K./S. S.) independently screened the search results to identify potentially eligible studies, and unrelated articles were excluded. Full manuscripts of the potential studies were retrieved with eligibility independently assessed by two reviewers against prespecified criteria and evaluated for inclusion [Figure 1]. At each step of selection, any disagreements were discussed and resolved by the third-party consensus.

Figure 1

Preferred reporting items for systematic reviews and meta-analyses flowchart of the studies included in the study

Outcomes of interest

The primary outcome was inhospital survival rate which was defined as 7-day survival rate, 30-day survival rate, or survival to hospital discharge. We chose these as a primary outcome since they are the actual patient-oriented outcomes that can provide the most important reasons why we give this medication to the patients. The secondary outcomes included the prehospital ROSC, short-term survival, and neurological outcome at discharge. Short-term survival was defined as the rate of ROSC which sustained ≥2 h at the emergency department (ED). Favorable neurological outcome was defined by the cerebral performance category score of 1–2 or a modified Rankin Score of 0–3.

Data extraction and assessment of the trial risk of bias

Two authors (W. W./T. T.) independently extracted data from the original articles using a standard data collection form. The data extracted included (i) first author, (ii) publication year, (iii) type of study, (iv) study location and setting, (v) number and age of participants, (vi) initial cardiac rhythms, (vii) witnessed and bystander cardiac arrest, (viii) intervention and comparator, and (ix) outcomes of interest. In cases of missing or incomplete data in an original publication or for required clarification, we attempted to contact by e-mail the corresponding author. Two assessors (W. W./T. T.) independently evaluated the risk of bias of each trial using the standardized Good Research for Comparative Effectiveness (GRACE) checklist for observational studies and the modified version of the Cochrane collaboration's tool for assessing the trial risk of bias for RCTs.[1516] Any discrepancies that arose were resolved by discussion or referred to a third reviewer for a final decision.

Data synthesis and statistical analysis

Obtained relevant data were filled in a 2 × 2 contingency table. We used odds ratios (ORs) as a summary measure for the analysis of dichotomous outcomes. We calculated the pooled effect estimates of each outcome of interest using the Mantel–Haenszel fixed-effects meta-analysis. We assessed the statistical heterogeneity among included studies using the percentage of total variability across the studies due to heterogeneity (I statistics). The values of less than 40%, 40%–60%, and more than 60% were categorized as low, moderate, and high heterogeneity, respectively. A fixed-effect model was used to pool estimates. If evidence of high heterogeneity (I60%) was observed, a random-effects model was used, instead. Publication bias which might arise from small-study effects was evaluated through visual examination of funnel plots and Egger's test. We used the Review Manager Version 5.3 (Nordic Cochrane Center, Cochrane Collaboration, 2014, Copenhagen, Denmark) to perform the quantitative statistical analysis.[17] All tests were two tailed and any P < 0.05 was considered statistically significant.

RESULTS

From the PRISMA flow diagram [Figure 1], we identified 941 potentially relevant records through a systematic search. After removing duplicates, nine full-text articles were retrieved and examined for eligibility. A total of 4 articles, published between 2015 and 2019, were included for data extraction and finally included in the meta-analysis. All were observational cohort and multicenter studies. All of the included studies were conducted in Asia: two from Japan, one from Taiwan, and the other from Qatar. The meta-analysis involved a total of 7158 traumatic OHCAs with 1909 exposed to epinephrine and 5249 nonexposed individuals. Participants' median age ranged from 33 to 61 years old. About one-third of the cardiac arrests were witnessed, but the bystander CPR varied among the trials. All studies reported the predefined primary outcome: inhospital survival. Two studies reported prehospital ROSC. Three studies reported short-term survival, and only one study reported neurological outcome at discharge. Exposure to epinephrine was defined as the administration of intravenous epinephrine in the prehospital setting, whether that be a scene or during ambulance transport in all included studies, except for one study which defined the exposure as epinephrine administration during cardiac arrest at the EDs. Table 1 summarizes the characteristics and details of each included study. Since all of the included trials were observational studies, we assessed the trial risk of bias using the GRACE checklist. Three studies were classified as “sufficient quality” or “low risk of bias” studies, whereas one study was classified as “fair risk of bias” study [Table 2].

Table 1

Characteristics of included trials

Study	Country (study period)	Type of study	Sample size	Age (years), median (IQR)	Initial cardiac rhythms (%)		Witnessed arrest (%)	Bystander CPR (%)	Intervention	Comparator	Outcomes
					Shockable	Nonshockable
Aoki et al., (2019)[13]	Japan (2012-2015)	Cohort, MC	5204	61 (40-75)	2.2	97.8	30.4	19.0	1 mg of epinephrine (prehospital)	No epinephrine	1 month survival Prehospital ROSC
Chiang et al., (2015)[12]	Taiwan (2010-2013)	Cohort, MC	514	48 (30-64)	4.7	95.3	37.7	21.4	1 mg of epinephrine (prehospital)	No epinephrine	Prehospital ROSC Sustained ROSC Survival to discharge Neurologic status on discharge
Irfan et al., (2017)[3]	Qatar (2010-2015)	Cohort, MC	410	33 (27-46)	3.0	97.0	11.0	5.0	1 mg of epinephrine (prehospital)	No epinephrine	ROSC at the ED Survival to discharge
Yamamoto et al., (2019)[18]	Japan (2012-2013)	Cohort, MC	1030	54	N/A	N/A	57.5	15.3	1 mg of epinephrine (at the hospital)	No epinephrine	7 day survival ROSC at the ED

CPR: Cardiopulmonary resuscitation, ED: Emergency department, IQR: Interquartile range, MC: Multicenter, N/A: Not applicable, ROSC: Return of spontaneous circulation

Table 2

Risk of bias assessment by good research for comparative effectiveness checklist

Article	Domains
	D1	D2	D3	D4	D5	D6	M1	M2	M3	M4	M5
Aoki et al., (2019)	+	+	+	+	+	+	−	+	+	+	−
Chiang et al., (2015)	+	+	+	+	+	+	−	+	−	+	−
Irfan et al., (2017)	+	+	+	+	+	−	−	−	−	+	−
Yamamoto et al., (2019)	+	+	+	+	+	+	-	+	+	+	−

The good research for comparative effectiveness checklist domains were as follow: (D1) adequate treatment, (D2) adequate outcomes, (D3) objective outcomes, (D4) valid outcomes, (D5) similar outcomes, (D6) covariates recorded, (M1) new initiators, (M2) concurrent comparators, (M3) covariates accounted for, (M4) immortal time bias, and (M5) sensitivity analysis. The symbol positve (+) means sufficient and the symbol negative (-) means insufficient

Inhospital survival

Four studies (n = 7,158) reported inhospital survival.[3121318] Based on the heterogeneous data (I91%), patients who received epinephrine during traumatic OHCA might not demonstrate a benefit for inhospital survival [OR: 0.61, 95% confidence interval [CI]: 0.11–3.37, Figure 2]. Moreover, due to a limited number of included trials, the Egger's test could not be analyzed.

Figure 2

Forest plot comparing inhospital survival between exposure to epinephrine and control groups

Prehospital return of spontaneous circulation

Two studies (n = 5,718) reported prehospital ROSC.[1213] The heterogeneous data (I93%) showed no significant improvement of prehospital ROSC [OR: 4.67, 95% CI: 0.66–32.81, Figure 3].

Figure 3

Forest plot comparing prehospital return of spontaneous circulation between exposure to epinephrine and control groups

Short-term survival

Three studies (n = 1,954) reported short-term survivals.[31218] Epinephrine might not increase the chance of short-term survival based on the combined data of the included studies [OR: 1.41, 95% CI: 0.53–3.79, I90%, Figure 4].

Figure 4

Forest plot comparing short-term survival between exposure to epinephrine and control groups

DISCUSSION

This review summarizes the latest evidence on the use of epinephrine in traumatic OHCA after the recently updated guideline for cardiac arrest.[19] Unfortunately, we did not find any RCTs in our searches. This meta-analysis demonstrates that epinephrine administration might not show benefits, including inhospital survival, prehospital ROSC, and short-term survival, in traumatic OHCA. Although epinephrine showed a positive trend for prehospital ROSC, the result was not statistically significant. The overall trial risk of bias of included studies ranged from low to fair, mainly due to no enough information about new initiators of treatment and sensitivity analysis.

Epinephrine has been recognized as the mainstay for the treatment of cardiac arrest for decades[19] since it has potentially positive effects in CPR via the constrictions of arteries and arterioles mediated by α-adrenergic receptors.[10] Vasoconstriction increases aortic diastolic pressure, resulted in increasing coronary perfusion pressure (CPP) and myocardial blood flow, which is indicated as the potential factor of ROSC.[20] However, nonspecific vasoconstriction may worsen postresuscitation outcomes. A preclinical study demonstrated that epinephrine plus endothelin-1, an intense vasoconstrictor, improved CPP during CPR but had negative results in the postresuscitation period.[21] This study demonstrated that TCA patients who received epinephrine might not have a significantly higher chance of favorable outcomes, especially inhospital survival. These findings are correlated with a narrative review by Smith et al., finding that there is no sufficient evidence to support the use of intravenous epinephrine in patients with TCA.[2] Most TCA patients died from hypovolemia resulted from acute blood loss and head injury. Such a state of shock does not generally occur suddenly after cardiac arrest. Acute blood loss causes catecholamine surge leading to an increased heart rate, increased cardiac contraction, and peripheral vasoconstriction. As the patient's volume state continues to drop, the blood flow is diverted from an internal organ to the brain and heart. Lactic acid continuously accumulates within cells due to organ ischemia, eventually, leading to death. Previous studies have stated that the patient might experience maximal catecholamine surge and vasoconstriction during the period of deterioration until the cardiac output is lost.[2] Injection of vasopressors during this time may worsen tissue perfusion except for patients with neurologic shock where their sympathetic vascular tone was lost.[2223]

However, this review highlights some important points. First, Aoki et al. revealed a positive association between prehospital administration of epinephrine and prehospital ROSC in TCA patients caused by traffic collisions, whereas Chiang et al. did not find that benefit. The major difference between these two studies is the total prehospital time. The median prehospital time of patients receiving epinephrine in Aoki et al.'s study was 38 min (interquartile range [IQR]: 30–48), while the median prehospital time of the other study was 23 min (IQR 20–29). There are two phases of pathophysiological response to acute blood loss.[24] The initial phase is defined by the activation of the sympathetic system resulting in vasoconstrictions of arteries and arterioles to normalize blood pressure. In the late phase, as hemorrhaging continues and a massive amount of preload declines, the systemic sympathetic tone becomes inadequate, therefore, leading to a decrease in vascular resistance and bradycardia which could abruptly advance to cardiac arrest. This means that a longer prehospital time provides a better chance that prehospital epinephrine administration is beneficial. Second, bystander CPR varied among the included trials. Irfan et al. found that prehospital epinephrine administration lowered survival in TCA patients.[3] Notably, bystander CPR in that study was only 5% which markedly lower than the other studies (15.3–21.4%). This emphasizes the importance of public bystander CPR which has already been mentioned in the previous literatures.[2526] Furthermore, of all included studies, only a study by Yamamoto et al. assessed the epinephrine used in inhospital resuscitation.[18] The results for prehospital resuscitation may bias the generalizability and must be interpreted within the context of each study design. For this reason, we additionally performed analyses by excluding this study and we found that the results have not differed from the initial analyses [Supplementary data].

Limitations

This review has some limitations. To minimize the risk of bias for assessing the outcomes of interventions, RCTs are the most appropriate study design. Unfortunately, we have found only observational studies in our search. Furthermore, all of the meta-analyses in this study were highly heterogeneous which might arise from the differences of concomitant drugs and other interventions (total IV fluid administered, the use of blood components, airway management techniques, etc.,). Therefore, the results might be inconcludable. Besides, according to the included studies of this review, heterogeneity can never be completely prevented due to variation between clinical studies. There are differences between the included studies that might contribute to inevitably high heterogeneity including administration of epinephrine, definitions of the outcome, bystander CPR, and patient characteristics. Finally, the included trials were conducted in different places and applied different protocols of intervention. This led to a variance in prehospital treatments that might be occurring for ROSC as well as inhospital treatments for inhospital survivals. Basis of trauma care includes airway management, c-spine protection, breathing and ventilation, hemodynamic control, and neurological assessment. We believe that the basic trauma care and procedures for each country must be consistent with the standard guideline (advanced trauma life support), but the details might be different due to the national committee's consensus for each country. Several factors may give rise to differences in treatment outcome including available drugs, competency of the first aider, and time on the scene of the accident. However, we and the authors of the included studies used proper strategies to eliminate possible confounding factors. Yet, to confirm the true effects of intervention, an RCT is warranted.

CONCLUSIONS

The use of epinephrine for traumatic OHCA might not demonstrate the benefit to improve either inhospital survival or prehospital ROSC and short-term survival. The mainstay for the management of patients in traumatic OHCA is to correct all reversible causes such as hypoxia, tension pneumothorax, cardiac tamponade, and hypovolemia as appropriate.

Research quality and ethics statement

This systematic review was registered with PROSPERO international prospective register of systematic reviews in health and social care (ID: CRD42020199195). The authors followed applicable EQUATOR Network (http://www.equator-network.org/) guidelines during the conduct of this research project.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.