Therapeutic and adverse effects of adrenaline on patients who suffer out-of-hospital cardiac arrest: a systematic review and meta-analysis

Worldwide, out-of-hospital cardiac arrest (OHCA) is still one of the main causes of death [1]. The key to successful cardiopulmonary resuscitation (CPR) after cardiac arrest (CA) first depends on the time of CPR initiation. Meanwhile, effective coronary perfusion and timely restoration of myocardial blood supply also play important roles in succeeding CPR. Epinephrine has been the first choice of medicine with stimulating effects on α and β receptors in treating CA since the 1960s [2]. During CPR, the activation of α-adrenergic receptors can increase aortic diastolic pressure and myocardial blood flow. Numerous studies indicated that epinephrine increased the rate of return of spontaneous circulation (ROSC) by the activation of its alpha receptors [3, 4].

However, epinephrine increases cardiac output, while the activation of its β-adrenergic leads to dysrhythmias and increases myocardial oxygen demand [5]. It has been reported that although epinephrine improves ROSC rates, it does not improve survival to hospital discharge or favorable neurologic outcomes [6, 7]. Some studies also suggested that epinephrine does not improve survival to hospital discharge. On the contrary, it even causes deterioration in neurological function. According to a randomized controlled study by Perkins et al. [8], a higher rate of survival to hospital discharge was observed in the epinephrine group compared with the placebo group, but among patients who survived at discharge, the incidence of brain injury in the adrenaline group nearly doubled compared with the placebo group, and other outcomes such as survived to hospital discharge with a favorable neurologic outcome, survival at 3 months, or neurologic outcomes at 3 months were no significant differences between the two groups. It can be noticed that epinephrine may be unprofitable or even harmful. Although epinephrine has been widely used to treat OHCA, its beneficial effect remains controversial [9‐11].

Recent meta-analysis results such as Kempton et al. indicated that the epinephrine group was better than the placebo group in ROSC rate and survival to hospital admission. Survival to hospital discharge and neurological status between the two groups were not significantly different. However, this study included only five randomized controlled studies [12]. Vargas et al. [13] included 15 randomized controlled trials (RCTs) in their meta-analysis. Standard dose of epinephrine was compared with placebo, high doses of epinephrine, and vasopressin. The results showed that CA patients' survival rates and outcomes improved when epinephrine was administered, but there was no subgroup analysis on different initial cardiac rhythms included. Based on a recent meta-analysis, epinephrine improved ROSC rates and survival rate of leave hospital in CA patients but worsened the neurological prognosis of OHCA patients [14]. The original literature included in this meta-analysis did not limit the population characteristics, but contained CA patients both in-hospital and out-of-hospital into the study; Prognostic factors, such as age, co-morbidity, etiology, and initial cardiac rhythms, were different in patients with in-hospital cardiac arrest (IHCA) and OHCA. Compared with OHCA patients, the time from CA starts to the point when CPR is performed is shorter, same as the duration of defibrillation, the time of administration of medicine in patients who suffered from CA in the hospital. It might affect the effect of epinephrine administration during resuscitation. Consequently, epinephrine's impact on the outcome of patients with OHCA needs to be evaluated again through systematic reviews and meta-analyses. The meta-analysis only included the results of RCTs and cohort studies of OHCA patients, and divided the initial cardiac rhythms of OHCA patients into shockable rhythms and non-shockable rhythms subgroups to sufficiently illustrate the effect of epinephrine.

We searched 4699 studies from PubMed, EMBASE, and Cochrane library first, and excluded 913 repetitive literatures. After reading the title and abstract, 3701 articles were removed based on the inclusion and exclusion criteria. 85 studies underwent full-text review. Then, we excluded 67 studies by reading the full text. Finally, 18 articles were included, involving 3 RCTs [8, 20, 21] and 15 cohort studies [3, 6, 16, 17, 22‐31]. The document screening process is illustrated in Fig. 1.

In Table 1, we summarized the basic characteristics of the included studies. Among the included studies, 15 were cohort studies and 3 were randomized controlled studies. There were 863,952 patients included in the study, of which 127,178 were treated with adrenaline and 736,774 were not. A total of 16 studies [3, 8, 16, 17, 20‐28, 30‐32] comprised patients with shockable or non-shockable rhythms, and only 2 studies [6, 29] had no records of the patient's initial cardiac rhythms. Among 3 randomized controlled studies [8, 20, 21], all of them reported ROSC and survival to discharge, 2 studies [8, 21] reported the neurologic outcomes at discharge, and the survival rates and neurologic outcomes at 3 months were reported in only one study [8]. In 15 cohort studies, all of them but one study [30] reported survival to discharge, 13 studies [3, 6, 16, 17, 22‐27, 29, 31, 32] reported ROSC, and 12 studies [3, 6, 16, 17, 22‐24, 26‐28, 30‐32] reported the favorable neurological status, and only 1 study [31] reported 1-year survival rate. In all studies, a standard dose of adrenaline administration was compared with no adrenaline administration or placebo.

Based on the latest literature, our systematic review and meta-analysis were used to appraise whether epinephrine is effective and safe during the resuscitation of OHCA patients. The results of RCTs and cohort studies indicated that epinephrine increased the rate of ROSC in OHCA patients. The underlying mechanism could be that epinephrine can mediate the contraction of small arteries to increase aortic diastolic pressure by activating α-adrenergic receptors, thereby increasing coronary artery blood flow, preferentially delivering blood to the heart and brain, and increasing the probability of ROSC [33, 34]. This finding is consistent with the meta-analyses by Loomba et al. [35] and Morales et al. [36] that epinephrine increased the rate of ROSC in patients with OHCA.

Although adrenaline is known to increase the ROSC rate in OHCA patients, whether it is beneficial to the survival rate at discharge and favorable neurological outcomes in OHCA patients remains debatable. In this article, the results of RCTs showed that whether adrenaline was used or not had no effect on the survival rate at discharge and good neurological status of OHCA patients, which was consistent with the meta-analysis results of Lin et al. [37] Therefore, why did not the survival rate at discharge and good neurological prognoses increase as the incidence of ROSC in patients receiving epinephrine treatment? The reasons are uncertain, it may be that although epinephrine can promote ROSC by increasing coronary blood flow and cerebral perfusion through its powerful α-adrenergic effects [38], β-adrenergic effects can also lead to arrhythmias and increased myocardial oxygen demand, and even recurrent cardiac arrest [5]. Additionally, platelets are activated by α-adrenergic stimulation, thereby promoting thrombosis [39] and impairing microvascular blood flow in the brain. Thus, cerebral ischemia becomes more severe during CPR and after ROSC [40]. The brain is extremely sensitive to cerebral ischemia and reperfusion injury and has a poor ability to regain functionality than hearts and other organs after circulation is restored [41]. The cohort studies showed that adrenaline not only reduced the survival rate at discharge but also worsened neurological outcomes. A study published by Ong et al. [9] that compared OHCA patients who were treated with adrenaline and those who were not found that the duration of CPR was an important confounding factor affecting the outcome of adrenaline on OHCA patients. For example, due to early ROSC, adrenaline treatment was not given to some patients, and these patients often had better neurological prognoses. However, in our meta-analysis, the majority of original studies included did not record the duration of CPR or have inaccurate records, so no relevant subgroups were set up to analyze the impact of the duration of CPR on adrenaline.

The current CPR guidelines recommend that 1 mg of adrenaline, a standard dose of it, is given every 3–5 min during CPR, but the total cumulative dose is not mentioned [42]. Fukuda et al. [24] showed that repeated administration of epinephrine is harmful. Although the optimal dose of epinephrine is still unclear, increasing the cumulative dose of epinephrine may worsen the survival rate and neurological prognoses of patients with OHCA [30, 43]. This is because repeated administration of epinephrine indicates that the time required for resuscitation will be longer and the adverse reaction of epinephrine after resuscitation may be stronger. As for the timing of epinephrine administration, Hayakawa et al. [26] showed that in OHCA patients, neurological prognoses in 30 days may improve when it was administered early after CA. The frequency of positive neurological outcomes increased by 1.1 times when the epinephrine was administered 1 min earlier. Hayashi et al. [27] found that only when using adrenaline within 10 min of CA can increase the survival rate of patients and improve neurological outcomes, but it is clinically very difficult to give adrenaline in this early period and only a few patients received intravenous epinephrine within 10 min after the occurrence of OHCA. These kinds of OHCA patients are needed to better determine the impact of early use of adrenaline.

RCTs and cohort studies failed to reach an agreement on survival to discharge and good neurological prognosis. In addition to the different nature of the two study methods, it is also possible that most of the original literature included did not record the administration time, dosage, CPR time, and other confounding factors, which is also the reason for the high heterogeneity of this meta-analysis. In addition, there are also some differences in the treatment of OHCA patients after hospital admission, and these differences are often not reported or difficult to control. Good neurological outcomes, together with health-related quality of life and survival, were ranked as the most important outcomes. If the chance of rehabilitation is very small or the risk of nervous system damage is high, which leads to a decrease in the quality of life after rehabilitation, some patients may not be willing to receive heavy treatment [44]. Therefore, the outcomes of OHCA patients may be greatly affected when they choose to leave the hospital after discontinuing treatment without medical treatment such as target temperature management [45] or percutaneous coronary intervention [46].

Only two studies reported long-term outcomes. Perkins et al. [8] pointed out that although epinephrine can increase the 3-month survival rate of OHCA patients, there is no improvement in neurological prognoses. Olasveengen et al. [31] reported that adrenaline reduced the 1-year survival rate of OHCA patients. However, the above results are not convincing enough. We still need more well-designed trials to appraise the long-term outcomes of OHCA patients after using adrenaline. In summary, we should reconsider the use of adrenaline. In future studies, confounding factors, such as the administration time, duration of CPR, hospitalization treatment methods, and dosage regimen, should be recorded in detail. Therefore, we can control these potential confounding factors, and the effectiveness and safety of adrenaline on OHCA patients can be fully confirmed.

Should OHCA patients with different initial rhythms be treated differently? Subgroup analysis showed that epinephrine decreased the survival rate at discharge and worsened the neurological prognoses of OHCA patients with shockable rhythms; however, no effects were observed on ROSC between patients who used epinephrine and those who did not. In contrast, among OHCA patients with non-shockable rhythms, epinephrine increased ROSC rates but worsened neurological prognoses, and has no effect on survival to hospital discharge. It was suggested by the latest CPR guideline that using epinephrine after initial defibrillation failure could be appropriate for CA patients with shockable rhythms [42]. Andersen et al.’s [47] study on CA patients with shockable rhythms indicated that the worst prognosis at discharge could be observed when epinephrine was administered within 2 min of the first defibrillation. There is a possibility that early use of adrenaline may interfere with some necessary steps, such as high-quality chest compressions, airway support, and defibrillation, but the characteristics and resuscitation strategies of in-hospital CA patients differ from those of OHCA patients, so the applicability of the observed results to the out-of-hospital setting remains uncertain. Therefore, administering epinephrine at the right time is particularly important. Further research is needed to determine the best resuscitation strategy for OHCA patients with different initial rhythms.

However, there are some weaknesses in our study. First, most studies included in this meta-analysis are observational studies, which makes it difficult to adjust confounding factors, such as administration time of adrenaline, CPR quality, etc. Second, CPR treatment should be individualized according to the etiology and progression of the patient. Consequently, it is difficult to implement a strictly standardized intervention protocol between the trial and control groups. And there are also differences in the dosage and duration of epinephrine treatment in different studies. Furthermore, the included studies may have potential confounding factors, such as CA time, bystander CPR, the response time of emergency medical service of various countries, differences in-hospital treatment, and rescue experience of medical staff, etc. The final results and the credibility of the research will be affected by the factors above, and they are also the cause of heterogeneity in outcome indicators.

In summary, this meta-analysis found that both RCTs and cohort studies showed that adrenaline increased ROSC in OHCA patients. However, they were unable to agree on a long-term prognosis. The cohort studies showed that adrenaline had an adverse effect on the long-term prognosis of OHCA patients (discharge survival rate and good neurological prognosis), but adrenaline had no adverse effect in the RCTs. In addition to the differences in research methods, there are also some potential confounding factors in the included studies. Therefore, more high-quality studies are needed to fully confirm the effect of adrenaline on the long-term results of OHCA.