Prove it: Giving epinephrine early during cardiac arrest improves neurological outcome
Mechanism that inhibits long-term favorable neurologic outcome after epinephrine despite initial hemodynamic improvement remains unexplained
After a short response interval, Engine and Medic 44 arrive at an office building in the business district. Inside a first-floor office, the rescuers find bystanders performing chest compressions on a male, aged 57. After confirming the absence of a palpable pulse, two firefighters take over CPR while the medics attach the monitor and begin preparing the advanced life support equipment.
The ECG reveals ventricular fibrillation. Medic Chavez immediately delivers a 150-joule countershock; the firefighters switch positions and resume CPR.
Medic Davis quickly inserts a supraglottic airway and confirms placement and effective ventilation with waveform capnography. Medic Chavez is having difficulty establishing IV access.
At the two-minute mark, Medic Davis confirms VF and delivers a second countershock. During the ensuing two-minute period of CPR, both medics continue to attempt IV access but are unsuccessful. The patient remains in VF and, at the next two-minute mark, receives a third countershock, after which the firefighters switch positions and resume CPR.
Medic Chavez inserts an intraosseous catheter in the patient's left tibia, verifies patency and secures the line. After being on scene for approximately 11 minutes, Medic Chavez administers the first one-milligram dose of epinephrine.
Medic Davis delivers a fourth countershock, and the firefighters resume CPR. The crew spends the next two-minute period placing the patient onto a backboard and cot. After moving the patient to the ambulance, Medic Davis notes that the patient is asystolic. On the way to the hospital, the patient receives one-milligram doses of epinephrine every three minutes, and the patient's ECG rhythm does not change.
The emergency department (ED) team continues resuscitation attempts for 10 additional minutes, but the patient fails to respond.
Later, in the station, both medics wonder if the patient could have survived if they could have administered IV epinephrine a little bit sooner.
Researchers in Japan hypothesized that prehospital epinephrine administration within the first 10 minutes after arrival on scene would result in improved neurological outcomes for patients who suffer but survive cardiac arrest (Hayashi et al., 2012).
Researchers identified all patients over the age of 18 in a centralized registry of out-of-hospital cardiac arrest data. Each patient experienced a bystander-witnessed cardiac arrest of presumed cardiac etiology within a two-year period ending in 2009 and received a resuscitation attempt by EMS personnel. The study included patients whom EMS personnel found in both shockable and non-shockable rhythms.
Ambulance staffing in Osaka Prefecture consists of three EMS providers – one of whom is known as the emergency life-saving technician (ELST), trained in ALS procedures.
Upon receiving authorization from online medical control, ELSTs may administer a one-milligram bolus of epinephrine every four minutes, to a maximum of three milligrams, to victims of cardiac arrest who present in a shockable rhythm or develop a non-shockable rhythm in the presence of EMS. However, local protocols do not permit administration of vasopressin, atropine or lidocaine.
The primary outcome measurement for this study was the patient's neurological status at one month after the cardiac arrest. The physician in charge of the patient's care at that point determined the status using the Cerebral Performance Category (CPC) scale, which uses a range of values from one to five (Jennett & Bond, 1975).
A score of one means the patient is conscious, alert and able to work. There may be some minor psychological or neurological deficits but nothing so severe that it interferes with daily activities of normal life.
A CPC score of two indicates that the patient is conscious and independently capable of daily activities such as dressing and self-feeding but can only work part-time. Patients with this score may suffer from seizures, hemiplegia or permanent memory or mental changes.
On the other end of the scale, a score of four indicates a vegetative state, and a score of five is consistent with brain death (Cummins et al., 1991). For the purpose of this investigation, the researchers defined "neurologically intact" as any survivor with a CPC score of one or two.
During the study period, epinephrine-equipped ELSTs attempted resuscitation from cardiac arrest for 9,204 patients over the age of 18 (Figure 1). Of those, bystanders witnessed only 3,295 of the cases. The researchers excluded 134 cases because the first rhythm was not recorded or the patient regained spontaneous circulation with the first countershock, leaving 3,161 patients eligible for the study. Of those, 1,013 patients received epinephrine, and 2,148 patients did not.
The researchers categorized the patients who received epinephrine into one of three groups:
1. Those who received the drug within the first 10 minutes after EMS arrival
2. Those who received the drug between 11 and 20 minutes after EMS arrival
3. Those who received the drug more than 21 minutes after EMS arrival
Figure 1: Sample selection flowchart of patients who suffered out-of-hospital cardiac arrest and received a resuscitation attempt by epinephrine equipped Emergency Life-saving Technicians (ELSTs)
In a comparison of patients who received epinephrine with those who did not, the two groups were not significantly different in whether bystanders initiated CPR, mean interval from call to EMS arrival or mean interval from call to first shock by EMS.
The patients who received epinephrine were younger (72.1 years vs. 73.9 years, p = .002) and more likely to be male (65.2 percent vs. 57.9 percent, p < .001), have the cardiac arrest in a public place (15.4 percent vs. 11.8 percent, p = .005), have a cardiac etiology of the arrest (72.8 percent vs. 64.7 percent, p < .001), have VF as the presenting arrhythmia (20.2 percent vs. 14.0 percent, p < .001), receive endotracheal intubation in the field (60.1 percent vs. 39.8 percent, p < .001) and have longer call-to-hospital arrival intervals (33.9 minutes vs. 28.6 minutes, p < .001). The mean time to first epinephrine administration was 21.3 minutes.
Figure 2 shows the results for the outcome variable. There was no statistical difference in one-month survival between patients who received epinephrine and those who did not (13.5 percent vs. 12.0 percent, respectively, p = .245). A p value of .245 means that there is about a 25 percent probability that the 1.5 percent absolute difference between the two groups was caused by chance. Normally in research, the test for statistical significance is a p value of .05 or less (5 percent probability).
For patients who survived for at least one month after the cardiac arrest, those who received epinephrine were less likely to be neurologically intact (4.1% vs. 6.1% respectively, p = .028). The low p value in this case means there is less than a 3 percent probability that the difference between the two groups was caused by random chance.
Figure 2: Outcome metrics for overall sample
This same relationship between poor neurological outcome at one month and epinephrine administration held true regardless of the presenting arrhythmia (Figure 3). Patients who presented in VF, survived for at least one month after the cardiac arrest, and received epinephrine were less likely to be neurologically intact compared to those who did not receive epinephrine (14.1 percent vs. 25.2 percent respectively, p = .006).
Similarly, patients who presented in a non-shockable rhythm (PEA or asystole) and received epinephrine were less likely to be neurologically intact compared to those who did not receive epinephrine (3.0 percent vs. 1.5 percent respectively, p = .027).
Figure 3: Relationship between one-month neurologically intact survival and epinephrine administration based on the presenting arrhythmia
What the authors were most interested in, however, was whether early administration of epinephrine improved the outcome. Recall that 1,013 patients received epinephrine (Figure 1). Of those, 205 patients presented in VF.
Table 1 describes the outcomes for three categories of patients who presented in VF and received epinephrine as well as one group of patients (n = 301) who did not receive epinephrine.
Neurologically intact one-month survival for patients who did not receive epinephrine was 24.9 percent. Nine patients received the first epinephrine dose within 10 minutes after EMS arrival and six (66.7 percent) were neurologically intact one month after the cardiac arrest.
For the 103 patients who received epinephrine between 11 and 20 minutes after the arrival of EMS, only 18 (17.5 percent) were neurologically intact one month after the cardiac arrest.
Of the 93 patients who waited 21 minutes or longer for their first epinephrine dose, only 9 (6.5 percent) remained neurologically intact one-month after the cardiac arrest.
The last column in Table 1 provides a measure of the effect of the intervention known as odds ratio (OR) reporting. OR represents the number of times an event occurred divided by the number of times it did not occur (Riegelman, 2005). An OR greater than one suggests an event is more likely to happen, while a ratio less than one suggests the event is less likely to happen.
An adjusted OR means that the researchers performed the mathematical calculation after holding constant the values of all other measured variables known to impact survival following cardiac arrest.
One way to think of this concept, using the data on the first row, is that patients are about 6.3 times more likely to achieve neurologically intact one-month survival if paramedics administer epinephrine within 10 minutes of arrival on scene.
The number underneath the 6.34 is the 95-percent confidence interval for that measurement. This means that if you repeated the experiment using a similar sample of patients and similarly trained EMS personnel, you could be 95-percent confident that the new OR for that outcome would lie between 1.49 (1.5 times greater) and 27.02 (27 times greater).
Patients Presenting in Ventricular Fibrillation
Neurologically Intact 1-month Survival (n)
Adjusted Odds Ratio
No epinephrine administered
Epinephrine administered ≤ 10 minutes
(1.49 – 27.02)
Epinephrine administered between 11 and 20 minutes
(0.36 – 1.20)
Epinephrine administered ≥ 21 minutes
(0.08 – 0.47)
From this data, we can conclude that epinephrine administration for most patients decreases neurologically intact one-month survival. However, for a very small subset of patients who receive epinephrine within 10 minutes of EMS arrival, epinephrine administration may actually improve neurologically intact one-month survival.
Early in the history of modern resuscitation, physicians touted epinephrine as the best resuscitation drug to stimulate myocardial contractions (Phillips & Burch, 1964). In 1941, Claude Beck described the use of intracardiac epinephrine injections during periods of cardiac arrest to improve heart muscle tone, reduce the degree of dilatation that often accompanies VF and stimulate contraction of the myocardium.
Later, researchers suggested that any survival benefit comes primarily from epinephrine's ability to promote peripheral vasoconstriction (Pearson & Redding, 1963; Pearson & Redding, 1965), which increases coronary perfusion pressure (Paradis & Koscove, 1990).
Indeed, when rescue crews cannot generate coronary perfusion pressures greater than 15 mm Hg, return of spontaneous circulation (ROSC) is virtually impossible (Paradis et al., 1990).
Despite the theoretical benefits offered by epinephrine administration, there is very little evidence that the medication provides long-term survival advantages for patients who suffer out-of-hospital cardiac arrest. In a retrospective evaluation of more than 400,000 patients who suffered an out-of-hospital cardiac arrest in Japan, prehospital administration of epinephrine doubled the adjusted odds of achieving ROSC but slightly decreased the odds of one-month survival (Hagihara, Hasegawa, Abe, Nagata, Wakata, & Miyazaki, 2012).
Researchers in Singapore were unable to demonstrate improved survival rates after adding epinephrine to the list of medications administered to victims of cardiac arrest (Ong et al., 2007).
A five-year observational study in Sweden found a statistically significant association between epinephrine administrations and decreased one-month survival following out-of-hospital cardiac arrest (Holmberg, Holmberg, & Herlitz, 2002).
Investigators in Vienna demonstrated that the odds of favorable neurological outcome decrease with increasing cumulative epinephrine doses in patients presenting with asystole or PEA in the out-of-hospital environment (Arrich, Sterz, Herkner, Testori, & Behringer, 2012).
After adjusting for confounders, a post-hoc analysis of resuscitation data revealed a 48 percent decrease in survival to hospital discharge when paramedics administered epinephrine to patients who suffered an out-of-hospital cardiac arrest (Olasveengen, Wik, Sunde, & Steen, 2012).
A double-blind, placebo-controlled investigation demonstrated that patients who received epinephrine after suffering out-of-hospital cardiac arrest were three times more likely to achieve ROSC, but they were no more likely to survive to hospital discharge (Jacobs, Finn, Jelinek, Oxer, & Thompson, 2011). The results of this study are consistent with previous research.
Experts based the original recommendation of IV injections of one-milligram epinephrine on responses observed following similar intracardiac doses administered in the operating room (Beck & Rand, 1949; Bodon & Rath, 1923). During the 1980's, epinephrine dose-response curves suggested optimal results might require higher epinephrine doses (Brown, Taylor, Werman, Luu, Spittler, & Hamlin, 1988; Brown, Werman, Davis, Hamlin, Hobson, & Ashton, 1986; Kosnik, Jackson, Keats, Tworek, & Freeman, 1985).
Subsequent trials demonstrated that although patients receiving high-dose epinephrine were more likely to achieve ROSC and survive to hospital admission when compared to standard-dose epinephrine, they were no more likely to survive to hospital discharge (Gueugniaud et al., (1998).
Additionally, using CPC scores, researchers could not demonstrate improved neurological function in survivors who received high-dose epinephrine compared to a standard dose (Callaham, Madsen, Barton, Saunders, & Pointer, 1992).
However, most of these investigations did not consider the administration interval as a possible confounder to survival measurements. Although the sample was small, results from this study suggest that patients presenting in VF who receive epinephrine within 10 minutes of EMS arrival are six times more likely to achieve neurologically intact one-month survival.
A recent observational study on vasopressor administration in out-of-hospital cardiac arrest found the adjusted odds of survival doubled if paramedics administer epinephrine within the first 10 minutes after the 911 call center receives the emergency call (Cantrell, Hubble, & Richards, 2012).
The mechanism that inhibits long-term favorable neurologic outcome despite initial hemodynamic improvement remained unexplained. Animal and human studies suggest epinephrine administration increases both myocardial oxygen consumption rates and post-ROSC myocardial dysfunction (Ditchey & Lindenfeld, 1988; Tang, Weil, Sun, Noc, Yang, & Gazmuri, 1995; Tovar & Jones, 1997). One animal study suggests that cardiac arrest duration is a significant predictor of epinephrine's efficacy, producing hemodynamic benefits if administered soon after the onset of pulselessness but depressing myocardial function if administered later (Angelos et al., 2008).
The results of this study add to the body of knowledge concerning the administration of epinephrine in the prehospital environment.
First, this was a retrospective evaluation of patient charts, meaning that the EMS personnel provided care long before researchers envisioned the study. Looking at data that already exists prohibits researchers from controlling variables that might alter the outcome. Retrospective data is useful for illuminating potential problems and providing guidance for designing future investigations, but clinicians cannot use the data to establish cause and effect.
One uncontrolled variable in almost all cardiac arrest studies, both in- and out-of-hospital, is CPR quality. Improving chest compression depth to meet American Heart Association recommendations increases defibrillation success (Edelson et al., 2006) and results in higher rates of short-term survival (Kramer-Johansen et al., 2006). The Resuscitation Outcomes Consortium recently found a strong association between increased compression depth and survival outcomes (Stiell et al., 2012).
At least one animal study suggests that epinephrine administered during field-quality CPR produces no hemodynamic benefit but administration during high-quality CPR can significantly improve coronary perfusion pressure and cortical cerebral blood flow (Pytte et al., 2006).
This study also did not address any post-cardiac arrest therapies known to improve both survival and neurological function, such as oxygenation and ventilation support, hemodynamic optimization, revascularization strategies and therapeutic hypothermia (Neumar et al., 2008).
Finally, recall that the researchers measured the patient's neurological status using the CPC scale, which uses a range of values from one to five (Jennett & Bond, 1975). Lower scores indicate better neurological function, but survivors with a CPC score of 2 require much more intensive long-term care than survivors with a CPC score of 1. Categorizing the neurological function of both of the groups as good may introduce a bias that would not be present if statisticians kept the two groups separate.
The American Heart Association (Neumar et al., 2010) acknowledges the lack of evidence to support or refute the administration of any sequence of medications to human cardiac arrest victims with the intent of increasing survival to hospital discharge. Almost all evidence to date suggests that epinephrine administration does not improve long-term survival rates for patients who suffer an out-of-hospital cardiac arrest.
Epinephrine may improve neurologically intact long-term survival in a small subset of patients (about 2 percent) who present in VF and can receive the drug within the first few minutes of the cardiac arrest. However, response logistics will likely prevent most American EMS systems from reaching these patients soon enough for epinephrine to be of much value.
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