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Prove It: Epinephrine may have a role during resuscitation from cardiac arrest

Measuring the time to epinephrine administration as a continuous variable shows time-dependent nature of epinephrine administration


The author has no financial interest, arrangement or direct affiliation with any corporation that has a direct interest in the subject matter of this presentation, including manufacturer(s) of any products or provider(s) of services mentioned.

Engine 12 and Medic 20 respond to a reported cardiac arrest in a small office building. Medic 20 was already mobile in the district and arrives on the scene within about two minutes. One of the patient’s co-workers is performing CPR but there was no AED in the office.

Paramedic Martin verifies pulselessness, activates the built-in metronome on the monitor and takes over chest compressions from the bystander. Paramedic Turner places defibrillation pads on the patient’s chest and reviews the patient’s ECG. After confirming ventricular fibrillation, Turner begins to charge the defibrillator but directs Martin to continue chest compressions. When the defibrillator is charged, Turner signals Martin to clear and then delivers the shock. Martin resumes chest compressions.

Turner prepares the bag mask device and begins to ventilate the patient using 100 percent oxygen. The crew from Engine 12 arrives and the firefighters take over CPR from the medics. Martin quickly establishes an intraosseous line. With 15 seconds to go before the next rhythm check, Martin decides to administer one milligram of epinephrine.

EMS agencies and medical directors must find ways to reduce or eliminate barriers to earlier drug administration once paramedics are on scene. (Courtesy photo)
EMS agencies and medical directors must find ways to reduce or eliminate barriers to earlier drug administration once paramedics are on scene. (Courtesy photo)

At the next rhythm check, the monitor continues to display ventricular fibrillation. During the subsequent resuscitation attempt, the patient received three additional shocks, 300 milligrams of amiodarone, and one additional milligram of epinephrine. The patient achieves ROSC, but does not regain consciousness. Martin successfully intubates the patient’s trachea and transports without complications.

In the emergency department, Martin and Turner discuss the call. Both medics realize that epinephrine administered before the second shock is a violation of the agency’s clinical treatment guidelines. They report the violation to the agency’s medical director, who is on duty in the emergency department. She tells them not to worry about it and that the earlier administration of the epinephrine may have actually helped the patient to achieve ROSC in the field.

Study review

A research team composed entirely of paramedics investigated whether the timing of vasopressor administration affected the likelihood of adult patients achieving ROSC in the field following an episode of out-of-hospital cardiac arrest [1]. The team from Western Carolina University searched a statewide EMS database for patients 18 years of age or older who suffered a bystander-witnessed, but non-trauma related cardiac arrest and received paramedic administration of epinephrine, vasopressin or both. Patients were not eligible for inclusion if a member of the EMS response team witnessed the onset of the cardiac arrest, because the care received before the arrest could have biased the results.

Researchers measured time in one-minute intervals beginning when the 911 operators received the emergency call. Interval measurement ended when the patient received the first dose of a vasopressor. The researchers also measured a number of other variables in order to gain a better understanding of how prehospital factors influence outcomes in cardiac arrest. However, this study is about whether earlier administration of a vasopressor improves the odds of a patient achieving ROSC.

Results

During the six-month study period, EMS personnel in North Carolina attempted resuscitation in 3,263 cases. Of those, 2,141 were excluded from analysis for reasons such as being an unwitnessed arrest, a pediatric patient under the age of 18 years or because the arrest occurred as the result of trauma. This left 1,122 patients for inclusion in the final analysis.

All patients in the sample received some form of vasopressor during the resuscitation attempt. The overwhelming majority (81.5 percent) received epinephrine as the only vasopressor while 17.6 percent received both epinephrine and vasopressin. Less than 1 percent of the patient received vasopressin as the only vasopressor.

About 48 percent (n = 542) of the patients in the sample achieved transient or sustained ROSC. Not surprisingly, those patients were more likely to present in a shockable rhythm and less likely to be intubated in the field when compared to those who did not achieve ROSC. Paramedics established IV or IO access and administered a vasopressor significantly sooner in the group who achieved ROSC.

What is interesting is the relationship the researchers found between when paramedics administered the vasopressor and whether the patient achieved ROSC. Using a statistical process called logistic regression, researchers were able to isolate the effects that single variables have on the outcome of interest. In this analysis, researchers found that for every one-minute delay in vasopressor administration measured from the moment the 911 center received the emergency call, there was a 4 percent decrease in the odds of the patient achieving ROSC.

What this means for you

Animal studies have demonstrated improved short-term survival following the administration of intravenous epinephrine [2,3]. Unfortunately, clinical trials have not demonstrated improved long-term survival or neurologically favorable outcomes associated with the prehospital administration of epinephrine in patients who suffer out-of-hospital cardiac arrest [4-12].

One reason for the difference in effectiveness between animal studies and clinical trials may be related to how quickly after the onset of cardiac arrest rescuers administer the first dose of epinephrine. On average, time to first drug administration in animal studies is about 9.5 minutes, compared to 19.4 minutes for clinical trials [13]. Similarly, a systematic review of clinical studies between 1990 and 2005 found the time from dispatch to first drug administration ranges between 10 and 25 minutes, with an average of about 18 minutes [14].

Some have speculated the failure to demonstrate a survival advantage related to drug administration may actually be a reflection of this delay rather than the ineffectiveness of the drug action itself. This changes the question from “Does epinephrine administration improve the odds of survival” to “Does epinephrine only improve the odds of survival if given early?”.

Retrospective analysis of large cardiac arrest registry in Japan (> 212,000 cases) found the adjusted odds of achieving neurologically intact survival increased by 39 percent when EMS personnel administered epinephrine early [15]. For that study, researchers defined early as drug administration within the first ten minutes after EMS personnel began chest compressions. Since the study did not consider EMS response time in the analysis, which is often around five to eight minutes, it is difficult to interpret the significance of the results.

Similarly, another study found a 92 percent increased odds of achieving ROSC if epinephrine was given within the first ten minutes measured from the moment the 911 center receives the call [16]. Advanced airway control procedures before epinephrine administration delayed the time to first drug administration and significantly reduced ROSC rates.

Although much of the delay to earlier drug administration by paramedics results from response intervals, together these studies suggest EMS agencies and medical directors must find ways to reduce or eliminate barriers to earlier drug administration once paramedics are on scene. One strategy may be for paramedics to use IO rather than IV access routes. An animal model suggests EMS personnel can administer epinephrine about 6 minutes sooner by using an IO rather than an IV [17].

An interesting proposition is whether alternative administration route might offer even greater time savings and clinical improvement. A pilot study of cardiac arrest using piglets weighing less than 6 kilograms found ROSC rates were not significantly different between the animals who received epinephrine via IM or IV routes [18]. However, both groups had significantly greater ROSC rates when compared to animals who received placebo. Although promising, this study was limited by two very important factors. First, the size of the piglets makes the results more applicable to children than to adults. Also, the researchers induced cardiac arrest in these animals by infusing a local anesthetic until the animal achieved cardiovascular collapse. This etiology is significantly different from factors that cause cardiac arrest in most human adults and children. However, if researchers could reproduce these results in asphyxial or other causes of arrest, it is reasonable to think strategies targeting early IM administration of epinephrine could further improve survival rates following cardiac arrest.

One of those strategies could be the development of an epinephrine auto injector containing a higher-dose than is currently available. These auto injectors could be placed with AEDs, making early administration possible by first responders and even bystanders.

Limitations of the present study

One significant limitation of the present study is the retrospective nature of the analysis. The lack of data control inherent with retrospective analysis always introduces the possibility that other unmeasured variables may explain the results. For example, the registry used in this study did not measure CPR quality, which includes significant predictors of survival such as chest compression fraction, depth, and rate. Any or all of those factors could have influenced the outcome of the study.

The accuracy of the registry data also represents a limitation to the study. There is no way to know whether the time points for first drug administration represent estimates made by the paramedics after the call was complete or whether they were recorded by a time keeper at the actual moment of drug administration in the field. One recent study comparing documentation of critical care interventions in a patient care record to time-stamped audio recordings of 192 patients who suffered an out-of-hospital cardiac arrest found a median difference of two minutes between when paramedics recorded completion of the intervention and when the intervention actually occurred [19].

Summary for EMS providers

This study found the odds of achieving ROSC decline by 4 percent for every 1-minute delay in vasopressor administration. This decline challenges EMS agencies to eliminate any factors that delay drug administration once paramedics arrive on the scene. What is significant about the present study is it is one of the first to measure the time to epinephrine administration as a continuous variable rather than simply a dichotomous variable (less than or more than ten minutes). This provides a clearer picture of the time-dependant nature of epinephrine administration and demonstrated that even within the first ten minutes, epinephrine should be given as early as possible.

References
1. Hubble, M. W., Johnson, C., Blackwelder, J., Collopy, K., Houston, S., Martin, M., Wilkes, D., & Wiser, J. (2015). Probability of return of spontaneous circulation as a function of timing of vasopressor administration in out-of-hospital cardiac arrest. Prehospital Emergency Care, 19(4), 457-463. doi:10.3109/10903127.2015.1005262

2. Palácio, M. Â., Paiva, E. F., Azevedo, L. C., & Timerman, A. (2013). Experimental cardiac arrest treatment with adrenaline, vasopressin, or placebo [Article in English, Portuguese]. Arquivos Brasileiros de Cardiologia, 101(6), 536-544. doi:10.5935/abc.20130213

3. Zuercher, M., Kern, K. B., Indik, J. H., Loedl, M., Hilwig, R. W., Ummenhofer, W., Berg, R. A., & Ewy, G. A. (2011). Epinephrine improves 24-hour survival in a swine model of prolonged ventricular fibrillation demonstrating that early intraosseous is superior to delayed intravenous administration. Anesthesia and Analgesia, 112(4), 884-890. doi:10.1213/ANE.0b013e31820dc9ec

4. Arrich, J., Sterz, F., Herkner, H., Testori, C., & Behringer, W. (2012). Total epinephrine dose during asystole and pulseless electrical activity cardiac arrests is associated with unfavourable functional outcome and increased in-hospital mortality. Resuscitation, 83(3), 333-337. doi:10.1016/j.resuscitation.2011.10.027

5. Hagihara, A., Hasegawa, M., Abe, T., Nagata, T., Wakata, Y., & Miyazaki, S. (2012). Prehospital epinephrine use and survival among patients with out-of- hospital cardiac arrest. Journal of the American Medical Association, 307(11), 1161–1168. doi:10.1001/ jama.2012.294

6. Holmberg, M., Holmberg, S., & Herlitz, J. (2002). Low chance of survival among patients requiring adrenaline (epinephrine) or intubation after out-of-hospital cardiac arrest in Sweden. Resuscitation, 54(1), 37–45. doi:10.1016/S0300-9572(02)00048-5

7. Jacobs, I. G., Finn, J. C., Jelinek, G. A., Oxer, H. F., & Thompson, P. L. (2011). Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomized double-blind placebo-controlled trial. Resuscitation, 82(9), 1138–1143. doi:10.1016/j.resuscitation.2011.06.029

8. Koscik, C., Pinawin, A., McGovern, H., Allen, D., Media, D. E., Ferguson, T., Hopkins, W., Sawyer, K. N., Boura, J., & Swor, R. (2013). Rapid epinephrine administration improves early outcomes in out-of-hospital cardiac arrest. Resuscitation, 84(7), 915-920. doi:10.1016/j.resuscitation.2013.03.023

9. Machida, M., Miura, S., Matsuo, K., Ishikura, H., & Saku, K. (2012). Effect of intravenous adrenaline before arrival at the hospital in out-of-hospital cardiac arrest. Journal of Cardiology, 60(6), 503–507. doi:10.1016/j.jjcc.2012.07.001

10. Olasveengen, T. M., Wik, L., Sunde, K., & Steen, P. A. (2012). Outcome when adrenaline (epinephrine) was actually given vs not given—post hoc analysis of a randomized clinical trial. Resuscitation, 83(3), 327-332. doi:10.1016/j.resuscitation.2011.11.011

11. Ong, M. E., Tan, E. H., Ng, F. S., Panchalingham, A., Lim, S. H., Manning, P. G., Ong, V. Y. K., Lim, S. H. C., Yap, S., Tham, L. P., Ng, K. S., & Venkataraman, A. (2007). Survival outcomes with the introduction of intravenous epinephrine in the management of out-of-hospital cardiac arrest. Annals of Emergency Medicine, 50(6), 635–642. doi:10.1016/j.annemergmed.2007.03.028

12. Tanaka, H., Takyu, H., Sagisaka, R., Ueta, H., Shirakawa, T., Kinoshi, T., Takahashi, H., Nakagawa, T., Shimazaki, S., Ong Eng Hock, M. (2016). Favorable neurological outcomes by early epinephrine administration within 19 minutes after emergency medical service call for out-of-hospital cardiac arrest patients. American Journal of Emergency Medicine, [Epub ahead of print]. doi:10.1016/j.ajem.2016.08.026

13. Reynolds, J. C., Rittenberger, J. C., & Menegazzi, J. J. (2007). Drug administration in animal studies of cardiac arrest does not reflect human clinical experience. Resuscitation, 74(1), 13–26. doi:10.1016/j.resuscitation.2006.10.032

14. Rittenberger, J. C., Bost, J. E., & Menegazzi, J. J. (2006). Time to give the first medication during resuscitation in out-of-hospital cardiac arrest. Resuscitation, 70(2), 201–206. doi:10.1016/j.resuscitation.2005.12.006

15. Nakahara, S., Tomio, J., Nishida, M., Morimura, N., Ichikawa, M., & Sakamoto, T. (2012).  Association between timing of epinephrine administration and intact neurologic survival following out-of-hospital cardiac arrest in Japan: A population-based prospective observational study. Academic Emergency Medicine, 19(7), 782–792. doi:10.1111/j.1553-2712.2012.01387.x

16. Cantrell, C. L. Jr., Hubble, M. W., & Richards, M. E. (2013). Impact of delayed and infrequent administration of vasopressors on return of spontaneous circulation during out-of-hospital cardiac arrest. Prehospital Emergency Care, 17(1), 15-22. doi:10.3109/10903127.2012.702193

17. Mader, T. J., Coute, R. A., Kellogg, A. R., & Nathanson, B. H. (2016). Blinded evaluation of combination drug therapy for prolonged ventricular fibrillation using a swine model of sudden cardiac arrest. Prehospital Emergency Care, 20(3), 390-398. doi:10.3109/10903127.2015.1086848

18. Mauch, J., Ringer, S. K., Spielmann, N., & Weiss, M. (2013). Intravenous versus intramuscular epinephrine administration during cardiopulmonary resuscitation - a pilot study in piglets. Paediatric Anaesthesia, 23(10), 906-912. doi:10.1111/pan.12149

19. Frisch, A., Reynolds, J. C., Condle, J., Gruen, D., & Callaway, C. W. (2014). Documentation discrepancies of time-dependent critical events in out of hospital cardiac arrest. Resuscitation, 85(8), 1111–1114. doi:10.1016/j.resuscitation.2014.05.002

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