From Bedside to Curbside: Prehospital Clinical Research Update

Clinical research guides the care your patients are receiving before they reach you. It pays to stay up to date with out-of-hospital evidence-based practices.

PARAMEDIC-2 Trial
The efficacy of advanced airways, drug therapy, and even traditional advanced life support (ALS) care in cardiac arrest have been challenged in recent years. Now, the use of epinephrine is again being questioned.

A July 2018 New England Journal of Medicine article by Perkins, et al. studied epinephrine use in 8,014 out-of-hospital cardiac arrest (OHCA) cases in the United Kingdom, randomized to either epinephrine or placebo.¹ The Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC-2) trial is the first randomized, controlled trial in recent years to reexamine the efficacy of epinephrine in OHCA. The article first reviews the theory behind the use of epinephrine: constricting arterioles and increasing aortic diastolic pressure during CPR, hopefully improving coronary blood flow in the process. Other theoretical benefits include cardiac inotropy and chronotropy as well as increased cerebral perfusion pressure. 

The majority of historical studies were retrospective or observational and demonstrated increased return of spontaneous circulation (ROSC) with epinephrine, but not necessarily an improved neurologic outcome. These studies were done mostly using animal models where assessing neurological outcome was difficult and extrapolation of data to humans was problematic. A 2015 Journal of Critical Care article by Loomba, et al. presented a meta-analysis of 14 studies involving 655,853 patients, which concluded that epinephrine does not increase survival to discharge but does make it more likely for those discharged to have poor neurologic outcomes.² A 2014 Resuscitation article by Lin, et al. also presented a meta-analysis of 14 randomized controlled trials drawing a similar conclusion: there is no benefit of epinephrine use in survival to discharge or neurological outcomes, but there were improved rates of survival to admission and ROSC with epinephrine versus placebo.³

The primary end goal for Perkins, et al. in the most recent study was survival at 30 days with a secondary endpoint of a favorable neurological outcome at 30 days (ie, Modified Rankin score of ≦3). Those with a non-favorable neurological outcome had a Modified Rankin Score of 4 or 5. 130 of the 4015 (3.2%) in the epinephrine group survived to 30 days as compared to only 94 of the 3999 (2.4%) in the placebo group.

While the use of epinephrine did lead to higher rates of 30-day survival, there was no difference in favorable neurological outcome because more survivors had severe neurological impairment in the epinephrine group. While some patients did have a favorable neurological outcome after receiving epinephrine, the numbers were similar in the non-epinephrine group as well. These results are congruent with previous studies. However, this new study is not only the most recent, but is also randomized and controlled, adding validity and supporting the conclusions of previous studies.

These results have significant implications in the ongoing debate regarding OHCA pharmacotherapy. However, they also raise new social, ethical, economic, and moral questions that are less frequently discussed. For example, what would you say to a physician who told you, “We can give your mother a medication for her heart problem that would increase the chances of her living by almost 1%. But, if she did survive, she would likely be unable to walk or take care of herself and may be bedridden and require a diaper”?

Is it worth it? Would the increased rates of (at least, initial) survival allow a family to say goodbye before their loved one passes away? Would it allow for an increased likelihood of viable organ donation? Or, would it lead to a prolonged ICU stay, giving the family a false sense of hope because the patient has a pulse and brainstem reflexes but little hope of neurological and functional recovery?

Further complicating this analysis is that the data seem to suggest that patients who end up walking out of the hospital neurologically intact after suffering cardiac arrest may have done so without ever receiving epinephrine anyway. Loomba, et al. also found that the NNT for epinephrine in OHCA was 7, and there was no benefit to hospital discharge or survival at 1 month.

Epinephrine is also recommended regardless of underlying rhythm -- whether it be PEA, VFib, VTach, asystole, torsades de pointes, or bradycardia in a pediatric patient. While the authors of this study did mention that about 17% of patients presented in VFib, they did not discuss if outcomes were different based on which rhythm the patient had when receiving epinephrine versus placebo. Given recent discussions of withholding epinephrine (and even giving esmolol in refractory VFib⁴), it would have been interesting to see if, in this study, patients in VFib who were randomized to the placebo group happened to do better than those receiving epinephrine.

PAMPer Trial

The Prehospital Plasma During Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock (PAMPer) trial is a pragmatic, multicenter, cluster-randomized study that included patients at risk for hemorrhagic shock who were transported via air medical transport.⁵ Patients included in the study were those transported from the scene of an injury or referred from an outside emergency department to a participating trauma center. They were eligible for the study if they were between 18-90 years old and sustained blunt or penetrating trauma. Patients included were those who experienced at least one episode of hypotension (SBP <90 mm Hg) and tachycardia (HR >108) or severe hypotension (SBP <70) prior to arrival at the receiving trauma center.

The intervention group received two units of either group AB or group A with a low anti-B antibody titer (<1:100) thawed plasma, which was initiated during transport by the air medical team. The study protocol included infusion of both units of plasma even if administration was ongoing upon arrival to the trauma center. Plasma administration was followed with standard care as defined by the provider’s local protocol.

The control group was composed of the same population and was provided with standard-care resuscitation. This included infusion of crystalloid as primary resuscitative fluid, although 13 of the participating 27 air medical bases had the ability to administer 2 units of universal donor red cells in accordance with local protocols.

Upon study completion, a total of 501 patients were evaluated; 230 patients were included in the plasma group and 271 patients were in the standard-care group. The primary outcome was 30-day mortality. This was significantly lower in the plasma group when compared with the standard-care group (23.2% vs. 33.0%; 95% confidence interval, -18.6 to -1.0; P=0.03). Secondary outcomes that favored the intervention group included 24-hour mortality, in-hospital mortality, amount of blood transfused in 24 hours, and INR (1.2 in the plasma group and 1.3 in standard-care). Of these, only the difference in INR was found to be statistically significant after adjustment for multiple comparisons. There were no documented cases of transfusion-related lung injury. Transfusion-related reactions occurred in 2.2% of patients in the plasma group, and personnel at blood bank services at the sites where they were reported assessed them as minor. There was no significant difference between the two groups in multiorgan failure, nosocomial infection, or vasopressors received in the first 24 hours.

This is a potentially practice-changing study in the management of hemorrhage in the prehospital air transport setting. While it is logistically challenging to provide thawed plasma to prehospital providers, it appears it will help to decrease mortality in patients suffering from hemorrhagic shock. The number needed to treat in regard to 30-day mortality is staggering at 10. It seems possible that the early administration of this product helps to prevent downstream coagulopathy, perhaps than if it were to be administered immediately upon hospital arrival.

Large-scale administration of plasma in the prehospital setting would come with challenges. There would need to be agreements between prehospital providers and the facilities receiving patients. Administration of plasma is also not likely to be useful in all settings. This was a study that was restricted to air medical transport during which the transport time was 40 minutes in the standard care group and 42 in the plasma group. This is not representative of what many ground EMS services experience in terms of transport time. It would likely be impractical for urban prehospital providers with short transport times to begin these interventions; another study has shown that there is no significant mortality benefit to prehospital plasma use in an urban ground transport setting.⁶ The relatively short shelf life of thawed plasma must also be taken into account, meaning that this may only be a viable treatment option for transport services that experience a high volume of trauma patients. Nonetheless, this provides further evidence that severe hemorrhagic shock needs to be treated with blood, not “salt water” (saline). Not only is it important to replace oxygen-carrying red blood cells (RBCs) but also the clotting factors that are critical in hemostasis.

References
1. Perkins GD, Chen J, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):711-721.
2. Loomba RS, Nijhawan K, Aggarwal S, Arora RR. Increased return of spontaneous circulation at the expense of neurologic outcomes: Is prehospital epinephrine for out-of-hospital cardiac arrest really worth it? J Crit Care. 201530(6):1376-1381.
3. Lin S, Callaway CW, Shah PS, Wagner JD, Beyene J, Ziegler CP, Morrison LJ.  Adrenaline for out-of-hospital cardiac arrest resuscitation: a systematic review and meta-analysis of randomized controlled trials. Resuscitation. 2014;85(6):732-740.
4. Lee YH, Lee KJ, Min YH, et al. Refractory Ventricular Fibrillation Treated with Esmolol. Resuscitation. 2016;107:150-155.
5. Sperry JL, Guyette FX, Brown JB, et al. Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock. N Engl J Med. 2018;379(4):315-326.
6. Moore HB, Moore EE, Chapman MP, et al. Plasma-first resuscitation to treat haemorrhagic shock during emergency ground transportation in an urban area: a randomised trial. Lancet. 2018;392(10144):283-291.