Prove It: Improving neurological outcome following cardiac arrest
Study suggests adding vasopressin and steroids to standard resuscitation measures improves long-term neurological recovery following in-hospital cardiac arrest
Author’s Note:Although this column normally reports on research conducted in the out-of-hospital arena, the results from a very interesting in-hospital cardiac arrest trial recently appeared. Although one must be careful about extrapolating the results of an investigation conducted in-hospital to the out-of-hospital environment, it is my hope that you will find this as interesting as did I.
Medic 24 and Engine 3 respond to a report of an unconscious person on the loading dock of a local grocer. They arrive to find co-workers performing CPR on a 45-year-old male who collapsed. There was no AED on the dock.
Firefighters take over CPR while Paramedic Jacobson attaches the manual defibrillator/monitor. The presenting arrhythmia is ventricular fibrillation. Jacobson charges the defibrillator to 200 joules and delivers the first shock. The firefighters immediately resume CPR.
Paramedic Doyle quickly establishes intraosseous access in the patient’s left tibia. She administers one milligram of epinephrine while Jacobson inserts a supraglottic airway. The initial capnography reading is about 18 mm Hg. Two minutes after the first shock, the patient remains in ventricular fibrillation. The medics deliver a second shock at 300 joules and the firefighters immediately resume chest compressions.
During the ensuing resuscitation efforts, the patient receives an additional defibrillation attempt, 2 milligrams of epinephrine and 300 milligrams of amiodarone. After placing the patient on a backboard for transport to the patient to the hospital, Jacobson notices an organized rhythm with a capnography reading of 64 mmHg. Doyle verifies the presence of a femoral pulse.
Transport to the hospital was uneventful. The initial emergency department blood pressure was 110/64 mmHg. The patient never regained consciousness and was discharged to a nursing home two weeks later in a persistent vegetative state.
Researchers in Greece utilizing a double-blind, randomized, controlled trial, compared outcomes for patients who suffered an in-hospital cardiac arrest and received standard resuscitation measures to those who received standard measures along with vasopressin and methylprednisolone (Mentzelopoulos et al., 2013). The researchers excluded all patients
- under the age of 18 years
- resuscitated prior to the administration of a vasopressor
- whose arrest was thought to be caused by exsanguination
- with a terminal illness and a life expectancy of less than 6 weeks
- with DNRs
- treated with corticosteroids prior to the cardiac arrest.
Before beginning the study, a pharmaceutical company prepared two types of resuscitation kits. Each kit contained standard open-labeled 1 mg syringes of epinephrine along with a series of syringes marked only with a registration number. In one of the kits, the unlabeled syringes contained saline only. One series of unlabeled syringes in the other kits contained 20 milligrams of vasopressin and the other series contained 40 milligrams of methylprednisolone.
By having these syringes unlabeled (except for the registration number) the research team could create a treatment and a control group with both the caregivers and the researchers blinded to enrollment. This double-blinded strategy helps to reduce treatment bias and offers more error-free results.
Upon verifying cardiac arrest, medical personnel immediately initiated cardiopulmonary resuscitation according to the 2005 European Resuscitation Council Guidelines and randomized each patient to one of the resuscitation kits (Nolan, Deakin, Soar, Böttiger, & Smith, 2005). Patients in the control group received one standard epinephrine syringe and two syringes that contained only saline. Patients randomized to the treatment group received one milligram of epinephrine along with the vasopressin and methylprednisolone. Randomization helps ensure that individual patient differences that might affect the outcome of the study will be evenly spread between the treatment and the control group.
At three-minute intervals for the duration of the resuscitation effort, the medical team administered an additional round of medications. Although the control group continued to received epinephrine and saline placebo, the treatment group now only received epinephrine and vasopressin with no additional doses of methylprednisolone.
The team also had the latitude to administer any other condition specific resuscitation drugs, such as antiarrhythmics, sodium bicarbonate, atropine, blood products, or electrical therapies (defibrillation, TCP).
Fifteen minutes after the onset of the cardiac arrest, the resuscitation team provided standard resuscitation efforts for all patients who remained in cardiac arrest. From that point forward, they did not administer any additional study medications.
Physicians managed any complications associated with the post ROSC period using standard therapies. At four-hours post ROSC, a physician determined whether each survivor showed any evidence of post-resuscitation shock, which was also treated according to standard therapy (norepinephrine infusion). In addition, patients who received the vasopressin-steroids-epinephrine (VSE group) who showed evidence of post resuscitation shock also received a stress dose of hydrocortisone over the subsequent 7-day post arrest period.
What the study was looking for
There were two primary end points for this study. The first was ROSC sustained for at least 20 minutes. The second was survival to hospital discharge with a favorable neurological score on the Glasgow-Pittsburgh 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 is able to work. On the other end of the scale, a score of four indicates a vegetative state while a score of five is consistent with brain death (Cummins et al., 1991). For the purposes of this investigation, the researchers defined favorable neurologic outcome intact as a CPC score of one or two.
During the 25-month enrollment period, the research team evaluated 364 patients for eligibility into the study. Ninety-six patients were excluded because they either achieved ROSC before the resuscitation team could administer any study drugs or they previously received a steroid injection for their in-patient condition. This resulted in a sample size of 268 patients randomized into a treatment group (N = 130) and the control group (N = 138).
There were no statistical differences between the two groups with respect to location of arrest within the hospital, presenting arrhythmia, time to ALS initiation, or endotracheal intubation. Patients who received the vasopressin and steroids had a significantly shorter duration of ALS interventions during the arrest (13 minutes vs. 19 minutes, respectively, p = .01), fewer CPR cycles (4 vs. 5, respectively, p = .001), and received less epinephrine during the arrest (4 mg vs. 5 mg, respectively, p = .002). There were no other significant differences in treatment between the two groups.
Upon analysis of the results, researchers found a statistically significant difference between the two groups in the first primary endpoint (ROSC for 20 minutes or longer). A greater percentage of patients who received vasopressin and steroids in addition to the standard resuscitation measures achieved ROSC compared to the control group (83.9% vs. 65.9%, p=.005).
In fact, the odds of achieving and maintaining ROSC for 20 minutes or longer was three times greater for patients who received vasopressin and steroids compared to patients who received the standard resuscitation medications (OR, 2.98; 95% CI 1.39, 6.40).
Patients in the VSE group were more likely to survive to hospital discharge with favorable neurological outcome when compared to the control group (13.9% vs. 5.1%, p = .02). Translated into English, patients who received vasopressin and methylprednisolone during the resuscitation attempt were three times more likely to have a favorable neurological outcome at discharge compared to patients who received standard resuscitation measures (OR, 3.28; 95% CI, 1.17-9.20).
In a secondary analysis of the data, researchers found a number of characteristics associated with an increased hazard for poor outcome or worse neurological outcome or both. These included
- the use of epinephrine, atropine, or sodium bicarbonate during the resuscitation period
- failure to use therapeutic hypothermia
- non-shockable initial arrest rhythm
- non-cardiac cause of the arrest
- cardiac arrest that occurred at night or on the weekend
What this means for you
This study seems to suggest that adding vasopressin and steroids to standard resuscitation measures improves survival to hospital discharge with favorable neurological outcome when compared to standard resuscitation measures alone. One additional published randomized control trial supports this hypothesis (Mentzelopoulos et al., 2009).
In that study, patients who received vasopressin and corticosteroids in addition to standard resuscitation measures had more frequent ROSC and improved overall survival to hospital discharge rates when compared to standard resuscitation measures alone. However, that trial did not measure the neurological outcome of the patients.
Corticosteroids may enhance the vasopressor effects of both vasopressin (Ertmer et al., 2007) and epinephrine (Tsuneyoshi, Kanmura, & Yoshimura, 1996). Indeed, patients in this study who received corticosteroids had significantly improved hemodynamic measurements (systolic arterial blood pressure, mean arterial blood pressure, and diastolic blood pressure) during the resuscitation period.
Researchers in this study did not measure CPR performance of the resuscitation team. Even though the caregivers were blinded to the medication identity, it is possible that CPR quality was not the same between the two groups.
However, site-specific analyses did not demonstrate a difference in outcome measures between the three participating hospitals. It is therefore reasonable to assume no significant differences in CPR quality between the treatment and the control group. Unfortunately, that is just an assumption; without measurement, one cannot be sure.
One must also be careful when attributing improved outcomes to vasopressin and corticosteroid administration. Patients in the control group actually received more epinephrine during the resuscitation attempt. Multiple studies suggest that epinephrine administration during a resuscitation attempt worsens long-term survival with favorable neurologic outcome (Chang et al., 2007; Jacobs, Finn, Jelinek, Oxer, & Thompson, 2011; Olasveengen et al., 2009; Ong et al., 2007; Tang, Weil, Sun, Noc, Yang, & Gazmuri, 1995).
It is possible that the improved neurological outcome observed in the treatment group actually occurred because these patients received significantly less epinephrine.
The results of this study combined with a previous RCT suggest that the addition of vasopressin and corticosteroids to standard resuscitation measures may improve long-term neurological recovery following in-hospital cardiac arrest.
No emergency department or EMS agency should immediately alter their treatment protocols, as these results are far from conclusive. However, these results provide a foundation upon which researchers can continue to explore.
Chang, W. T., Ma, M. H., Chien, K. L., Huang, C. H., Tsai, M. S., Shih, F. Y., Yuan, A., Tsai, K. C., Lin, F. Y., Lee, Y. T., & Chen, W. J. (2007). Postresuscitation myocardial dysfunction: Correlated factors and prognostic implications. Intensive Care Medicine, 33(1), 88-95. doi:10.1007/s00134-006-0442-9
Cummins, R. O., Chamberlain, D. A., Abramson, N. S., Allen, M., Baskett, P. J., Becker, L., Bossaert, L., Delooz, H. H., Dick, W. F., Eisenberg, M. S., Evans, T. R., Holmberg, S., Kerber, R., Mullie, A., Ornato, J. P., Sandoe, E., Skulberg, A., Tunstall-Pedoe, H., Swanson, R., & Thies, W. H. (1991). Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: The Utstein Style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation, 84(2), 960-975. doi:10.1161/01.CIR.84.2.960
Ertmer, C., Bone, H. G., Morelli, A., Van Aken, H., Erren, M., Lange, M., Traber, D. L., & Westphal, M. (2007). Methylprednisolone reverses vasopressin hyporesponsiveness in ovine endotoxemia. Shock, 27(3), 281-288. doi:10.1097/01.shk.0000235140.97903.90
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
Jennett, B., & Bond, M. (1975). Assessment of outcome after severe brain damage. Lancet, 305(7905), 480–484. doi.org/10.1016/S0140-6736(75)92830-5
Mentzelopoulos, S. D., Malachias, S., Chamos, C., Konstantopoulos, D., Ntaidou, T., Papastylianou, A., Kolliantzaki, I., Theodoridi, M., Ischaki, H., Makris, D., Zakynthinos, E., Zintzaras, E., Sourlas, S., Aloizos, S., & Zakynthinos, S. G. (2013). Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. Journal of the American Medical Association, 310(3), 270-279. doi:10.1001/jama.2013.7832.
Mentzelopoulos, S. D., Zakynthinos, S. G., Tzoufi, M., Katsios, N., Papastylianou, A., Gkisioti, S., Stathopoulos, A., Kollintza, A., Stamataki, E., & Roussos, C. (2009). Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Archives of Internal Medicine, 169(1), 15-24. doi:10.1001/archinternmed.2008.509
Nolan, J. P., Deakin, C. D., Soar, J., Böttiger, B. W., & Smith, G. (2005). European Resuscitation Council guidelines for resuscitation 2005: Section 4, Adult advanced life support. Resuscitation, 67(suppl 1), S39-S86. doi:10.1016/j.resuscitation.2005.10.009
Olasveengen, T. M., Sunde, K., Brunborg, C., Thowsen, J., Steen, P. A., & Wik, L. (2009). Intravenous drug administration during out-of-hospital cardiac arrest: A randomized trial. Journal of the American Medical Association, 302(20), 2222-2229. doi:10.1001/jama.2009.1729
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
Shizukuda, Y., Miura, T., Ishimoto, R., Itoya, M., Iimura, O. (1991). Effect of prednisolone on myocardial infarct healing: Characteristics and comparison with indomethacin. Canadian Journal of Cardiology, 7(10), 447-454.
Tang, W., Weil, M. H., Sun, S., Noc, M., Yang, L., & Gazmuri, R. J. (1995). Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation, 92(10), 3089-3093. doi:10.1161/01.CIR.92.10.3089
Tsuneyoshi, I., Kanmura, Y., & Yoshimura, N. (1996). Methylprednisolone inhibits endotoxin-induced depression of contractile function in human arteries in vitro. British Journal of Anaesthesia, 76(2), 251-257. doi:10.1093/bja/76.2.251
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.
Send correspondence concerning this article to Kenneth W. Navarro, The University of Texas Southwestern School of Health Professions, 5323 Harry Hines Blvd, MC 9134, Dallas, Texas 75390-9134. E-mail: firstname.lastname@example.org