July 25th, 2013
Vasopressin-Epinephrine Plus Corticosteroids Improve Neurologic Status After In-Hospital Cardiac Arrest – Implications for Out-of-Hospital Arrest?
Graham Nichol takes a close look at a recent randomized trial that examined whether combined vasopressin-epinephrine plus corticosteroids during CPR could improve survival and neurologic status in patients with in-hospital cardiac arrest. The trials results appear in JAMA.
Out-of-hospital and in-hospital cardiac arrest continue to be major public health problems in the U.S., with a combined burden of more than 500,000 fatalities annually.1,2 Many communities have not reported improved outcomes after out-of-hospital cardiac arrest (OHCA) for more than 30 years.3 Despite the apparent lack of progress, there is a more than fivefold variation in survival after treatment of OHCA across communities.4 This large variation suggests that cardiac arrest is a treatable condition that warrants further investigation.
Cardiac arrest involves sudden, global ischemia. Reperfusion occurs during cardiopulmonary resuscitation (CPR) and restoration of circulation, and is associated with a marked release of circulating inflammatory molecules including cytokines, activated complement and polymorphonuclear leukocytes, and endothelial cell adhesion molecules.5-8 After cardiac arrest, non-survivors demonstrate plasma interleukin-6 concentrations 20-fold greater than survivors,5 which is approximately 50-fold greater than normal human baseline values.9 In addition, patients with cardiac arrest have lower serum cortisol levels than those observed in other stress states.10 There is an association between serum cortisol and short-term outcomes in this population. Impaired response to corticotropin stimulation is not modified by application of induced hypothermia.11 These inflammatory and coagulation changes contribute to poor capillary perfusion, tissue ischemia, multi-organ dysfunction, and death.12-15 But many patients with early hemodynamic dysfunction that is reduced or treated do survive to have good neurologic outcomes.5,16 Therefore, treatments that decrease early mortality related to inflammation and intractable shock could increase the number of survivors with good outcomes.
Differences in how manual chest compressions are applied to patients with OHCA by EMS providers are associated with differences in outcomes. Greater chest compression fraction,17 greater depth of chest compression,18 greater chest compression rate,19 and briefer perishock pauses are associated with better outcomes.20 Thus, potential improvements in advanced cardiac life support should not be implemented at the expense of good basic care.
Previous studies provide conflicting estimates of the effect of intravenous epinephrine and vasopressors in patients with cardiac arrest. A randomized trial reported that use of intravenous drugs – including, but not limited to, epinephrine – improved survival to admission but not discharge compared with no intravenous drugs in patients with OHCA.21 Large effectiveness trials reported no survival benefit with vasopressin compared with epinephrine in patients with cardiac arrest.22-24 A recent large observational study derived from a Japanese OHCA registry suggested that use of epinephrine was not associated with improved outcomes compared with no epinephrine.25 However, concurrent analyses of overlapping datasets from the same registry suggested that early use of epinephrine was associated with improved outcomes compared with late or no epinephrine.26,27 Importantly, the only trial of epinephrine versus placebo in patients with OHCA did not achieve its intended sample size because of lack of EMS provider equipoise. Nonetheless, this trial reported that epinephrine significantly improved restoration of circulation and admission to hospital and tended to improve survival to discharge.28 Opinions of experts differ as to whether the consistent effect estimate and inconsistent significance observed in this trial reflects lack of power or lack of effect. In the absence of a randomized trial with adequate power to detect a significant difference in a clinically important outcome such as survival to discharge, I believe that the current standard of care during attempted resuscitation is to provide epinephrine as early as possible without disrupting provision of high-quality CPR.
Previously, a single-center, randomized, double-blind, placebo-controlled trial in Greece evaluated whether early immune modulation with or without vasopressors could improve outcomes in patients with in-hospital cardiac arrest with a first recorded rhythm of ventricular fibrillation.29 Eligible patients allocated to the intervention group received intravenously vasopressin 20 IU during the first five CPR cycles and methylprednisonlone 40 mg during the first CPR cycle (n=48), followed by treatment of post-resuscitation shock with hydrocortisone 300 mg daily for 7 days (n=27). Patients allocated to the control group received intravenous saline placebo during each time period (n=52 in resuscitation phase; n=15 in post-resuscitation phase). Concurrent interventions in both groups included intravenous epinephrine 1 mg during each CPR cycle. Intervention group patients, compared with controls, had greater restoration of circulation (81% vs. 52%, p=0.003) and survival to discharge (19% vs. 4%, p=0.02). Among patients with post-resuscitation shock (apparently defined as inability to maintain mean arterial pressure greater than 70 mm Hg without vasopressors after volume loading), those who received corticosteroids had improved survival to discharge compared with controls (30% vs. 0%, p=0.02). The significant and important benefits of vasopressin and corticosteroids during attempted resuscitation and corticosteroids after resuscitation were considered sufficiently promising as to warrant replication in a larger trial.
Now, results from that larger trial have been published in JAMA. The multicenter, randomized, double-blind, placebo-controlled trial, also in Greece, used similar methods to the pilot study to evaluate similar interventions, with the notable exception that the current study enrolled patients with in-hospital cardiac arrest who required vasopressors as opposed to patients with a first-recorded rhythm of ventricular fibrillation. The intervention patients (n=130), who were allocated to vasopressin and corticosteroids during attempted resuscitation, had greater restoration of circulation than the control patients (n=138), who received saline alone (84% vs. 66%, p=0.005). The intervention group also had greater functional neurologic status at discharge (14% vs. 5%, p=0.02). Among patients with post-resuscitation shock (n=149), intervention patients who received corticosteroids had greater functional neurologic status at discharge than did controls (21% vs. 8%, p=0.02).
The study investigators should be congratulated on demonstrating significant and important benefits associated with the use of vasopressors and corticosteroids during attempted resuscitation as well as corticosteroids after resuscitation. The present trial used multiple methods to confirm its internal validity, including deploying chromatography to confirm drug stability, monitoring concurrent care, and achieving a high rate of follow-up. A notable strength of this trial was the use of masked allocation, as unblinding can increase estimates of treatment benefit by about 50%.30 Use or non-use of blinding may explain discordant estimates of the effect of interventions in patients with OHCA.31,32
The study has a few limitations that may affect whether these results apply to patients with OHCA or in-hospital arrest in other settings. First, patients who were randomized but had circulation restored before study drug administration were excluded from the analysis, so the aggregate benefit of the intervention may be overestimated. Second, the intervention group received both vasopressin and corticosteroids during attempted resuscitation, so it is difficult to determine their relative contributions to improved outcome. Of note, patients in the control group frequently received open-label corticosteroids. But given the prior lack of incremental benefit of vasopressin in addition to epinephrine, it seems plausible that the primary benefit is attributable to immune modulation with corticosteroids. Third, patients with post-resuscitation shock were not re-randomized to corticosteroids versus placebo. Instead, patients who were allocated to vasopressin and corticosteroids during resuscitation and then subsequently developed shock received additional doses of corticosteroids. Thus, the relative importance of early versus later corticosteroids warrants further study.
There is large regional variation in the processes of care for patients with cardiac arrest.33,34 Importantly, interventions may have differential effects in patients with OHCA versus in-hospital cardiac arrest.35,36 Interventions that improve outcomes in one geographic region may not improve it in another due at least in part to differences in patient characteristics and processes of care.37,38 In addition, corticosteroids can impair myocardial healing in patients with acute myocardial infarction, which is commonly observed in patients with OHCA. The promising results of this trial warrant replication in a multicenter trial in centers that provide high-quality care to a high volume of patients with OHCA before adoption into clinical practice.
1. Go AS et al. Heart Disease and Stroke Statistics–2013 Update: A Report From the American Heart Association. Circulation. 2013 Jan 1;127(1):e6-e245.
2. Merchant RM et al. Incidence of treated cardiac arrest in hospitalized patients in the United States. Crit Care Med. 2011 Nov;39(11):2401-6.
3. Sasson C et al. Predictors of survival from out-of-hospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2010 Jan;3(1):63-81.
4. Nichol G et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008 Sep 24;300(12):1423-31.
5. Adrie C et al. Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome. Circulation. 2002 Jul 30;106(5):562-8.
6. Shyu KG et al. Concentrations of serum interleukin-8 after successful cardiopulmonary resuscitation in patients with cardiopulmonary arrest. Am Heart J. 1997 Sep;134(3):551-6.
7. Gando S et al. Alterations of soluble L- and P-selectins during cardiac arrest and CPR. Intensive Care Medicine. 1999;25(6):588-93.
8. Bottiger BW et al. Marked activation of complement and leukocytes and an increase in the concentrations of soluble endothelial adhesion molecules during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans. Crit Care Med. 2002 Nov;30(11):2473-80.
9. Vgontas AN et al. I-6 and its circadian secretion in humans. Neuroimmunomodulation. 2005;12(3):131-40.
10. Schultz CH et al. A characterization of hypothalamic-pituitary-adrenal axis function during and after human cardiac arrest. Crit Care Med. 1993 Sep;21(9):1339-47.
11. Hekimian G et al. Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation. Shock. 2004 Aug;22(2):116-9.
12. Lefer DJ and Granger DN. Oxidative stress and cardiac disease. Am J Med. 2000;109(4):315-23.
13. Anderson T and Vanden Hoek TL. Preconditioning and the oxidants of sudden death. Curr Opin Crit Care. 2003 Jun;9(3):194-8.
14. Chen Q et al. Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem. 2003 Sep 19;278(38):36027-31.
15. Nolan JP et al. Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation. Circulation. 2003 Jul 8;108(1):118-21.
16. Laurent I et al. Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest. J Am Coll Cardiol. 2002 Dec 18;40(12):2110-6.
17. Christenson J et al. Chest compression fraction determines survival in patients with out-of-hospital ventricular fibrillation. Circulation. 2009 Sep 29;120(13):1241-7.
18. Stiell IG et al. What is the role of chest compression depth during out-of-hospital cardiac arrest resuscitation? Crit Care Med. 2012 Apr;40(4):1192-8.
19. Idris AH et al. Relationship Between Chest Compression Rates and Outcomes From Cardiac Arrest. Circulation. 2012 Jun 19;125(24):3004-12.
20. Cheskes S et al. Perishock pause: an independent predictor of survival from out-of-hospital shockable cardiac arrest. Circulation. 2011 Jul 5;124(1):58-66.
21. Olasveengen TM et al. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial. JAMA. 2009 Nov 25;302(20):2222-9.
22. Stiell IG et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001 Jul 14;358(9276):105-9.
23. Gueugniaud PY et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008 Jul 3;359(1):21-30.
24. Wenzel V et al. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004 Jan 8;350(2):105-13.
25. Hagihara A et al. Prehospital epinephrine use and survival among patients with out-of-hospital cardiac arrest. JAMA. 2012 Mar 21;307(11):1161-8.
26. Nakahara S et al. Association between timing of epinephrine administration and intact neurologic survival following out-of-hospital cardiac arrest in Japan: a population-based prospective observational study. Acad Emerg Med. 2012 Jul;19(7):782-92.
27. Hayashi Y et al. Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest. Circ J. 2012;76(7):1639-45.
28. Jacobs IG et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011 Sep;82(9):1138-43.
29. Mentzelopoulos SD et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009 Jan 12;169(1):15-24.
30. Bero L et al. Factors associated with findings of published trials of drug-drug comparisons: why some statins appear more efficacious than others. PLoS Med. 2007 Jun;4(6):e184.
31. Aufderheide TP et al. Standard cardiopulmonary resuscitation versus active compression-decompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial. Lancet. 2011 Jan 22;377(9762):301-11.
32. Aufderheide TP et al. A trial of an impedance threshold device in out-of-hospital cardiac arrest. N Engl J Med. 2011 Sep 1;365(9):798-806.
33. Zive D et al. Variation in out-of-hospital cardiac arrest resuscitation and transport practices in the Resuscitation Outcomes Consortium: ROC Epistry-Cardiac Arrest. Resuscitation. 2011 Mar;82(3):277-84.
34. Glover BM et al. Wide variability in drug use in out-of-hospital cardiac arrest: a report from the resuscitation outcomes consortium. Resuscitation. 2012 Nov;83(11):1324-30.
35. Bernard SA et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002 Feb 21;346(8):557-63.
36. Nichol G et al. Does induction of hypothermia improve outcomes after in-hospital cardiac arrest? Resuscitation. 2013 May;84(5):620-5.
37. Stiell IG et al. The Ontario trial of active compression-decompression cardiopulmonary resuscitation for in-hospital and prehospital cardiac arrest. JAMA. 1996 May 8;275(18):1417-23.
38. Plaisance P et al. A comparison of standard cardiopulmonary resuscitation and active compression-decompression resuscitation for out-of-hospital cardiac arrest. French Active Compression-Decompression Cardiopulmonary Resuscitation Study Group. N Engl J Med. 1999 Aug 19;341(8):569-75.