Why You Should More Than Consider a Vasopressin, Steroid, and Epinephrine (VSE) Cocktail

29 Oct
October 29, 2015

VSE in Cardiac Arrest1The newly published 2015 AHA guidelines recommend that:
“In IHCA, the combination of Vasopressin, Epinephrine, and Methylprednisolone and post-arrest Hydrocortisone as described by Mentzelopoulos et al. maybe considered; however, further studies are needed before recommending the routine use of this strategy (Class IIb, LOE C-LD)”

Mentzelopoulos et al. [2][3] have published two separate randomized, double-blind, placebo-controlled studies out of Greece examining the role of this Vasopressin, Steroid, and Epinephrine (VSE) cocktail. These studies looked at in-hospital cardiac arrest for patients and enrolled patients immediately with non-shockable rhythms or patients in refractory VFib/VTach. The first study included 100 patients from a single center, while the second study included 268 patients from multiple centers.

First, What does ClassIIb, LOE C-LD Mean in the New 2015 AHA Guidelines?

ClassIIb, LOE C-LD

What Were the Intervention & Control Arms?

VSE

The results demonstrate an increase in Return of Spontaneous Circulation (ROSC), an increase in survival to hospital discharge with a NNT = 7 [2], and an increase in neurologically favorable survival to hospital discharge with a NNT = 12 [3].

More Detailed Results:

Mentzelopoulos et al. 2009 [2]

  • VSE
    • n=100
    • Increase ROSC: 39/48 (81%) vs. 27/52 (52%) p=0.003
    • Increase Survival to Discharge: 9/48 (19%) vs. 2/52 (4%) p=0.02
    • Following ROSC: Increase MAP, Decrease Vasopressor Requirements, Decrease Cytokine Levels, Increase Central Venous Oxygen Saturation, Decrease Lactate, Increase Renal-Failure Free Days
  • Stress Dose Steroids
    • Increase Hospital Discharge 8/27 (30%) vs. 0/15 (0%) p=0.02
    • Increase Organ Failure Free Days
    • No Difference in Incidence of Adverse Effects due to Steroids Noted

Mentzelopoulos et al. 2013 [3]

  • VSE
    • n=268
    • Increase ROSC: 109/130 (84%) vs. 91/138 (66%) p=0.005
    • Increase Discharge with CPC Score 1 or 2: 18/130 (14%) vs. 7/138 (5%) p=0.02
    • Decrease Duration ACLS, Total Epinephrine Dose, and Organ Dysfunction
    • Increase Hemodynamics, Central Venous Oxygen Saturation, Cerebral Perfusion Pressure, and Renal-, Neurologic-, Ventilator-Failure Free Days
    • Similar Adverse Effects
  • Stress Dose Steroids:
    • Increase Discharge with CPC Score of 1 or 2: 16/76 (21%) vs. 6/73 (8%) p=0.02
    • 15 Epi Patients Received Hydrocortisone
    • Increase Circulatory-, Renal-, Hepatic-, Coagulation-, Respiratory-Failure Free Days
    • No Difference in Incidence of Adverse Effects due to Steroids Noted

fp-showcase3

Physiologic Rationale Behind VSE

Benefits in ROSC are likely due to the combination of Vasopressin and Epinephrine

banner-promotion-new_0

Combination of Vasopressin and Epinephrine

  • Has not shown a survival benefit overall
  • Studies were all conducted in the out-of-hospital cardiac arrest setting
  • Have many inherent limitations including delays in initiation of basic life support and delays in time to vasopressor therapy
  • Largest Epinephrine and Vasopressin Combination Study [4] was associated with:
    • Time to arrival of emergency medical technicians was ~7 minutes
    • Time to arrival of the advanced cardiac life support team was ~16 minutes
    • Time to the first vasopressor administration was ~21 minutes
      • Delays in administration of vasopressors (specifically epinephrine) have been associated with worse outcomes

banner-promotion-new_0

Epinephrine and Vasopressin Alone

  • Have both been associated with increased rates of ROSC
  • Vasopressin is an endogenous peptide and antidiuretic hormone which increases peripheral vascular resistance through stimulation of smooth muscle V1 receptors
    • Increase in coronary perfusion pressure, cerebral vasodilation, minimal effects on pulmonary vasculature, a longer half-life and duration of effect than epinephrine
    • Potentiates release of cortisol and has a greater stability in acidic environments compared to catecholamines
  • Epinephrine is a potent catecholamine with alpha and beta agonist effects:
    • Alpha effects result in vasoconstriction
      • Increased coronary perfusion pressure which may be responsible for the increased ROSC rates
      • Increased cerebral perfusion pressure
      • Animal data suggests this may not be as beneficial as previously thought due to a decrease in microcirculatory cerebral blood flow and ischemia during CPR
    • Beta effects are more controversial
      • Increased myocardial work, oxygen and ATP consumption, lactic acid production, secondary VFib, pulmonary arteriovenous shunting resulting in transient hypoxemia, and post ROSC myocardial dysfunction

banner-promotion-new_0

Neurologically Favorable Survival

  • Likely due to steroid attenuation of post-resuscitation complications
  • Adrenal Insufficiency of Cardiac Arrest
    • Adrenal gland ischemia
    • Associated with increased mortality, hemodynamic instability, and diminished response to catecholamines
  • Inflammatory Mediated Ischemic/Reperfusion Injury
    • Activation of the inflammatory cascade after cardiac arrest due to injury from ischemia
    • Further damages ischemic organs and can compound neurologic damage
    • Physiologic response to cytokines is release of cortisol
      • Blunted due to adrenal insufficiency
    • Elevated cytokine levels have been associated with increased mortality and unfavorable neurologic outcomes
  • Post-Resuscitation Shock
    • Associated with myocardial stunning and decreased cardiac index
      • May lead to multi-system organ dysfunction (may also decrease cerebral blood flow and compound neurologic damage) and may progress to mortality
    • Risk factors associated with post-resuscitation shock include: >15 minute duration of code, more frequent doses of epinephrine, greater number of defibrillation attempts
  • Steroids Attenuate Post-Resuscitation Complications
    • Steroids help decrease inflammatory response and regulate homeostasis by regulating gene expression
      • Physiologic effects include: positive inotropy, anti-inflammatory effects which counter ischemic reperfusion injury (decrease neurologic damage), decrease vascular permeability/increase vascular reactivity to catecholamines and angiotensin II which increase systemic vascular resistance (increased cerebral perfusion), supplements cortisol which may not be sufficiently produced due to adrenal insufficiency
      • Takes ~30 minutes to a few hours to produce physiologic effects
      • Potential side effects include electrolyte disturbances, risk of infections, and negative regulation on the HPA axis
        • Not demonstrated in studies; however, not powered to determine difference
      • Higher cortisol plasma concentrations have been associated with increased neurologically intact survival

The Bottom Line

Clinical Bottom Line

  • The VSE cocktail increases neurologically favorable survival to hospital discharge for IHCA with a NNT = 12
  • Prior investigations of vasopressin and epinephrine should be interpreted cautiously due to delays in initiation to basic life support and time to vasopressor therapy
  • Early administration of steroids attenuates complications of post-resuscitation care such as inflammatory mediated ischemic/reperfusion injury, post-resuscitation shock, and adrenal insufficiency

Guest Post By:

Hannah Davis, PharmD
PGY2 Emergency Medicine Pharmacy Resident
University of Texas Health Science Center at San Antonio/University Health Systems

References

  1. Link M, Berkow L, Kudenchuk P, et al. Part 7: Adult advanced cardiovascular life support: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132:S444-644. [Table of Contents]
  2. Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med 2009;169:15-24. PMID: 19139319
  3. Mentzelopoulos S, Malachias S, Chamos C, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3):270-9. PMID: 19139319
  4. Gueugniaud P, David J, Chanzy E, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. New Engl J Med. 2008;359(1):21-30. PMID: 23860985
  5. Varvarousi G, Stefaniotou A, Varavaroussis D, et al. Glucocorticoids as an emergency pharmacologic agent for cardiopulmonary resuscitation. Cardiovasc Drugs Ther. 2014;28:477-88. PMCID: PMC4163188

For More on This Topic Checkout:

Post Peer Reviewed By: Salim Rezaie (Twitter: @srrezaie)

The following two tabs change content below.

Darrel Hughes

University Health System Clinical Specialist, Emergency Medicine at University of Texas Health Science Center at San Antonio (UTHSCSA)
REBEL EM Guest Contributor and Author
Tags: , , ,
7 replies
  1. Micheal Massoud says:

    Great review, thanks for bringing this up! Hopeful to see where this goes in the future.

    Reply
  2. Rogue Medic says:

    There may be a benefit to this cocktail, but these are small studies and we see a large decrease in the difference between the still unproven standard treatment (epinephrine) as the number of patients increases.

    We need to study this more, but we also need good evidence on epinephrine alone.

    Is epinephrine beneficial in cardiac arrest? It probably is, but it is unlikely to be indicated for all cardiac arrest patients.

    If epinephrine is beneficial in cardiac arrest, which patients are the ones who benefit and how do we identify them?

    Is the benefit of the cocktail just the law of small numbers? Is it an example of the steroid decreasing the harm caused by epinephrine?

    We don’t know.

    We have been doing this for over half a century and it is about time started to find out what we are doing to our patients.

    .

    Reply
    • Salim Rezaie says:

      Hello Rogue Medic,
      368 patients is certainly not the largest numbers, but the fact that the first study was single center and the subsequent study was multi center showing the same results does add some merit to the trials. I can think of a single center study from the late 90s that changed the way we manage sepsis (i.e. EGDT), with my point being we have changed practice for far less studies. I agree having an even larger population would add even more to the current evidence provided, and certainly the best recommendation we can make at this time from best available evidence is that in cardiac arrest (i.e. already dead), early evidence does show promise (NNT = 12 for neuro intact survival), with no evidence of harm at this time.
      As for the epinephrine question, there is already a RCT underway in the UK called the PARAMEDIC 2 trial: http://www2.warwick.ac.uk/fac/med/research/hscience/ctu/trials/critical/paramedic2/ that is already trying to answer the question of epi vs no epi.
      The second point you bring up, I am not sure anyone has the answer to. Was it the combination of epi/vasopressin/steroids that was somehow magical or was it one of the isolated medications (i.e. steroids) that improved outcomes)? We don’t really know. What I do know however, is that these are the 1st two trials showing improved neuro intact survival from any medication in cardiac arrest (Take that last statement with a grain of salt.)
      So what is the bottom line here: We need more evidence I agree, but in an already dead person, how can you make someone who is dead…more dead? The staples of cardiac arrest are still high-quality, uninterrupted CPR & Early Defibrillation, but not considering this cocktail with best available evidence would be a mistake IMHO.

      Salim

      Reply
  3. Rogue Medic says:

    Sorry, switched the quotation marks for html.

    Salim,

    “my point being we have changed practice for far less studies.”

    We can come up with much worse examples of additions to standards of care, An example of worse behavior does not make something good behavior. Each year, we have hundreds of thousands of patients to try this. We should find out if it works and what parts of it works – assuming that there is any benefit when compared to placebo.

    Are there any studies comparing this cocktail to placebo, rather than compared to something that has no valid evidence of being better than placebo.

    “As for the epinephrine question, there is already a RCT underway in the UK called the PARAMEDIC 2 trial:”

    Yes. Let’s hope that enough of the doctors involved resist the pressure from politicians and the media that prevented 90% of the patients who would have been included in the Jacobs study.

    http://www.ncbi.nlm.nih.gov/pubmed/21745533

    “This study was designed as a multicentre trial involving five ambulance services in Australia and New Zealand and was accordingly powered to detect clinically important treatment effects. Despite having obtained approvals for the study from Institutional Ethics Committees, Crown Law and Guardianship Boards, the concerns of being involved in a trial in which the unproven “standard of care” was being withheld prevented four of the five ambulance services from participating.”

    “In addition adverse press reports questioning the ethics of conducting this trial, which subsequently led to the involvement of politicians, further heightened these concerns. Despite the clearly demonstrated existence of clinical equipoise for adrenaline in cardiac arrest it remained impossible to change the decision not to participate.”

    “We need more evidence I agree, but in an already dead person, how can you make someone who is dead…more dead?”

    We can use treatments that cause harm to the brain of the resuscitated patients. We can use treatments that prevent the survival of patients who obtain ROSC. Brief resuscitation or resuscitation only to a coma, when the patient could otherwise have been resuscitated with a good neurological outcome is worse than dead.

    We do not know whether the patients would have had better outcomes if we used treatments with good evidence of benefit, rather than treatments that have only been shown to increase the rate of survival in a coma.

    “not considering this cocktail with best available evidence would be a mistake IMHO.”

    We should consider this cocktail worthy of further study.

    Are there any good reason to use this treatment outside of controlled trials? It has taken half a century to start looking at epinephrine, which is based on extrapolation from basic research and on the resuscitation of rats, pigs, dogs, . . . who have induced cardiac arrest in the absence of cardiovascular disease.

    Is epinephrine beneficial in those with medical causes of cardiac arrest, but without cardiovascular disease?

    How many millions of patients did we not resuscitate because of a perceived need to provide ALS treatments that are based on expert opinion, while we paused chest compressions?

    One thing is certain. We have demonstrate horrible judgment, when treating cardiac arrest patients.

    We need to admit that we are almost exclusively using treatments based on the flimsiest of evidence – expert opinion – and the experts have been horribly wrong. Continuous chest compressions (and defibrillation for shockable rhythms) work. The rest is opinion.

    We even add ventilation to CPR for cardiac causes of cardiac arrest, not because of any valid evidence of improvements in outcome, but because of opinions. If our patients matter, we should limit ourselves to treatments that work and restrict everything else to controlled trials until there is evidence to determine whether the harms are greater than the benefits.

    We have too many people advocating for treatments that make us feel good, with inadequate evidence of any benefit for the patient. We should be better than those pushing homeopathy, acupuncture, Reiki, and other expert opinion-based placebos.

    If we want to provide the best care, for the best outcomes, we must find out what works.

    Dr. John Ioannidis and Dr. Vinay Prasad express this well in the abstract to one of their papers.

    “Abandoning ineffective medical practices and mitigating the risks of untested practices are important for improving patient health and containing healthcare costs. Historically, this process has relied on the evidence base, societal values, cultural tensions, and political sway, but not necessarily in that order. We propose a conceptual framework to guide and prioritize this process, shifting emphasis toward the principles of evidence-based medicine, acknowledging that evidence may still be misinterpreted or distorted by recalcitrant proponents of entrenched practices and other biases.”

    http://www.implementationscience.com/content/9/1/1

    .

    Reply
    • Salim Rezaie says:

      No worries Rogue Medic,
      Great Discussion Thus Far…

      1. We Both Agree more studies would be nice
      2. Paramedic 2 Trial is coming, we will have to critically appraise when it comes out, but meanwhile hoping it is done well
      3. The two studies to date do not show harm (NNT = 12 for Neuro Favorable Survival), hard to ignore, but yes more needed before complete change of practice
      4. Still advocate for BLS first (High Quality CPR & Early Defib) over medications

      Appreciate your input on this post and convo. 🙂

      Salim

      Reply
      • Rogue Medic says:

        Salim,

        Thank you for eliminating the poorly formatted comment.

        Then it appears that our real point of disagreement is point three.

        “3. The two studies to date do not show harm (NNT = 12 for Neuro Favorable Survival), hard to ignore, but yes more needed before complete change of practice”

        Unfortunately, harm often requires many more patients to be identified. This is one of the reasons for post-approval study of medications. The best known example of this is probably CAST – The Cardiac Arrhythmia Suppression Trial. The study was set up to figure out which drug provided the most benefit, but the results showed that some of the drugs were killing a lot of patients. The placebo arm had the best outcomes., but it required a large study (and a placebo group) to identify this danger in what was considered an obviously beneficial treatment.

        Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.
        Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, Arensberg D, Baker A, Friedman L, Greene HL, et al.
        N Engl J Med. 1991 Mar 21;324(12):781-8.
        PMID: 1900101 [PubMed – indexed for MEDLINE]

        http://www.ncbi.nlm.nih.gov/pubmed/1900101

        “CONCLUSIONS. There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown.”

        .

        Reply

Trackbacks & Pingbacks

  1. […] EM reviews the argument for VSE therapy in in-hospital-cardiac arrest along with and explanation of the potential physiologic rationale. […]

Leave a Reply

Want to join the discussion?
Feel free to contribute!

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.

Optimization WordPress Plugins & Solutions by W3 EDGE