VSE

VSE: Vasopressin, Steroids and Epinephrine and Neurologically Favourable Survival After In-Hospital Cardiac Arrest A Randomized Clinical Trial

Mentzelopoulos. JAMA.2013;310(3):270-279. doi:10.1001/jama.2013.7832

Clinical Question

  • In patients in cardiac arrest, does vasopressin + epinephrine during CPR combined with steroid supplementation during and after CPR, improve survival to discharge with a good neurological outcome, in comparison to the use of epinephrine alone?

Design

  • Randomized, double-blind, placebo-controlled, parallel-group trial
    • blinding of staff assessing neurological outcome
  • Block randomisation stratified by centre
  • Modified intention to treat
    • randomised patients who did not require vasopressors were excluded
    • randomised patients that survived but who did not have  post-resuscitation shock were excluded from subgroup analysis
  • Based on a predicted survival with favourable neurological recovery of 15% in the intervention group and 4% in the control group, the study was powered at 80%, with alpha set at 0.05, if 244 patients enrolled.
  • Multi-variance logistic regressions used to determine Odds Ratios (OR)

Setting

  • 3 tertiary centres in Greece
  • September 1, 2008, to October 1, 2010

Population

  • Inclusion: in-hospital vasopressor-requiring cardiac arrest
    • Location of cardiac arrest: 16% ED, 41% ICU/CCU/Operating room, 43% hospital ward
  • Exclusion: age<18, terminal illness/DNAR, cardiac arrest due to exsanguination, pre-hospital cardiac arrest, treatment with IV steroids prior to arrest
  • 300 randomised out of 364 assessed for eligibility
    • 32 patients excluded post-randomisation as ROSC prior to need for vasopressors
    • Comparing intervention vs. control group, similar baseline characteristics apart from:
      • male sex 73.1% vs. 63.8%
      • hospital stay before arrest (median)  5 days vs 2 days
      • cause of cardiac arrest
        • metabolic 8.5% vs 15.2%
        • hypotension 46.9% vs. 37%
        • myocardial ischaemia/infarction 23.1% vs. 17.4%
      • Initial rhythm
        • asytole 63.8% vs. 70.3%, P=0.3
        • PEA 19.2% vs. 13%, P=0.19
    • No significant differences in use of primary PCI or therapeutic hypothermia between study groups

Intervention

  • Combination of
    • vasopressin 20 IU/CPR cycle for 5 cycles
    • adrenaline 1mg/CPR cycle
    • steroids
      • methylprednisolone 40mg during 1st cycle of CPR
      • surviving patients received hydrocortisone 300mg/d for <7days and gradual taper if postresuscitation shock
        • >4hrs requirement of vasopressors to maintain MAP >70 after volume loading, in patients not previously on vasopressors;  (if already on vasopressors, >50% increase in vasopressors/inotropes)

Control

  • Adrenaline 1mg/CPR cycle + placebos
Average CPR cycle duration ~3min in both intervention and control groups

Outcome

  • Primary outcome:
    • survival to hospital discharge with favourable neurological outcome (Glasgow-Pittsburgh Cerebral Performance Category 1/2)
      • significant improvement in intervention group
        • 13.9% vs. 5.1%; (OR 3.28, 95% C.I. 1.17-9.2, P=0.02, NNT 12)
  • Secondary outcome:
    • ROSC for >20 minutes (stated as a 2nd primary outcome, but power calculation not performed for this outcome)
      • significant improvement in intervention group
        • 83.9% vs. 65.9%, (OR 2.98 95% C.I. 1.39-6.4, P=0.005, NNT 6)
    • Patients with post-resuscitation shock had significant improvement of survival to discharge with a good neurological outcome in the intervention group vs. control group
      • 21.1% vs 8.2%, OR 3.74 (95% C.I. 1.2-11.62, P=0.02)
    • Number of patients receiving insulin treatment within 1st 10 days – significantly higher in intervention group
      • 50.4% vs. 36%, P<0.001
    • There was no significant difference in rates of infection or gastro-intestinal bleeding between the two groups

Authors’ Conclusions

  • Patient in cardiac arrest requiring vasopressors, have an improved survival with a good neurological outcome if they are treated with combined vasopressin/epinephrine/steroids compared with epinephrine alone

Strengths

  • Randomised
  • Double blinded, and blinding of those assessing neurological status
  • Placebo controlled

Weaknesses

  • Single geographical area
  • Small number of patients in total survived with a good neurological outcome (25 in total) making it difficult to make any definite decisions
  • Therapeutic hypothermia only used in 24.6% of patients
  • Atropine and bicarbonate used on a number of patients which is not consistent with current practice
  • Differences in baseline characteristics between the 2 groups
  • Large number of patients had cardiac arrest in critical care environment. These results may be be generalisable to centres at which this does not happen.
  • Bundle approach means that we do not know whether it was the whole bundle or any of the bundle elements that caused any differences in results found

The Bottom Line

  • This study has shown a significant improvement for survival to discharge with a good neurological outcome following cardiac arrest when treated with combination steroids/vasopessin/epinephrine in comparison to epinephrine alone. Of note, no RCT has shown this improvement when using epinephrine alone compared with placebo.
  • However, before introducing this into routine practice I am waiting for a validation study in a different setting. This is a single study, set in only 3 centres in 1 country. There were only 18 patients who survived with a good outcome in the intervention group. We know that a number of promising treatments have been disproven when studies have been repeated in larger trials. I hope that someone takes up the challenge of attempting to validate this trial on an urgent basis so that a more evidenced based decision can be made.

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