Vasopressors in Adult Cardiac Arrest

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Vasopressors in Adult Cardiac Arrest

Citation

Welsford M, Berg KM, Neumar RW, Paiva EF, Andersen LW, Böttiger BW, Callaway CW, Deakin CD, Drennan I, Kleinman M, Nicholson TC, O’Neil BJ, Parr MJ, Reynolds JC, Sandroni C, Holmberg MJ, Wang TL, Nolan JP, Morley PT, Soar J and Donnino MW. Vasopressors in adult cardiac arrest: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2019 March 1.

Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of the Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of adult cardiac arrest patients (Holmberg MJ, 2019; PROSPERO - CRD42018116989) conducted by Katherine M. Berg, Mathias J Holmberg , and Michael Donnino with involvement of methodologic and clinical content experts. Evidence for adult literature was sought and considered by the expert systematic reviewers and the Advanced Life Support Task Force. A priori determined that high-dose vs standard-dose epinephrine studies would not be re-analyzed unless new controlled trials were published since the 2015 ILCOR review. The “no epinephrine” classification refers to placebo for randomized trials.

Systematic Review

Holmberg MJ, Issa M, Moskowitz A, Morley P, Welsford M, Neumar R, Paiva E, Coker A, Hansen C, Andersen LW, Donnino MW, Berg KM for the Advanced Life Support Task Force at the International Liaison Committee on Resuscitation (ILCOR)*. Vasopressors during adult cardiac arrest: A systematic review and meta-analysis. Resuscitation (submitted 2019).

Vasopressors in Adult Cardiac Arrest PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults (>18 years) with cardiac arrest in any setting (out-of-hospital or in-hospital).

Intervention: Vasopressor or a combination of vasopressors provided intravenously or intraosseously during cardiopulmonary resuscitation.

Comparators: No vasopressor, or a different vasopressor, or a different combination of vasopressors provided intravenously or intraosseously during cardiopulmonary resuscitation.

Outcomes: Short-term survival (return of spontaneous circulation (ROSC) and survival to hospital admission), mid-term survival (survival to hospital discharge, 28 days, 30 days, or 1 month), mid-term favorable neurological outcomes (Cerebral Performance Category score of 1-2 or modified Rankin Scale 0-3 at hospital discharge, 28 days, 30 days, or 1 month) and long-term favorable and poor (modified Rankin Score 4-5) neurological outcomes (after 1 month).

Study Designs: Randomized trials, non-randomized trials, and observational studies (cohort and case-control studies) with a comparison group were included.

Timeframe: All years and all languages were included as long as there was an English abstract to November 23, 2018.

PROSPERO Registration CRD42018116989

Consensus on Science

Epinephrine compared to placebo – Any initial rhythm

For the critical outcome of favorable neurologic outcome at 3 months, we identified low certainty evidence (downgraded for risk of bias due to loss to follow up and imprecision) from 1 RCT (Perkins 2018 711), enrolling 7965 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of epinephrine, compared with placebo (RR=1.30, 95% CI 0.94-1.80; absolute risk difference (ARD)=0.5%, 95% CI, -0.1% to 1.3%, or 5 more patients/1000 had favorable neurologic outcome at 3 months with the intervention [95% CI, 1 fewer to 13 more patients/1000 had favorable neurologic outcome at 3 months with the intervention).

For the critical outcome of survival with unfavorable neurologic outcome at 3 months, we identified very low certainty evidence (downgraded for risk of bias due to loss to follow up and imprecision) from 1 RCT (Perkins 2018 711), enrolling 7965 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no harm from the use of epinephrine, compared with the use of placebo (RR=1.45, 95% CI 0.67-3.12; ARD=0.1%, 95% CI -0.1% to 0.6%; 1 more patient/1000 had unfavorable neurologic outcome at 3 months with the intervention, 95% CI, 1 fewer to 6 more patients/1000 had unfavorable neurologic outcome at 3 months with the intervention).

For the critical outcome of favorable neurologic outcome at hospital discharge, we identified moderate certainty evidence (downgraded for imprecision) from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 8535 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of epinephrine, compared with the use of placebo (RR=1.21, 95% CI 0.90 to 1.62; ARD=0.4%, 0.2% to 1.2%; 4 more patients/1000 had favorable neurologic outcome at hospital discharge with the intervention, 95% CI 2 fewer to 12 more patients/1000 had favorable neurologic outcome at hospital discharge with the intervention).

For the critical outcome of survival at 3 months, we identified moderate certainty evidence (downgraded for imprecision) from 1 RCT (Perkins 2018 711), enrolling 8000 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed benefit from the use of epinephrine, compared with the use of placebo (RR=1.40, 95% CI 1.07 to 1.84; ARD 0.9%, 95% CI 0.2% to 1.8%; 9 more patients/1,000 survived at 3 months with the intervention, 95% CI 2 more to 18 more patients/1000 survived at 3 months with the intervention).

For the critical outcome of survival to hospital discharge, we identified moderate certainty evidence (downgraded for imprecision) from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 8538 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed benefit from the use of epinephrine, compared with the use of placebo (RR=1.44, 95% CI 1.11 to 1.86; ARD=1%, 95% CI 0.2% to 1.9%; 10 more patients/1000 survived to hospital discharge with the intervention, 95% CI 2 more to 19 more patients/1000 survived to hospital discharge with the intervention).

For the important outcome of survival to hospital admission, we identified high certainty evidence from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 8489 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed benefit from the use of epinephrine, compared with the use of placebo (RR=2.88, 95% CI 2.57 to 3.22; ARD=15.6%, 95% CI 13.1% to 18.5%; 156 more patients/1000 survived to hospital admission with the intervention, 95% CI 131 more to 185 more patients/1000 survived to hospital admission with the intervention).

For the important outcome of return of spontaneous circulation (ROSC), we identified high certainty evidence from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 8469 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed benefit from the use of epinephrine, compared with use of placebo (RR=3.09, 95% CI 2.82 to 3.39; ARD 24.3, 95% CI 21.1% to 27.7&; 243 more patients/1000 had ROSC with the intervention, 95% CI, 211 more to 277 more patients/1000 had ROSC with the intervention).

Epinephrine compared to placebo – Shockable rhythms

For the critical outcome of favorable neurologic outcome at 3 months, we identified very low certainty evidence (downgraded for risk of bias due to loss to follow up and imprecision) from 1 RCT (Perkins 2018 711), enrolling 1482 patients with out-of-hospital cardiac arrest with an initial shockable rhythm, which showed no benefit when epinephrine was used, compared with the use of placebo (RR=1.16, 95% CI 0.83-1.62; ARD=1.3%, 95% CI -1.3% to 4.9%; 13 more patients/1000 had favorable neurologic outcome at 3 months with the intervention, 95% CI 13 fewer to 49 more patients/1000 had favorable neurologic outcome at 3 months with the intervention).

For the critical outcome of favorable neurologic outcome at hospital discharge, we identified moderate certainty evidence (downgraded for imprecision) from 1 RCT (Perkins 2018 711), enrolling 1505 patients with out-of-hospital cardiac arrest with an initial shockable rhythm, which showed no benefit from the use of epinephrine, compared with the use of placebo (RR=1.05, 95% CI 0.76 to 1.45; ARD=0.4%, 95% CI -2.1% to 3.9%; 4 more patients/1000 had favorable neurologic outcome at hospital discharge with the intervention, 95% CI 21 fewer to 39 more patients/1000 had favorable neurologic outcome at hospital discharge with the intervention).

For the critical outcome of survival to hospital discharge, we identified moderate certainty evidence (downgraded for imprecision) from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 1753 patients with out-of-hospital cardiac arrest with an initial shockable rhythm, which showed no benefit from the use of epinephrine, compared with the use of placebo (RR=1.23, 95% CI 0.94 to 1.62; ARD=2.2%, 95% CI -0.6% to 5.8%; 22 more patients/1000, 95% CI 6 fewer to 58 more patients/1000).

For the important outcome of ROSC, we identified moderate certainty evidence (downgraded for imprecision) from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 1741 patients with out-of-hospital arrest with an initial shockable rhythm, which showed benefit from the use of epinephrine, compared with the use of placebo (RR=1.68, 95% CI 1.48 to 1.92; ARD=18.5%, 95% CI 13%-25%; 185 more patients/1000 had ROSC with the intervention, 95% CI 130 more to 250 more patients/1000 had ROSC with the intervention).

Epinephrine compared to placebo – Non-shockable rhythms

For the critical outcome of favorable neurologic outcome at 3 months, we identified very low certainty evidence (downgraded for risk of bias due to loss to follow up and imprecision) from one randomized controlled trial (Perkins 2018 711), enrolling 6318 patients with out-of-hospital cardiac arrest with an initial non-shockable rhythm, which showed no benefit from the use of epinephrine, compared with the use of placebo (RR=3.03, 95% CI 0.98-9.38; ARD=0.3%, 95% CI 0% to 1.1%; 3 more patients/1000 with favorable neurologic outcome at 3 months with intervention, 95% CI 0 fewer to 11 more patients/1000 with favorable neurologic outcome at 3 months with intervention).

For the critical outcome of favorable neurologic outcome at hospital discharge, we identified low certainty evidence (downgraded for imprecision) from 1 RCT (Perkins 2018 711), enrolling 6330 patients with out-of-hospital cardiac arrest with an initial non-shockable rhythm, which showed no benefit from the use of epinephrine, compared with the use of placebo (RR=1.80, 95% CI 0.80 to 4.07; ARD=0.2%, 95% CI -0.1% to 0.9%; 2 more patients/1000 had favorable neurologic outcome at discharge with intervention, 95% CI 1 fewer to 9 more patients/1000 had favorable neurologic outcome at discharge with intervention).

For the critical outcome of survival to hospital discharge, we identified moderate certainty evidence (downgraded for imprecision) from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 6619 patients with out-of-hospital cardiac arrest with an initial non-shockable rhythm, which showed benefit from the use of epinephrine, compared with use of placebo (RR=2.56, 95% CI 1.37 to 4.80; ARD=0.6%, 95% CI 0.1% to 1.5%; 6 more patients/1000 survived to hospital discharge with intervention, 95% CI from 1 more to 15 more patients/1000 survived to hospital discharge with intervention).

For the important outcome of ROSC, we identified high certainty evidence from 2 RCTs (Jacobs 2011 1138, Perkins 2018 711), enrolling 6579 patients with out-of-hospital arrest with an initial non-shockable rhythm, which showed benefit from the use of epinephrine, compared with use of placebo (RR=4.45, 95% CI 3.91 to 5.08; ARD=25.4%, 95% CI 21.4% to 30.1%; 254 more patients/1000 had ROSC with intervention, 95% CI from 214 more to 301 more patients/1000 had ROSC with intervention).

Initial vasopressin compared to initial epinephrine – Any rhythm

For the critical outcome of favorable neurologic outcome at hospital discharge, we identified very low certainty evidence (downgraded for risk of bias, indirectness, and imprecision) from 2 RCTs (Wenzel 2004 105, Mukoyama 2009 755), including 1479 patients with out-of-hospital cardiac arrest with any initial rhythm, which suggested no benefit from the use of vasopressin, compared with the use of epinephrine (RR=0.93, 95% CI 0.58 to 1.49; ARD= -0.3%, 95% CI -1.9% to 2.3%; 3 fewer patients/1000 had favorable neurologic outcome at hospital discharge with intervention, 95% CI 19 fewer to 23 more patients/1000 had favorable neurologic outcome at hospital discharge with intervention). We identified low certainty evidence (downgraded for very serious imprecision) from 1 RCT (Stiell 2001 105), including 200 patients with in-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of vasopressin, compared with the use of epinephrine (RR=0.71, 95% CI 0.33-1.54; ARD= -3.9%, 95% CI -9.1% to 7.3%; 39 fewer patients/1,000 had favorable neurologic outcome at discharge with intervention 95% CI 91 fewer to 73 more patients/1000 had favorable neurologic outcome at dscharge with intervention).

For the critical outcome of survival to hospital discharge, we identified very low certainty evidence (downgraded for indirectness and very serious imprecision) from 3 RCTs (Lindner 1997 535, Wenzel 2004 105, Mukoyama 2009 755), enrolling 1542 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of vasopressin, compared with the use of epinephrine (RR=1.26, 95% CI 0.76 to 2.07; ARD=2.3%, 95% CI -2.1% to 9.4%; 23 more patients/1000 survived to hospital discharge with intervention, 95% CI 21 fewer to 94 more patients/1000 survived to hospital discharge with intervention). We identified low certainty evidence (downgraded for very serious imprecision) from 1 RCT (Stiell 2001 105), enrolling 200 patients with in-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of vasopressin, compared with use of epinephrine (RR=0.85, 95% CI 0.41-1.77; ARD=-2%, 95% CI -8.0% to 10.4%; 20 fewer patients/1000 survived to hospital discharge with intervention, 95% CI from 80 fewer to 104 more patients/1000 survived to hospital discharge with intervention).

For the important outcome of survival to hospital admission, we identified low certainty of evidence (downgraded for indirectness and imprecision) from 3 RCTs (Lindner 1997 535, Wenzel 2004 105, Mukoyama 2009 755), enrolling 1562 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of vasopressin, compared with the use of epinephrine (RR=1.17, 95% CI 0.82 to 1.66; ARD=4.9%, 95% CI -5.2% to 19.2%; 49 more patients/1000 survived to hospital admission with intervention, 95%CI from 52 fewer to 192 more patients/1000 survived to hospital admission with intervention).

For the important outcome of ROSC, we identified low certainty evidence (downgraded for indirectness and imprecision) from 3 RCTs (Lindner 1997 535, Wenzel 2004 105, Mukoyama 2009 755), including 1562 patients with out-of-hospital arrest with any initial rhythm, which showed no benefit from the use of vasopressin, compared with the use of epinephrine (RR=1.05, 95 %CI 0.80 to 1.39; ARD=1.4%, 95% CI -5.7% to 11.1%; 14 more patients/1000 people had ROSC with intervention, 95% CI 57 fewer to 111 more patients/1000 had ROSC with intervention). We identified low certainty evidence (downgraded for very serious imprecision) from 1 RCT (Stiell 2001 105), enrolling 200 patients with in-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of vasopressin, compared with use of epinephrine (RR=1.09, 95% CI 0.78-1.52; ARD=3.6%, 95% CI -8.7% to 20.6%; 36 more patients/1000 had ROSC with intervention, 95% CI from 87 fewer to 206 more patients/1000 had ROSC with intervention).

There was no benefit in the effect of the intervention on any of the outcomes above when separated by initial rhythm.

Epinephrine plus vasopressin compared to epinephrine only – Any rhythm

For the critical outcome of favorable neurologic outcome at hospital discharge, we identified low certainty evidence (downgraded for very serious imprecision) from 1 RCT (Gueugniaud 2008 21), enrolling 2887 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin, compared with the use of epinephrine only (RR=0.53, 95% CI 0.24 to 1.19; ARD= –0.6%, 95% CI -0.9% to 0.2%; 6 fewer patients/1000 had favorable neurologic outcome at hospital discharge with intervention, 95% CI 9 fewer to 2 more patients/1000 had favorable neurologic outcome at hospital discharge with intervention).

For the critical outcome of survival to hospital discharge, we identified very low certainty evidence (downgraded for inconsistency, indirectness, and imprecision) from 3 RCTs (Callaway 2006 1316, Gueugniaud 2008 21, Ducros 2011 453), enrolling 3242 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin, compared with the use of epinephrine only (RR=0.76, 95% CI 0.47 to 1.22; ARD= –0.6%, 95% CI -1.3% to 0.5%; 6 fewer patients/1000 survived to discharge with intervention, 95% CI from 13 fewer to 5 more patients/1000 survived to discharge with intervention).

For the important outcome of survival to hospital admission, we identified low certainty evidence (downgraded for indirectness and imprecision) from 3 RCTs (Callaway 2006 1316, Gueugniaud 2008 21, Ducros 2011 453), enrolling 3249 patients with out-of-hospital cardiac arrest with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin, compared with the use of epinephrine only (RR=0.95, 95% CI 0.83 to 1.08; ARD= –1.1%, 95% CI -3.7% to 1.7%; 11 fewer patients/1000 survived to hospital admission with intervention, 95% CI 37 fewer to 17 more patients/1000 survived to hospital admission with intervention).

For the important outcome of ROSC, we identified very low certainty evidence (downgraded for inconsistency, indirectness, and imprecision) from 3 RCTs (Callaway 2006 1316, Gueugniaud 2008 21, Ducros 2011 453), enrolling 3299 patients with out-of-hospital arrest with any initial rhythm, which showed no benefit from the use of epinephrine plus vasopressin, compared with the use of epinephrine only (RR=0.97, 95% CI 0.87 to 1.08; ARD= -0.9%, 95% CI -3.9% to 2.4%; 9 fewer patients/1000 had ROSC with the intervention, 95% CI 39 fewer to 24 more patients/1000 had ROSC with the intervention).

There was no difference in the effect of the intervention on any of the outcomes above when separated by initial rhythm.

Treatment Recommendations

  • We recommend administration of epinephrine during cardiopulmonary resuscitation (strong recommendation, low to moderate certainty of evidence).
  • For non-shockable rhythms (PEA/asystole), we recommend administration of epinephrine as soon as feasible during cardiopulmonary resuscitation (strong recommendation, very low certainty of evidence).
  • For shockable rhythms (VF/VT), we suggest administration of epinephrine after initial defibrillation attempts are unsuccessful during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).
  • We suggest against the administration of vasopressin in place of epinephrine during cardiopulmonary resuscitation (weak recommendation, very low certainty of evidence).
  • We suggest against the addition of vasopressin to epinephrine during cardiopulmonary resuscitation (weak recommendation, low certainty of evidence).

Justification and Evidence to Decision Framework Highlights

This topic was prioritized by the ALS Task Force based on a recent large RCT comparing administration of epinephrine compared with placebo in over 8000 patients during out-of-hospital cardiopulmonary resuscitation (Perkins 2018 711).

We recommend the administration of epinephrine during cardiopulmonary resuscitation but the current review did not include comparison of different doses of epinephrine. Standard-dose epinephrine (1mg) compared to high-dose epinephrine (>1mg) was evaluated in the previous ILCOR review in 2015, and it was recommended that high-dose epinephrine not be used. We performed a systematic search and did not identify any significant new trials since the 2015 review. As there were no additional trials identified on this comparison, the ALS task force chose not to re-review this data. No trials comparing doses lower than 1mg were identified. We therefore chose not to specify a dose, although the recommendation against the use of high-dose epinephrine from 2015 has not been changed. The dose used in the RCTs that were evaluated was 1mg. There was no statistical benefit or harm shown for the use of epinephrine plus vasopressin or vasopressin alone compared to epinephrine. We therefore suggest the use of epinephrine only compared to vasopressin or the combination of these vasopressors in order to minimize the complexity of treatment algorithms.

In making the recommendation for epinephrine during cardiopulmonary resuscitation we considered the findings that epinephrine compared with placebo substantially improves ROSC, and also improves hospital admission and survival. The task force made a strong recommendation given that the intervention may reduce mortality in a life-threatening situation and adverse events are not prohibitive. A very high value is placed on an uncertain but potentially life preserving benefit. However, the impact on neurologic outcome remains uncertain, with no statistically significant evidence of benefit or harm on neurologic outcome at 3 months.

Cardiac Arrest Rhythm (and timing of administration):

There appears to be a more pronounced effect of epinephrine on ROSC and survival to hospital discharge in non-shockable rhythms compared to shockable rhythms but assessment of these sub-groups should be taken with caution. There is also very limited data to guide the specific timing of administration of epinephrine during cardiopulmonary resuscitation.

For non-shockable rhythms, there are limited alternative interventions in most cases and chances of survival decrease rapidly over time. Therefore, we recommend provision of epinephrine as soon as feasible. Exceptions may exist where a clear reversible cause can be rapidly addressed.

For shockable rhythms, the studies evaluating administration of epinephrine included protocols for provision after the third defibrillation. Therefore, the optimal timing for epinephrine in relation to defibrillations remains unknown at this time but we suggest administering epinephrine after initial defibrillation attempts have been unsuccessful.

In-hospital cardiopulmonary resuscitation:

There was no direct evidence on the use of epinephrine compared to placebo for in-hospital cardiopulmonary resuscitation. There was no statistical benefit or harm from the administration of vasopressin either instead of or in addition to epinephrine for in-hospital cardiopulmonary resuscitation.

Other comparators:

There were two randomized trials found comparing norepinephrine to epinephrine (Lindner 1991 427; Callaham 1992 2667) and one trial that compared phenylephrine to epinephrine {Silvast 1985 610} during cardiac arrest. No new trials were found evaluating these comparisons in the past twenty five years. Due to the lack of any recent data on this comparison, and as the above studies were all neutral, the treatment recommendations do not address norepinephrine or phenylephrine.

Knowledge Gaps

  • There were no RCTs identified on the optimal timing of epinephrine administration in relationship to defibrillations
  • There were no RCTs identified on the optimal dosing interval for epinephrine
  • There were no RCTs identified on the optimal dosage of epinephrine for individual patients
  • In spite of large RCTs, uncertainty regarding the impact of epinephrine on favourable or unfavourable neurological outcome remains
  • There were no RCTs identified evaluating epinephrine for in-hospital cardiac arrest
  • There were no studies identified on the cost-effectiveness of epinephrine
  • There were no studies identified on the effect of increased ROSC on organ donation

Evidence to Decision Tables

Vasopressors during cardiac arrest – epinephrine compared to placebo

Vasopressors during cardiac arrest - vasopressin or vasopressin plus epinephrine compared to epinephrine

References

Callaway CW, Hostler D, Doshi AA, Pinchalk M, Roth RN, Lubin J, Newman DH, Kelly LJ. Usefulness of vasopressin administered with epinephrine during out-of-hospital cardiac arrest. AJC. 2006;98(10):1316–21.

Ducros L, Vicaut E, Soleil C, Le Guen M, Gueye P, Poussant T, Mebazaa A, Payan D, Plaisance P. Effect of the addition of vasopressin or vasopressin plus nitroglycerin to epinephrine on arterial blood pressure during cardiopulmonary resuscitation in humans. Journal of Emergency Medicine. 2011;41(5):453–9.

Gueugniaud P-Y, David J-S, Chanzy E, Hubert H, Dubien P-Y, Mauriaucourt P, Braganca C, Billeres X, Clotteau-Lambert M, Fuster P, Thiercelin D, Debaty G, Ricard-Hibon A, Roux P, Espesson C, Querellou E, Ducros L, Ecollan P, Halbout L, Savary D, Guillaumee F, Maupoint R, Capelle P, Bracq C, Dreyfus P, Nouguier P, Gache A, Meurisse C, Boulanger B, Lae C, Metzger J, Raphael V, Beruben A, Wenzel V, Guinhouya C, Vilhelm C, Marret E Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008;359(1):21–30.

Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation. 2011;82(9):1138–43.

Lindner KH, Dirks B, Strohmenger HU, Prengel AW, Lindner IM, Lurie KG. Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation. The Lancet. 1997;349(9051):535–7.

Mukoyama T, Kinoshita K, Nagao K, Tanjoh K. Reduced effectiveness of vasopressin in repeated doses for patients undergoing prolonged cardiopulmonary resuscitation. Resuscitation. 2009;80(7):755–61.

Perkins GD, Ji C, Deakin CD, Quinn T, Nolan JP, Scomparin C, Regan S, Long J, Slowther A, Pocock H,

Black JJM, Moore F, Fothergill RT, Rees N, O’Shea L, Docherty M, Gunson I, Han K, Charlton K, Finn J,

Petrou S, Stallard N, Gates S, Lall R, for the PARAMEDIC2 Collaborators. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):711–21.

Stiell IG, Hebert PC, Wells GA, Vandemheen KL, Tang AS, Higginson LA, Dreyer JF, Clement C, Battram E, Watpool I, Mason S, Klassen T, Weitzman BN. Vasopressin versus epinephrine for in-hospital cardiac arrest: a randomised controlled trial. The Lancet. 2001;358(9276):105–9.

Wenzel V, Krismer AC, Arntz HR, Sitter H, Stadlbauer KH, Lindner KH, for the European Resuscitation Council Vasopressor during Cardiopulmonary Resuscitation Study Group. A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation. N Engl J Med. 2004;350(2):105–13.

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Discussion

profile avatar
ILCOR staff
Bob Neumar and Gavin Perkins will be discussing the CoSTR at SMACC 2019 in Sydney from 25-29 March (#SMACC) Looking forwards to a lively debate and some great discussion on this forum!
Reply
Jasmeet Soar (7 posts)
The ALS Task Force look forward to feedback on the review of the science and treatment recommendations for vasopressors during CPR. These Treatment Recommendations will help inform national resuscitation guidelines around the world. Jasmeet Soar - ILCOR ALS Task Force Chair
Reply
GUEST
Rory Spiegel (102 posts)
The ILCOR treatment recommendations concerning vasopressors in cardiac arrest call for the administration of epinephrine during cardiopulmonary resuscitation This is designated as a strong recommendation with low to moderate certainty of evidence. The authors justify this recommendation stating, “the findings that epinephrine compared with placebo substantially improves ROSC, and also improves hospital admission and survival. The task force made a strong recommendation given that the intervention may reduce mortality in a life-threatening situation and adverse events are not prohibitive.” In their literature review, the authors discuss Perkins et al (1), the major RCT examining the use of bolus-dose epinephrine in cardiac arrest. They note Perkins et al demonstrated a statistically significant difference in 30-day survival (3.2% vs 2.4% unadjusted odds ratio for survival 1.39; 95% confidence interval 1.06 to 1.82; P=.02), when the use of bolus dose epinephrine was compared to placebo. Perkins et al also reported an increase in the number of patients who were transported to the hospital (50.8% vs 30.7%) and survived to ICU admission (14.1% vs 6.8%). Despite a small increase in overall survival, there was no difference in the rate of neurologically intact survival in patients randomized to receive epinephrine versus placebo. When writing the ILCOR recommendations, the authors state they balanced the potential benefits and harms associated with the use of bolus-dose epinephrine in cardiac arrest. Despite this assertion, Perkins et al demonstrates a clear signal of harm not discussed by the authors. In this case we are asked to weigh a 0.8% increase in survival to hospital discharge with the harms associated with its use. The harms come in the form of a significant increase in the risk of survival with neurologic devastation. Although more patients who received epinephrine were transported to the hospital (50.8% vs 30.7%) and survived to ICU admission (14.1% vs 6.8%), 31% of the survivors in the epinephrine group had a modified Rankin Scale score of 4 or 5 (unable to walk or bedridden), compared with 17% in the placebo group. These results suggest the use of bolus-dose epinephrine does not result in a larger number of neurologically intact survivors. Rather it shifts a small number of patients from death to a state of neurological devastation. This is not a small price. Imagine the increase in societal resources required to care for the large increase in the number of patients transported to the hospital alive, the moderate increase in the number of patients that survive to ICU admission, and the few neurologically devastated patients requiring long-term care. All with no increase in clinically meaningful neurologically intact survival. Sources Cited: Perkins GD, Ji C, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N. July 2018. doi:10.1056/nejmoa1806842
Reply
GUEST
Tom Evans (102 posts)
I find Rory Spiegel's arguments against the use of epinephrine in cardiac arrest very persuasive. A minimal number of extra survivors at a very high price in terms of the neurologically impaired ones, who will suffer themselves, cause suffering to their relatives and consume a lot of expensive health care resources in the long term. ROSC is only the first step in successful resuscitation. The goal is a neurologically or "nearly neurological " intact survivor. Remember Peter Safar's writings on "Cardiopulmonary - Cerebral Resuscitation". I would respectfully ask the committee to review the evidence again and reconsider their recommendations,which will have an impact over the next 5 years.If epinephrine was a new drug - would it be recommended.
Reply
GUEST
Tim Noonan (102 posts)
The primary source for the recommendation to keep things the same is a brand new study - PARAMEDIC2. This showed no statistically significant improvement in the only outcome that matter - survival without severe brain damage. A larger study might show that there is a real improvement - or it may put the epi hypothesis out of its misery. I will eventually have a cardiac arrest. If I am resuscitated, whom will ILCOR send to change my diaper, and attend to the other things I can no longer attend to? We need evidence of a significant benefit in order to justify distracting everyone from interventions that actually do improve survival without severe brain damage. .
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GUEST
Anne Beaudoin (102 posts)
I am not a researcher. I am a retired paediatrician and the mother of a CPR survivor. I have just published a book about my son's incredible journey and I would like to share it with you. I hope this testimony can contribute positively to the field of cardiopulmonary resuscitation. I will try to give you the link; but in case I don't succeed, please take note that the book is available at Amazon under the title “Why was I resuscitated?” , by Anne Beaudoin. Here is the link: https://www.amazon.ca/dp/298169684X/ref=cm_sw_em_r_mt_dp_U_YUIOCb2WPVNF3
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GUEST
Hugh Montgomery (102 posts)
I am not convinced that epinephrine should be routinely administered. There are cost implications to the use of the drug itself. There are huge costs (fiscal and suffering, for healthcare systems/ relatives/ patients) implications to caring for people with poor neurological outcome even to hospital discharge, and beyond. I doubt that this cost is worthwhile given the few who may survive with good neuro-outcome. I am not sure that the suffering faced by those who do badly can be traded for the good outcome for others.
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GUEST
PARAMEDIC2 Investigators (102 posts)
Conflicts of interest: Grants
We thank ILCOR and the ALS Task Force for inviting comment on the draft consensus on science and treatment recommendations on the use of vasopressors for cardiac arrest. As authors of the PARAMEDIC2 study[1] we wish to share the following insights. The Core Outcome Set for Cardiac Arrest (COSCA)[2] highlights the difficulty of identifying the optimal time for measuring neurological outcomes after cardiac arrest. Assessment at hospital discharge has the advantage of ease of data collection but does not allow sufficient time for any functional recovery to occur over the months ahead. Follow-up at 3 to 12 months may provide a more stable assessment of long term outcomes, but is limited by loss to follow-up. This increases the risk of attrition bias as those with worse outcomes are more likely to be lost to follow-up.[3, 4] In PARAMEDIC2, loss to follow-up amongst survivors at hospital discharge was 5 (4%) in the placebo group and 8 (6%) in the adrenaline group. By 3 months this had increased to 20 (23%) in the placebo and 29 (24%) in the adrenaline group. Sensitivity analyses exploring the different possible reasons for loss to follow-up are contained in the electronic supplemental material presented with the main paper. Our assessment of the PARAMEDIC2 data on longer term outcomes is that adrenaline increases survival with both good and poor neurological outcomes. The overall effect is small (0.8% absolute difference in survival). Resource use is high – extrapolating PARAMEDIC2 data across the UK National Health Service, the use of adrenaline in out of hospital cardiac arrest contributes to 3555 additional hospital admissions each year (1643 ITU admissions, for 5143 ICU days) for 68 additional survivors with a favourable neurological outcome and 135 with an unfavourable neurological outcome at hospital discharge. We suggest the cost to health care systems should be highlighted in the undesirable effects section of the evidence to decision framework. The balance of survival, survival with a favourable neurological outcome and survival with an unfavourable neurological outcome will mean different things to different people and will likely vary between communities. We suggest it should be noted in the evidence to decision tables that societal values and preferences may vary and should inform the treatment recommendations in different settings. Furthermore, our lack of knowledge about patient and public preferences for outcomes should be specifically identified as a knowledge gap. The presence of resuscitation time bias[5] limits the interpretation of observational studies which seek to evaluate the influence of time to treatment. Our preliminary analyses of time to treatment in PARAMEDIC2, support the recommendation, that if adrenaline is going to be given, it is better given as soon as possible. We did not find evidence of an interaction favouring early administration by shockable or non-shockable rhythms, but note the difficulty in interpretation of the shockable rhythm data (as some patients will convert to a non-shockable rhythm after the first attempt at defibrillation). In the PARAMEDIC2 trial, treatment protocols recommended deferring adrenaline until after the third attempt at defibrillation for patients with shockable rhythms.[6, 7] The findings for the ILCOR review and consensus on science is broadly similar to our Cochrane review of vasopressors for cardiac arrest.[8] Small differences are noted which appear to relate to whether a random effects or fixed effects Mantel-Haenszel meta-analysis was performed. These differences do not materially affect interpretation. Data on adjusted analyses are presented in both the PARAMEDIC2[1] and PACA[9] trial publications should the Task Force wish to use these in the meta-analysis as has been performed in other ILCOR consensus on science reviews. Finally, we believe the PARAMEDIC2 trial highlights the importance of the community response to cardiac arrest (early access (NNT 11), early bystander CPR (NNT 15), early defibrillation(NNT 5). PARAMEDIC2 and this ILCOR review draws attention to the gap in our knowledge around treatments that can enhance neurological recovery after cardiac arrest. It highlights the urgent need for further research to ensure both successful cardio and cerebral recovery. PARAMEDIC2 investigators https://warwick.ac.uk/paramedic2/ Clinical Trial Registration: ISRCTN73485024 This project was funded by the NIHR HTA Programme (ref 12/127/126). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. References 1. Perkins GD, Ji C, Deakin CD, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med 2018;379(8):711-21. doi: 10.1056/NEJMoa1806842 [published Online First: 2018/07/19] 2. Haywood K, Whitehead L, Nadkarni VM, et al. COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation. Resuscitation 2018;127:147-63. doi: 10.1016/j.resuscitation.2018.03.022 [published Online First: 2018/05/01] 3. Nichol G, Guffey D, Stiell IG, et al. Post-discharge outcomes after resuscitation from out-of-hospital cardiac arrest: A ROC PRIMED substudy. Resuscitation 2015;93:74-81. doi: 10.1016/j.resuscitation.2015.05.011 4. Ji C, Lall R, Quinn T, et al. Post-admission outcomes of participants in the PARAMEDIC trial: A cluster randomised trial of mechanical or manual chest compressions. Resuscitation 2017;118:82-88. doi: 10.1016/j.resuscitation.2017.06.026 [published Online First: 2017/07/10] 5. Andersen LW, Grossestreuer AV, Donnino MW. "Resuscitation time bias"-A unique challenge for observational cardiac arrest research. Resuscitation 2018;125:79-82. doi: 10.1016/j.resuscitation.2018.02.006 [published Online First: 2018/02/10] 6. Soar J, Nolan JP, Bottiger BW, et al. European Resuscitation Council Guidelines for Resuscitation 2015: Section 3. Adult advanced life support. Resuscitation 2015;95:100-47. doi: 10.1016/j.resuscitation.2015.07.016 7. Soar J, Deakin C, Lockey A, et al. Adult advanced life support. 2015. https://www.resus.org.uk/resuscitation-guidelines/adult-advanced-life-support/. 8. Finn J, Jacobs I, Williams TA, et al. Adrenaline and vasopressin for cardiac arrest. Cochrane Database Syst Rev 2019;1:CD003179. doi: 10.1002/14651858.CD003179.pub2 [published Online First: 2019/01/18] 9. Jacobs IG, Finn JC, Jelinek GA, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial. Resuscitation 2011;82(9):1138-43. doi: S0300-9572(11)00405-9 [pii] 10.1016/j.resuscitation.2011.06.029 [published Online First: 2011/07/13]
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Jasmeet Soar (7 posts)
Conflicts of interest: Consulting
Thank-you for your feedback. I will discuss and consider all your comments with my colleagues on the ILCOR ALS Task Force and post a response in the next few weeks. Regards, Jas. Jasmeet Soar ALS Task Force Chair
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