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
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