Use of Vasopressin and Corticosteroids during Cardiac Arrest

Conflict of Interest Declaration

The ILCOR Scientific Advisory Committee process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: Not applicable.

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: MJ. Holmberg, A. Granfeldt, and LW. Andersen (authors of both the systematic review used for the adolopment and one of the papers included in that systematic review).

CoSTR Citation

Nicholson TC, Couper K, Drennan I, Andersen LW, Garg R, Granfeldt A, Hirsch K, Holmberg MJ, Hsu C, Kudenchuk P, Nolan J, Ohshimo S, Reynolds J, Sandroni C, Skrifvars M, Soar J, Zelop C, Lavonas EJ, Morley P, and Berg KM, on behalf of the International Liaison Committee on Resuscitation Advanced Life Support Task Force. Use of Vasopressin and Corticosteroids during Cardiac Arrest in Adults: Consensus on Science with Treatment Recommendations, Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, Feb 2022. Available from: http://ilcor.org

Methodological Preamble (and if relevant, Link to Published Systematic Review)

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a detailed review of a recently published systematic review.¹ Two task force members independently assessed the overall confidence in the review results using the AMSTAR (A MeaSurement Tool to Assess systematic Reviews)-2 tool, which records overall confidence in a review as being critically low, low, moderate, or high. ² (Shea 2017 j4008). The task force member rated the overall confidence in the review as moderate, which reflects that there were one or more non-critical weaknesses, namely a lack of discussion about publication bias and important intellectual conflicts of interest, without a description of how these were managed.

As the systematic review was recent and of sufficient quality, an updated search was not deemed necessary and the TF deemed it appropriate to use the adolopment process for systematic reviews. As the review authors had led the index studies, two task force members independently assessed risk of bias of the review’s index studies using the Cochrane collaboration risk of bias (RoB 2) tool (Sterne 2009 l4898). Task force members extracted health-related quality of life from index studies as this outcome was viewed as of critical importance. The totality of this identified evidence was considered by the Advanced Life Support task force, and used to create evidence profile tables. These data were then used to formulate the Consensus on Science and Treatment Recommendations.

PICOST

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

Population: Adults who have cardiac arrest in any setting (in-hospital or out-of-hospital)

Intervention: Administration of vasopressin and corticosteroids during CPR

Comparators: Not using vasopressin and corticosteroids during CPR

Outcomes: Health-related quality of life;

Survival with favourable neurological outcome at discharge, 30, 60, 90 or 180 days AND/OR 1 year;

Survival only at discharge, 30, 60, 90 or 180 days AND/OR 1 year;

ROSC.

Study Designs: Randomized controlled trials (RCTs) were eligible for inclusion. Observational studies and unpublished studies (e.g., conference abstracts, trial protocols) were excluded.

Timeframe: All years and all languages were included as long as there was an English abstract.

Consensus on Science

In-hospital cardiac arrest

For the critical outcome of Health Related Quality of Life at 90-days measured by the EuroQol 5 Dimension 5 Level (EQ-5D-5L) tool, we identified:

• For the EQ-5D-5L visual analogue scale, moderate-certainty evidence (downgraded for imprecision) from one randomized controlled trial ⁵ of 501 patients (data available for the 44 who survived to 90 days), which showed no statistically significant difference from the intervention when compared with standard care (mean difference 1, 95% confidence interval -9 to 11).
• For the EQ-5D-5L health utility index, moderate-certainty evidence (downgraded for imprecision) from one randomized controlled trial ⁵ of 501 patients (data available for the 44 who survived to 90 days) which showed no statistically significant difference from the intervention when compared with standard care (mean difference -3, 95% confidence interval -20 to 14).

For the critical outcome of survival to discharge with favourable neurological outcome (CPC score of 1 or 2), there was low-certainty evidence (downgraded for inconsistency and imprecision) from three randomized controlled trials ^3,4,5 involving 869 patients that showed no statistically significant difference from the intervention when compared with standard care (OR 1.64, 95% CI 0.99 to 2.72; 37 more per 1,000 surviving with good neurological outcome, 95% CI from 1 fewer to 93 more).

For the critical outcome of survival to discharge, there was low-certainty evidence (downgraded for inconsistency and imprecision) from three randomized controlled trials^3,4,5 involving 869 patients that showed no statistically significant difference from the intervention when compared with standard care (OR 1.39, 95% CI 0.90 to 2.14; 34 more per 1,000 surviving to discharge, 95% CI from 9 fewer to 91 more).

For the important outcome of ROSC, there was moderate-certainty evidence (downgraded for inconsistency) from three randomized controlled trials ^3,4,5 involving 869 patients that showed a statistically significant difference between the intervention and standard care (OR 2.09, 95% CI 1.54 to 2.84; 181 more per 1,000 with ROSC, 95% CI from 108 more to 249 more).

Out-of-hospital cardiac arrest

We did not find any evidence specific to out-of-hospital cardiac arrest.

For the critical outcome of Health-Related Quality of Life at 90-days measured by the EuroQol 5 Dimension 5 Level (EQ-5D-5L) tool, we identified:

• For the EQ-5D-5L visual analogue scale, low-certainty evidence (downgraded for imprecision and indirectness) from one randomized controlled trial⁵ of 501 patients (data available for the 44 who survived to 90 days), which showed no statistically significant difference from the intervention when compared with standard care (mean difference 1, 95% confidence interval -9 to 11).
• For the EQ-5D-5L health utility index, low-certainty evidence (downgraded for imprecision and indirectness) from one randomized controlled trial⁵ of 501 patients (data available for the 44 who survived to 90 days), which showed no statistically significant difference from the intervention when compared with standard care (mean difference -3, 95% confidence interval -20 to 14).

For the critical outcome of survival to discharge with favourable neurological outcome (CPC score of 1 or 2), there was very low-certainty evidence (downgraded for inconsistency, indirectness and imprecision) from three randomized controlled trials ^3,4,5 involving 869 patients that showed no statistically significant difference from the intervention when compared with standard care (OR 1.64, 95% CI 0.99 to 2.72; 37 more per 1,000 surviving with good neurological outcome, 95% CI from 1 fewer to 93 more).

For the critical outcome of survival to discharge, there was very low-certainty evidence (downgraded for inconsistency, indirectness and imprecision) from three randomized controlled trials^3,4,5 involving 869 patients that showed no statistically significant difference from the intervention when compared with standard care (OR 1.39, 95% CI 0.90 to 2.14; 34 more per 1,000 surviving to discharge, 95% CI from 9 fewer to 91 more).

For the important outcome of ROSC, there was low-certainty evidence (downgraded for inconsistency and indirectness) from three randomized controlled trials ^3,4,5 involving 869 patients that showed statistically significant difference between the intervention and standard care (OR 2.09, 95% CI 1.54 to 2.84; 181 more per 1,000 with ROSC, 95% CI from 108 more to 249 more).

Treatment Recommendations

IHCA:

We suggest against the use of the combination of vasopressin and corticosteroids in addition to usual care for adult in-hospital cardiac arrest, due to low confidence in effect estimates for critical outcomes. (weak recommendation, low to moderate-certainty evidence)

OHCA

We suggest against the use of the combination of vasopressin and corticosteroids in addition to usual care for adult out-of-hospital cardiac arrest (weak recommendation, very low to low-certainty evidence).

Justification and Evidence to Decision Framework Highlights

This topic was prioritized by the ALS Task Force for consideration following the publication of a recent randomized controlled trial (Andersen 2021, 1586)⁵, and a subsequent systematic review with individual patient data meta-analysis, which was identified as suitable for adolopment (Holmberg et al, 2021)¹

In making these recommendations, the ALS Task Force considered the following:

• We noted that the intervention (vasopressin and corticosteroids) given intra-arrest improved ROSC, but this did not clearly translate into an effect on other outcomes (survival, survival with favorable neurological outcome, health-related quality of life).
• We noted of the three published randomized controlled trials, two were conducted in Greece across a small number of centres (one centre - Mentzelopoulos 2009, 15; three centres - Mentzelopoulos 2013, 270). The third was conducted in Denmark across ten hospitals (Andersen 2021, 1586).
• In all studies, the combination of vasopressin and corticosteroids was administered in addition to standard intra-arrest treatments, including adrenaline and defibrillation.
• We noted that the earlier two studies (Mentzelopoulos 2009, 15, Mentzelopoulos 2013, 270) reported improvements in outcomes beyond ROSC (e.g. survival, survival with good neurological outcome), but these effects were not observed in the latest study (Andersen 2021, 1586). The earlier two studies also included post-ROSC corticosteroids, in addition to the intra-arrest vasopressin and steroids, which was not the case in the more recent study. The earlier two studies were considered by the ILCOR ALS task force in 2015 (Soar 2015, 100) and it was determined that the studies were not sufficiently generalizable (e.g. rate of asystolic cardiac arrest, baseline survival rate) for the task force to make a treatment recommendation supporting the use of the combination of vasopressin and corticosteroids.
• We noted differences across studies, including patient location, initial rhythm, drug regimen, and time to study drug administration.
• We noted that the incorporation of these drugs into ALS treatment would present practical challenges since the addition of new drugs would add complexity to current treatment protocols. This would particularly be the case in out-of-hospital settings and systems where corticosteroids are only available in powdered form, requiring reconstitution prior to use.
• Time to drug administration may influence the effect of the intervention- time to drug administration was longer in the trial where this was led by the cardiac arrest team (Andersen 2021, 1586), rather than dedicated research staff (Mentzelopoulos 2009, 15;

Mentzelopoulos 2013, 270). We observed that the more recent trial would better reflect how the intervention would be implemented in clinical practice. Time to drug administration would likely be markedly longer in the pre-hospital setting.

• We discussed the potential interaction between vasopressin and corticosteroids, and current uncertainty as to whether either drug alone or the combination was driving the observed effect on ROSC.
• We discussed the potential value of an improvement in ROSC where there was no observed effect on longer-term outcomes. Obtaining ROSC is an essential step in the pathway to overall survival, but even in patients who do not survive, it might be viewed as positive as it may provide an opportunity for organ donation or for the patient's relatives to spend time with

them while they are alive. However, where there is no effect on longer-term outcomes, this may increase burden on the healthcare system (particularly ICU beds), which will be a particular challenge in systems where there is limited ICU capacity. We discussed the fact that the TF does suggest some other interventions without a clear survival benefit (e.g. amiodarone or lidocaine for refractory shockable rhythm). Those drugs did appear to have a survival benefit in some subgroups (ie witnessed arrest), which was not the clearly the case for vasopressin and steroids.

• We did not identify any RCTs for out-of-hospital cardiac arrest.
• We did not identify studies of cost-effectiveness, but noted that vasopressin is a relatively expensive drug.

Knowledge Gaps

There is a need for further trials of the use of vasopressin and corticosteroids in cardiac arrest, both in the in-hospital and out-of-hospital setting. These trials should be adequately powered to detect a difference in a critical outcome, such as survival or survival with favorable neurological outcome at 30-days. The trial should ensure that drugs are administered in a way that reflects normal clinical practice (i.e. by a cardiac arrest team) and carefully consider the optimum corticosteroid regimen (e.g. post-arrest administration of corticosteroids).

A trial that sought to identify the specific effects of vasopressin, corticosteroids, and the combination of vasopressin and corticosteroids through a factorial design may be informative.

Attachments

ALS Steroids Vaso Et D IHCA; ALS Steroids Vaso Et D OHCA

References

1. Holmberg MJ, Grandfeldt A, Mentzelopoulos SD, and Andersen LW, 2021. Vasopressin and Glucocorticoids for in-Hospital Cardiac arrest: A Systematic Review and Meta-Analysis of Individual Participant Data. Resuscitation; 2021. Doi:10.1016/j.resuscitation.2021.12.030

2. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, Moher D, Tugwell P, Welch V, Kristjansson E, Henry DA. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. bmj. 2017 Sep 21;358.

3. Mentzelopoulos SD, Zakynthinos SG,Tzoufi M,Katsios N,Papastylianou A,Gkisioti S,Stathopoulos A,Kollintza A,Stamataki E,Roussos C. Vasopressin, Epinephrine and Corticosteroids for In-Hospital Cardiac Arrest. Arch Intern Med. 2009;169(1):15-24. Doi:10.1001/archinternmed.2008.509

4. Mentzelopoulos SD, Malachias S, Chamos C, Konstantopoulos D, Ntaidou T,et al. Vasopressin, steroids, and epinephrine and neurologically favourable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA; 2013; 310(3) :270-279. Doi: 10.1001/jama2013.7832

5. Andersen LW, Isbye D, Kjærgaard J, Kristensen CM, Darling S et al.. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial. JAMA; 2021. Doi:10.1001/jama.2021.16628