Critical Care Alert: Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest

ARTICLE
Andersen LW, Isbye D, Kjærgaard J, 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 Sep 29;e2116628.

OBJECTIVE
To examine whether vasopressin and methylprednisolone given during in-hospital cardiac arrest (in conjunction with standard ACLS protocols) affected the likelihood of return of spontaneous circulation (ROSC).

BACKGROUND
The traditional approach towards in-hospital cardiac arrest has focused on early recognition, high-quality CPR, advanced life support (eg, defibrillation and medications), identification and treatment of reversible causes, and subsequent post-cardiac arrest care. Drugs used currently for in-hospital cardiac arrest arrests are epinephrine and amiodarone or lidocaine. However, questions remain about the role of other pharmacologic adjuncts such as vasopressin and glucocorticoids. Vasopressin (also known as antidiuretic hormone) results in vasoconstriction and has been shown to be an effective second-line agent in septic shock. Likewise, this effect may also be beneficial in cardiac arrest because the increase in blood pressure may increase coronary perfusion pressure and thereby increase the likelihood of ROSC. Prior trials examining vasopressin in cardiac arrest, however, have not demonstrated improved overall rates of sustained ROSC, long-term survival, or favorable neurological outcome.¹

Corticosteroids have beneficial hemodynamic and anti-inflammatory effects and are often used in the setting of septic shock due to reduced vasopressor requirements. Like vasopressin, there may be some potential to their use during CPR and in the early post-resuscitation period. For instance, studies in patients with cardiac arrest have demonstrated that levels of cortisol are higher in patients who were resuscitated when compared with those who died, illustrating a possible impaired endocrine response in nonsurvivors. Studies on their effectiveness during cardiac arrest are limited and have also shown conflicting results.⁴

Mentzelopoulos et al. have previously explored the use of vasopressin and methylprednisolone during in-hospital cardiac arrest in two smaller trials (348 patients in total) and demonstrated improved survival to hospital discharge with favorable neurological status.^2,3 This study by Andersen et al. looks to build upon this data, and further explore the potential role of vasopressin and glucocorticoids in achieving ROSC for patients with in-hospital cardiac arrest.

DESIGN
Multicenter, randomized, double-blind, placebo-controlled trial conducted at 10 hospitals in Denmark, including 4 large university hospitals. A total of 512 patients with in-hospital cardiac arrest were initially included (from 10/15/2018 - 1/21/2021) with 501 meeting final inclusion/exclusion criteria. 

• Trial Arm: 40 mg of methylprednisolone (Solu-Medrol, Pfizer) and 20 IU of vasopressin (Empressin, Amomed Pharma GmbH) as soon as possible after the first dose of epinephrine, and additional doses of 20 IU vasopressin with each subsequent dose of epinephrine for a maximum of 4 doses (80 IU total).
• Placebo Arm: received 9 mg/mL of sodium chloride (from identical vials) in place of vasopressin/methylprednisolone from pre-packaged, blinded study kits.

INCLUSION CRITERIA 

• Adults ≥18 years with in-hospital cardiac arrest
• Received at least 1 dose of epinephrine during cardiac arrest

EXCLUSION CRITERIA

• Cardiac arrest occurring outside the hospital
• Documented DNR order prior to the cardiac arrest
• Prior trial enrollment
• Invasive mechanical circulatory support (ECMO, LVAD, etc.) at the time of the cardiac arrest
• Known or suspected pregnancy at the time of the cardiac arrest
• Other unplanned logistical factors leading to exclusion from study data included insufficient personnel, lack of available study drug, inability to obtain surrogate consent and patients isolated with COVID-19

PRIMARY OUTCOME
Return of spontaneous circulation with no need for further chest compressions for at least 20 min

SECONDARY OUTCOMES

• Survival at 30 days
• Survival at 30 days with favorable neurologic outcome (assessed by Cerebral Performance Score of 1-2 out of 5)

TERTIARY OUTCOMES

• Neurologic outcome (using modified Rankin Scale and Glasgow Outcome Scale Extended) at days 30, 90, 180 and 1 year
• Health-related quality of life (using EuroQol 5 Dimension 5 Level) at days 30, 90, 180, and 1 year
• Sequential Organ Failure Assessment (SOFA) Score at hours 24, 48, and 72 after cardiac arrest
• Vasopressor and ventilator-free days within first 14 days after cardiac arrest
• Hospital disposition
• Adverse events including hyperglycemia, hypernatremia, infections (bacteremia, pneumonia, UTIs), GI bleeding, mesenteric and peripheral ischemia
• Adverse events including hyperglycemia, hypernatremia, infections (bacteremia, pneumonia, UTIs), GI bleeding, mesenteric and peripheral ischemia

KEY RESULTS

PRIMARY OUTCOME
Of the 501 patients analyzed, 100 patients (42%) in the vasopressin/methylprednisolone group and 86 patients (33%) in the placebo group achieved ROSC (risk ratio 1.30 [95% CI, 1.03-1.63]; risk difference, 9.6% [95% CI, 1.1%-18.0%]; P = .03).        

SECONDARY OUTCOMES
Of the 186 patients who achieved ROSC, 54 survived to 30 days, 23 patients (9.7%) in the vasopressin/methylprednisolone group and 31 patients (12%) in the placebo group, (risk ratio, 0.83 [95% CI, 0.50-1.37]; risk difference, −2.0% [95% CI, −7.5% to 3.5%]; P = .48)

A favorable neurologic outcome (based on the Cerebral Performance Category score of 1 or 2) was observed in 18 patients (7.6%) in the vasopressin/methylprednisolone group and 20 patients (7.6%) in the placebo group at 30 days (risk ratio, 1.00 [95% CI, 0.55-1.83]; risk difference, 0.0% [95% CI, −4.7% to 4.9%]; P > .99).

TERTIARY OUTCOMES
A favorable neurologic outcome at 30 days (based on the modified Rankin Scale score) was observed in 11 patients (4.6%) in the intervention group and 19 patients (7.2%) in the placebo group (risk ratio, 0.64 [95% CI, 0.32-1.31]; risk difference, −2.6% [95% CI, −6.9% to 1.7%]).

Neurologic outcome (as assessed by Rankin score), quality of life (as assessed by EuroQol 5 Dimension 5 Level) at 30 and 90 days, post–cardiac arrest organ dysfunction (as assessed by SOFA score), the number of vasopressor and ventilator-free days, and adverse events did not differ significantly between groups. 

STRENGTHS                                                                                    

• The largest randomized, double-blinded, placebo-controlled trial to date to examine the effects of vasopressin and methylprednisolone on in-hospital cardiac arrest care
• Multi-center and included hospitals of various sizes
• Included secondary, longer-term data on quality of life and neurologic outcome, with no loss to follow up

LIMITATIONS

• Prior studies by Mentzelopolous et al.^2,3 have also included protocols for treatment of post-resuscitation shock with stress dose steroids, potentially impacting the comparison of overall survival and other longer-term metrics.
• The median time from cardiac arrest to epinephrine and trial drug administration was 5 min and 8 min, respectively, and the speed with which vasopressin/methylprednisolone were given may have impacted outcome. The risk difference for patients who received trial drugs vs placebo ≤8 minutes after arrest was 16% [95% CI 3.7-28].
• Dosing was also fixed for all patients, and not based on weight. Future studies could explore ideal dosing strategies.
• 1055 patients of the 2362 screened were excluded from the study for reasons other than the preset inclusion/exclusion criteria (including logistical issues and early termination of resuscitation), which may negatively impact generalizability.
• Average age of patients included was 70, also possibly limiting generalizability
• Given the much lower proportion of patients with survival and favorable neurologic outcome, the trial was inadequately powered to assess these outcomes.
• Outcomes for cardiac arrest in Denmark are generally favorable, and perhaps not generalizable to all practice settings
• Prior studies have suggested that vasopressin/methylprednisolone may be most effective in achieving ROSC in asystolic arrest.² More adequately powered studies exploring the difference between initial arrest rhythm may be useful.

EM TAKE-AWAYS

In patients with in-hospital cardiac arrest, the addition of vasopressin and methylprednisolone led to a statistically significant increase in the likelihood of ROSC as compared with placebo.  However, unlike in prior smaller-scale studies, this trial did not demonstrate statistically significant differences in long-term survival or survival with favorable neurologic outcome. As such, routine use of vasopressin/methylprednisolone during in-hospital cardiac arrest cannot yet be recommended. Future analyses on this topic should explore ideal patient populations, cardiac arrest attributes and dosing strategies to provide more generalizability.

References

1. Mentzelopoulos SD, Zakynthinos SG, Siempos I, Malachias S, Ulmer H, Wenzel V. Vasopressin for cardiac arrest: meta-analysis of randomized controlled trials. Resuscitation. 2012;83(1):32-39.
2. Mentzelopoulos SD,Zakynthinos SG,Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009;169(1):15-24.
3. Mentzelopoulos SD,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):270-279.
4. Varvarousi G, Stefaniotou A, Varvaroussis D, Xanthos T. Glucocorticoids as an emerging pharmacologic agent for cardiopulmonary resuscitation. Cardiovasc Drugs Ther. 2014;28(5): 477-488.