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Date: November 10th, 2021

Reference: Andersen, et al: Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest. JAMA Sept 2021.

Guest Skeptic: Dr. Neil Dasgupta is an emergency physician and ED intensivist from Long Island, NY, and currently an assistant clinical professor and Director of Emergency Critical Care at Nassau University Medical Center.

Case: A code blue is called for a 71-year-old male in-patient that is boarding in the emergency department (ED). He had been admitted the night before for a new diagnosis of rapid atrial fibrillation. He has a history of hypertension, dyslipidemia, and type-2 diabetes. His medications include a beta-blocker, statin, angiotensin converting enzyme inhibitor (ACE-I), metformin, ASA and direct oral anticoagulant (DOAC). You arrive and see that the Advanced Cardiac Life Support (ACLS) algorithm is being followed for adult cardiac arrest patients with pulseless electrical activity (PEA). Cardiopulmonary resuscitation (CPR) is in progress. The monitor shows a non-shockable rhythm. Epinephrine is provided and you quickly place an advanced airway. A second dose of epinephrine is given, and you start to think about reversible causes and your next steps for in-hospital cardiac arrests (IHCA).

SGEM#50: Under Pressure

Background: We have looked an IHCA a couple of times on the SGEM. The first time we looked at this issue on (SGEM#50). This was also the first SGEM JC done where Dr. William Osler started the Journal Club initiative at McGill University. We reviewed a randomized, double-blind, placebo-controlled, parallel-group trial done in three Greek tertiary hospitals. This trial (n=268) reported increased return of spontaneous circulation (ROSC) and increased survival to hospital discharge with good neurologic function with a vasopressin, steroids, and epinephrine (VSE) protocol compared to epinephrine alone. We felt this was interesting but would need to be validated/replicated before changing our IHCA protocols.

Corticosteroids have been suggested as a possible therapy in these cardiac arrest situations. A SRMA published in 2020 on the use of steroids after cardiac arrest reported an increase in ROSC and survival to discharge but was limited by the availability of adequately powered high-quality RCTs (Liu et al JIMR 2020).

We covered another SRMA that was published in 2021 looking at the same issue of whether the use of corticosteroids impact neurologic outcomes and mortality in patients with a cardiac arrest (SGEM#329)? These authors reported a statistical increase in good neurologic outcome and survival to hospital discharge with steroids but not survival at one year or longer. This study provided weak evidence in support of using corticosteroids for IHCA as part of a VSE protocol.

Answering clinical questions about cardiac arrest with clinical trials has always been fraught with difficulty. However, cardiac arrest is something we regularly treat in the emergency department, and we need more high-quality data to inform our care. Vasopressin had been included as a part of the American Heart Association (AHA) ACLS protocol for quite a while but was removed in favor of a vasopressor monotherapy strategy with epinephrine.  The tide now is shifting in resuscitation research to shift our focus from obtaining ROSC to measuring functionality and good neurologic outcomes.  In the context of questioning epinephrine’s role in ACLS after Paramedic2, we look at using the VSE protocol in cardiac arrest.

Clinical Question: Does adding a combination of vasopressin and methylprednisolone increase the chance of achieving ROSC in cardiac arrest?

Reference: Andersen, et al: Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest. JAMA Sept 2021.

  • Population: Adult patients 18 years of age and older with an in-hospital cardiac arrest.
    • Excluded: Out-of-hospital cardiac arrest (OHCA), valid do-not-resuscitate order, invasive mechanical circulatory support and known or suspected pregnancy at the time of the cardiac arrest.
  • Intervention: Vasopressin 20 IU and methylprednisolone 40 mg given as soon as possible after first dose of epinephrine, followed by vasopressin 20 IU after each epinephrine up to four doses.
  • Comparison: Placebo of normal saline
  • Outcome:
    • Primary Outcome: ROSC defined as no further need of chest compressions for at least 20 minutes
    • Secondary Outcomes: 30-day survival and 30-day survival with favorable neurologic outcome (defined as a Cerebral Performance Category of 1 or 2)
  • Trial Design: Multicenter, single nation, multicenter, randomized, placebo-controlled, parallel group, double-blind, superiority trial

Authors’ Conclusions: “Among patients with in-hospital cardiac arrest, administration of vasopressin and methylprednisolone, compared with placebo, significantly increased the likelihood of return of spontaneous circulation. However, there is uncertainty whether this treatment results in benefit or harm for long-term survival.”

Quality Checklist for Randomized Clinical Trials:

  1. The study population included or focused on those in the emergency department. No
  2. The patients were adequately randomized. Yes
  3. The randomization process was concealed. Yes
  4. The patients were analyzed in the groups to which they were randomized. Yes
  5. The study patients were recruited consecutively (i.e. no selection bias). Yes
  6. The patients in both groups were similar with respect to prognostic factors. Yes
  7. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. Yes
  8. All groups were treated equally except for the intervention. Yes
  9. Follow-up was complete (i.e. at least 80% for both groups). Yes
  10. All patient-important outcomes were considered. Yes
  11. The treatment effect was large enough and precise enough to be clinically significant. No
  12. Was the study without any financial conflicts of interest. No

Results: They recruited and analyzed 501 patients with a mean age of 71 years, 64% were male and 2/3 were on a medical ward.

Key Result: More ROSC was achieved with VSE compared to epinephrine alone, but this did not translate into better long term-survival or with favorable neurologic outcome.

  • Primary Outcome: ROSC
    • 42% intervention group vs 33% in control group. Absolute difference of 9.6% (95% CI, 1.1% to 18.0%). Risk ratio of 1.30 (95% CI, 1.03 to 1.63) p=0.03.
  • Secondary Outcomes:No statistical difference between groups for both key secondary outcomes.
    • Survival at 30 days: 9.7% vs 12%. Absolute difference −2.0% (95% CI, −7.5% to 3.5%) with risk ratio, 0.83 (95% CI, 0.50-1.37); P = 0.48).
    • A favorable neurologic outcome at 30 days: 7.6% vs 7.6% with a risk ratio, 1.00 (95% CI, 0.55 to 1.83); P >0.99

1. ED Patients: These are not ED patients, but they are often emergency physicians’ responsibility. In many hospitals the only in-house physician at certain times is in the ED and will be responding to Code Blues. We need to be cautious not to over-interpret the data and directly apply it to patients who arrive in the ED and have an arrest. This data can help inform and guide our care, but it should not dictate our care.

These might be more like our patients than we think. Digging into the demographics of the included patients they seem like a surprisingly healthy cohort for IHCA. RRT (11% vs 8%), mechanical ventilation (8% vs 11%) and on pressor support (5% vs 9). Only 10% vs 7% of patients in the ICU, and 8% vs 14% in the ED.  This may actually help us to better extract its applicability to the ED population and what gets brought in via EMS.  It also may be a result of the inclusion/exclusion criteria set up.

2. Enrollment: This was surprisingly low. From 2,362 screened patients to 512 randomized, and 501 ultimately included for analysis. There were a lot of exclusions despite a liberal inclusion criteria and limited exclusion criteria. Large numbers of patients were excluded for not receiving epinephrine, ROSC prior to getting the drug, and a whole series of clinical team dependent factors (forgot about the study/early termination/physician preference/logistics). While the authors claim this did not have an impact on the outcome, it’s hard to imagine it didn’t have any impact on the included cohort or introduced some selection bias.

3. Patient-Oriented Outcome: The endpoint of ROSC is patient-centered, and a prerequisite for a good neurologic function. However, it is not a net benefit to save more people who have a poor quality of life. This is what was demonstrated in the PARAMEDIC2 trial (SGEM#238). There was an increase in survivors with epinephrine for OHCA. Unfortunately, the increase was mainly for patients having severe neurologic impairment was more common among survivors in the epinephrine groups compared to the placebo group (31.0% vs. 17.8%).

4. Cerebral Performance Category (CPC) Score: Speaking of POO. The outcome measure for favorable neurologic outcome was the CPC score. Legend of EM, Dr. Ian Stiell from Ottawa published some data from the classic OPALS trail. They said that while the CPC can be an important outcome tool, it should not be considered a substitute for the Health Utilities Index (Annals EM 2009).

The inter and intra-rater reliability of the CPC score has also been questioned. A cohort study of patients with OHCA reported poor kappa values for classifying favorable vs unfavorable neurologic status at hospital discharge (Ajam et al Scan J Trauma Resusc Emerg Med 2001)

Another study looked about both OHCA and IHCA patients and the interrater reliability of the CPC score. They too found poor kappa values suggesting substantial variability in determining neurologic outcomes (Grossestreuer et al Resuscitation 2016). This could introduce some fuzziness around the CPC point estimate of effect size.

5. Time to Intervention: The time to administering the study drugs seemed to lag behind the administration of epinephrine. Mean time to epinephrine administration was five minutes for both groups, while study drug administration at eight vs nine minutes. Based on the times presented in the paper and ACLS protocols, a subset patients may have received multiple doses of epinephrine prior to receiving the study combination. This is a clinically relevant difference between groups that is not accounted for, and may change our ability to measure a treatment effect.

Comment on Authors’ Conclusion Compared to SGEM Conclusion:  We generally agree with the authors’ conclusions.

SGEM Bottom Line: The routine use of vasopressin and steroids in addition to epinephrine cannot be recommended based on the available evidence in patients with in-hospital cardiac arrests.

Case Resolution: Thinking about the causes of PEA arrest you obtain a stat glucometer reading and find out this man is hypoglycemic. An amp of D50 is given which aborts the arrest. Further blood work is obtained and reported showing he is also mildly acidotic and hyperkalemic. He is moved to a higher level of care in the hospital and the internist takes over his care to address his ongoing glucose, pH and electrolyte management.

Dr. Neil Dasgupta

Clinical Application: We still do not have high-quality, clinically relevant information to support the use of  vasopressin, steroid, and epinephrine (VSE) protocol in patients with IHCA. That does not mean VSE should never be used and it will depend also on the clinicians’ judgment. We are now left with a difficult choice, deciding on which drugs can help us resuscitate someone while preserving their quality of life, and more and more it seems these goals are at odds with each other.

What Do I Tell My Patient?  Hopefully, you’ll say “you probably don’t remember me, and you might not believe me when I tell you this…but you had a cardiac arrest.  It’s very nice to be able to speak with you.”

Keener Kontest: There was no winner last week. The answer we were looking for was Dr. C. Miller Fisher is the Canadian neurologist credited as the founder of modern stroke neurology

Listen to the SGEM podcast for this weeks’ question. If you know, then send an email to thesgem@gmail.com with keener in the subject line. The first correct answer will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.