No beat and ‘roids to treat? Corticosteroids in cardiac arrest outcomes

In Medical Concepts by Aida OwliaLeave a Comment

SUMMARY:

The addition of intravenous (IV) corticosteroids to the standard Advanced Cardiovascular Life Support (ACLS) algorithm in the resuscitation of adult patients experiencing non-traumatic cardiac arrest may improve the chances of achieving survival to hospital discharge. These findings are based on a small number of studies with diverse methodology, significant variability in patient population, and poor-quality data. The optimal patient population, corticosteroid agent, dose, timing and duration of administration remains unclear and requires further research. Despite limited data, the potential benefits of corticosteroid administration may outweigh the small risks, and physicians should use their clinical judgment when administering this therapy.

Case Description: 

A 69-year-old male with a history of Chronic Obstructive Pulmonary Disease (COPD) and coronary artery disease (CAD) presents to the emergency department (ED) with shortness of breath. Shortly after arrival, the patient has a cardiac arrest with a non-shockable rhythm on the monitor. In addition to CPR and epinephrine, the physician running the code wonders about any other adjuncts he/she can consider to help improve the odds of Return of Spontaneous Circulation (ROSC) and hospital discharge in this patient.

Search Strategy:

A search of the existing literature was conducted in July 2018 using OVIDMEDLINE and EMBASE databases. Inclusion and exclusion criteria can be found in Table 1.  A total of 169 articles were identified. All articles were initially reviewed by title, and 50 articles were selected for abstract and/or full text review. Of these articles, four were selected for final inclusion based on relevance to the topic in question. 

Table 1: Inclusion and Exclusion Criteria Used for the Literature Review

Study Design and Participants:

The study design, setting, patient population and number of patients enrolled in control and intervention groups for all four studies included in this research project are outlined below (Table 2). Of note, 

  • There was variability among the size of the studies with the number of participants ranging from 36 to 4179 patients. 
  • All four studies were conducted in patients with non-traumatic cardiac arrest, three of which were conducted in patients with in-hospital cardiac arrest (IHCA) and one study investigated patients with out of hospital cardiac arrest (OHCA).
  • None of the studies were conducted in North America. 
  • Of the three studies that were done in patients with IHCA, only one study was based on arrests that happened in the ED; the other two were conducted with patients in a variety of locations within the hospital (i.e. intensive and coronary care units, ED, general wards and operating rooms). 

Table 2: Summary of Study Designs and Participants of Included Studies

Intervention: 

The treatments provided in the control and intervention groups in each study are outlined in Table 3. Specifically,

  • CPR was standard in all studies, both in the intervention and the control groups, and all studies included corticosteroids in the intervention group. 
  • There was significant variability with respect to the IV corticosteroid agents used in each study, though, as well as dosage and duration of administration.  
  • In both studies by Mentzelopoulos et al, the use of corticosteroids was not limited to the initial resuscitation period; the protocol extended the use of corticosteroids up to 7 days post resuscitation. ​1,2​

Table 3: Treatments Provided in Control and Intervention Groups of Included Studies 

Results: 

The primary and secondary outcomes measured in all four studies are outlined in Table 4. For the purposes of this review, the main outcomes of interest were: 1) ROSC and 2) survival to hospital discharge. The main findings were as follows:

  • The study by Tsai et al. conducted in Taiwan, was a non-randomized clinical trial that demonstrated that the use of hydrocortisone (solu-cortef 100 mg IV) improved ROSC (61% vs 39%, p=0.04).​3​ However, the study demonstrated no difference in survival to hospital discharge. In addition, the authors did not find any significant differences in survival rates or neurological outcomes at one and seven days between the two groups (8% vs. 10%, p=0.81). The authors proposed that ROSC is more likely if corticosteroids are given within 22 minutes after a witnessed collapse or within 6 minutes of arrival in the ED. 
  • Mentzelopoulos et al. studied a multi-agent protocol (Table 3). ​1,2​ Patients in the intervention group had significantly higher rates of survival to hospital discharge (19% vs 4% p=0.02).​1​ Mentzelopoulos et al. showed that a corticosteroid inclusive protocol resulted in improved ROSC (83.9% vs 65.9%, p<0.01) and survival to hospital discharge (13.9% vs 5.1%, p=0.02) with favorable neurological outcomes.​2​
  • The additional study conducted by Tsai et al. was a larger retrospective cohort study (review of insurance data) in adult non-traumatic cardiac arrest patients that took place in the ED.​4​ Here, the authors showed that the use of one of several corticosteroids in combination with CPR compared with CPR alone resulted in higher admission rates to hospital (38.3% vs 18.7%, p<0.0001) and improved survival to hospital discharge (14.5% vs 5.6% p<0.0001). However, the study does not comment on neurological outcomes among patients with survival to hospital discharge. The authors suggested that patients with COPD, asthma and non-shockable cardiac rhythms were most likely to benefit from corticosteroid administration during cardiac arrest and this benefit remained after matching for corticosteroid use in the past year.​4​

Each of the identified studies has several limitations: 

  • None of the included studies were performed in North American or Canadian populations which may limit the generalizability of results. The primary cause of cardiac arrest in Greek or Taiwanese populations may differ from North American populations, although this is unlikely. 
  • The biggest limitation of the study by Tsai et al.​3​ is the high risk of methodological bias as there was no randomization or blinding of study participants. Given this, the results of the study should be interpreted with caution. 
  • The second paper by Tsai et al.​4​ was an observational study design by the same investigators of the 2007 study. Although these studies were of different design, using the same group of investigators may limit the validity of results.  Given the non-blinded nature of the studies, it is possible that inherent cognitive biases of the investigators may have been carried forward from one study to another. Independent verification of observed study results is warranted.  
  • Due to the retrospective nature of the Tsai et al.​4​ study, the authors presented results of an association between the use of corticosteroids and survival to hospital discharge without adjusting for possible differences in post-resuscitative care which may have biased the observed results. By using information from an insurance database, the study is limited by the amount and accuracy of data collected and available in the insurance records. 
  • The papers by Mentzelopoulos et al.​1,2​ were conducted by the same investigators using very similar protocols. In the 2013 paper, the groups did differ at baseline in the cause of cardiac arrest (respiratory vs cardiac ischemia), which may have influenced the outcome.​2​ The most important limitation of these studies is the use of three interventions in the treatment group. Using a treatment cocktail rather than a single agent means the effect of corticosteroids alone and/or beneficial interactions between the agents within the treatment cocktail are impossible to determine.

Table 4: Summary of the Outcome Measures in Included Studies

Discussion: 

Cardiac arrest is a common presentation in the ED with high morbidity and mortality. Despite advances in cardiopulmonary resuscitation, morbidity and mortality rates remain high.​5​ Currently there is much debate on the short- and long-term benefits of many pharmacological agents used during cardiac arrest resuscitations. The role of epinephrine, which has been the pillar of pharmacological management in cardiac arrest resuscitation, has been questioned in recent literature.​6​ Identifying pharmaceutical agents that improve outcomes in patients with cardiac arrest is paramount to improving our management of this prognostically poor condition. From a pathophysiological standpoint, cardiac arrest is believed to cause a systemic inflammatory response with an increase in serum inflammatory cytokines, activation of apoptosis pathways, and reduction of levels of cortisol, leading to a global ischemia-reperfusion injury.​7​ Glucosteroid supplementation during CPR may be beneficial in improving outcomes by mitigating this state.​8​

The number of clinical studies investigating the role of corticosteroids in improving the outcomes of cardiac arrest are limited and heterogeneous in terms of their design, agents used and patient populations. This makes drawing conclusions across the totality of evidence difficult. The study by Tsai and colleagues​3​ was the only study that evaluated differences in CPR duration between the control and intervention groups. This is a potentially significant confounding variable affecting the hypothalamic-pituitary-adrenal (HPA) axis. Lindner et al. noted that there is a negative correlation between serum cortisol levels and the time from collapse to the start of CPR.​9​ It can be argued that the periods of no flow in delayed or ineffective CPR is what affects the HPA axis and accounts for the outcomes reported in these studies. The study by Tsai et al. does not allow for the analysis of “meaningful” survival given that neurological outcomes of survivors are not commented on.​4​ Furthermore, the variety of corticosteroid agents used in the intervention group makes it difficult to draw conclusions on the optimal agent or dose for use in non-traumatic cardiac arrest patients. There are also concerns with the design of the studies by Mentzelopoulos et al. which makes it difficult to analyze the role of corticosteroids. It is not possible to draw conclusions about the role of corticosteroids alone in improving cardiac arrest outcomes as the synergistic effects with other agents used in the intervention group may account for the study findings. Although a previous study had shown no benefit with vasopressin in resuscitation,​10​ it remains possible that the synergistic interaction of vasopressin and corticosteroids accounts for better outcomes in the intervention group. The other main issue with this study is the use of corticosteroids for one week post-resuscitation which raises the possibility that the use of corticosteroids in the post-resuscitative period drives the improved survival to hospital discharge data and therefore the role of corticosteroids in the initial resuscitation period remains unclear. This differentiation has significant implications for change of practice among Emergency Medicine physicians.

Future Directions:

More research is needed in this area before any definite conclusions can be drawn with confidence. Specifically, the corticosteroid agent of choice, optimal dose, time of administration of corticosteroids relative to the onset of cardiac arrest, and the effect of corticosteroid treatment post-arrest requires further study.  If other agents are used with corticosteroids in treatment groups, increased sample sizes are needed to evaluate the benefit of each agent on the outcome of interest and assess potential synergistic effects. It is also pertinent that quality and duration of CPR and any delays from cardiac collapse to initiation of CPR are reported in any future studies. Of note, the latest guidelines by the American Heart Association / American College of Cardiology and European Resuscitation Council do not recommend the routine use of corticosteroids during cardiac resuscitation. The studies to date are worthy of consideration but are not practice changing.  However, given the high mortality and paucity of effective pharmaceutical agents in cardiac arrest, further studies are warranted. 

Case Conclusion:

For the patient with a history of COPD who presents in cardiac arrest with a non-shockable rhythm a dose of IV corticosteroids should be considered early in the course of resuscitation as an adjunct to ACLS management to help improve ROSC and hospital discharge outcomes.

Important Key points:

  • Limited data on IV corticosteroids in cardiac arrest with few RCTs to date. Additional RCTs are needed to draw definitive treatment recommendations.
  • There is uncertainty around which steroid formulation is best and what dose provides optimal benefit.
  • The potential benefits of IV corticosteroids may exceed limited harms and warrant consideration in cardiac arrest.  Specifically, consider IV corticosteroids early (within 6 minutes of arrival in the ED) and as an adjunct agent in cardiac arrest particularly in patients with COPD, asthma and non-shockable cardiac rhythms.

References

  1. 1.
    Mentzelopoulos S, Zakynthinos S, Tzoufi M, et al. Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest. Arch Intern Med. 2009;169(1):15-24. doi:10.1001/archinternmed.2008.509
  2. 2.
    Mentzelopoulos S, 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. doi:10.1001/jama.2013.7832
  3. 3.
    Tsai M, Huang C, Chang W, et al. The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a pilot study. Am J Emerg Med. 2007;25(3):318-325. doi:10.1016/j.ajem.2006.12.007
  4. 4.
    Tsai M, Chuang P, Yu P, et al. Glucocorticoid use during cardiopulmonary resuscitation may be beneficial for cardiac arrest. Int J Cardiol. 2016;222:629-635. doi:10.1016/j.ijcard.2016.08.017
  5. 5.
    Ko P, Ma M, Yen Z, Shih C, Chen W, Lin F. Impact of community-wide deployment of biphasic waveform automated external defibrillators on out-of-hospital cardiac arrest in Taipei. Resuscitation. 2004;63(2):167-174. doi:10.1016/j.resuscitation.2004.04.002
  6. 6.
    Perkins G, Ji C, Deakin C, et al. A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):711-721. doi:10.1056/NEJMoa1806842
  7. 7.
    Adrie C, Laurent I, Monchi M, Cariou A, Dhainaou J, Spaulding C. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care. 2004;10(3):208-212. doi:10.1097/01.ccx.0000126090.06275.fe
  8. 8.
    Kornberger E, Prengel A, Krismer A, et al. Vasopressin-mediated adrenocorticotropin release increases plasma cortisol concentrations during cardiopulmonary resuscitation. Crit Care Med. 2000;28(10):3517-3521. doi:10.1097/00003246-200010000-00028
  9. 9.
    Lindner K, Strohmenger H, Ensinger H, Hetzel W, Ahnefeld F, Georgieff M. Stress hormone response during and after cardiopulmonary resuscitation. Anesthesiology. 1992;77(4):662-668. doi:10.1097/00000542-199210000-00008
  10. 10.
    Gueugniaud P, David J, Chanzy E, et al. Vasopressin and epinephrine vs. epinephrine alone in cardiopulmonary resuscitation. N Engl J Med. 2008;359(1):21-30. doi:10.1056/NEJMoa0706873

This post was copyedited by Kim Vella.

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Aida Owlia

Aida Owlia

Dr. Aida Owlia is an Emergency Medicine physician in Toronto, Ontario. Her interests include mentorship, medical education, leadership and physician wellness. She is a recent graduate of the CCFP-EM program from Queen’s University.
Chris Mykytyshyn

Chris Mykytyshyn

Dr. Chris Mykytyshyn is a Family Physician practicing out of the Ottawa area. He completed his medical degree at the University of Western Ontario and his residency in Family Medicine at the University of Ottawa. He currently manages his own family practice, with additional roles as emergency physician and hospitalist physician. He maintains an ongoing interest in the unique challenges of emergency care in rural practice.
Chris Mykytyshyn

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Melanie Walker

Melanie Walker

Dr. Melanie Walker is a Research Scientist and the Resident Research Director in the Department of Emergency Medicine at Queen's University.
Karen Graham

Karen Graham

Dr. Karen Graham is an Emergency Medicine physician and Associate Medical Director at the Kingston Health Sciences Centre in Kington, Ontario.