August EM journal club

“Epinephrine vs Norepinephrine for Cardiogenic Shock after Acute Myocardial Infarction” Levy, et al.

Study question:How does the safety and efficacy of norepinephrine compared to epinephrine when used in patients with cardiogenic shock after acute MI?

Methods:The primary efficacy outcome was change in cardiac index, defined as cardiac output divided by patient body surface area. The primary safety outcome was the occurrence of refractory cardiogenic shock, defined as sustained hypotension, end-organ hypoperfusion, hyperlactatemia, and high doses of vasopressors or inotropes. The study was a double-blinded, randomized, multi-center trial including patients in 9 ICUs in France. To be included in the study, patients must fulfill the following criteria: over 18 years old, cardiogenic shock due to AMI and successfully revascularized by PCI, SBP <90 or MAP <65, cardiac index <2.2, pulmonary artery occlusion pressure >15, EF <40%, evidence of tissue hypoperfusion, and insertion of pulmonary artery catheter.

Results: The study included 57 patients in total. Change in cardiac index was found to be statistically similar between the epinephrine and norepinephrine groups. There was a higher observed rate of refractory cardiogenic shock in the epinephrine treatment group, leading to early termination of the study. Compared to norepinephrine, epinephrine was associated with a higher heart rate, prolonged acidosis, and higher serum lactate levels.

Author’s conclusion: Use of epinephrine in cardiogenic shock secondary to acute MI was associated with a small, transient, insignificant improvement in cardiac index, but also associated with a higher rate of refractory shock.

Discussion:This study uses a specific population, namely, cardiogenic shock in a patient who suffered an acute MI and underwent successful PCI. This limited subset of patients makes the results of this study less generalizable to the management of patients with cardiogenic shock. As a result of the limited study population, this trial is also not sufficiently powered to provide a high level of evidence.

Bottom line:This trial is not sufficiently powered, nor sufficiently generalizable, to change the choice of vasopressors in patients with cardiogenic shock.

“Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits The PRISMS Randomized Clinical Trial”  Khatri, et al.

Study question:Does intravenous alteplase benefit patients with ischemic stroke presenting with minor neurologic deficits that are judged not clearly disabling?

Methods:The trial included 948 patients in a multicenter, randomized, double-blind, double-placebo design. Patients included suffered an acute ischemic stroke with an NIHSS of 0-5, with deficits judged as not clearly disabling, and could initiate treatment within 3 hours were included. The primary outcome was the difference in favorable functional outcome, defined by a modified Rankin score of 0 to 1 at 90 days. The primary safety end point was symptomatic intracranial hemorrhage within 36 hours. Patient were randomized into a group with IV tPA and oral placebo or oral aspirin with IV placebo.

Results:313 of the original 948 patients were included in the analysis. The study was terminated early. There was no significant difference in the adjusted percentage of functional outcome at 90 days in those treated with alteplase versus aspirin.

Discussion:This study has several ethical and logistical limitations. First, the NIH stroke scale greatly favors identification of anterior circulation strokes. Second, administration of tPA is not a benign intervention. The risk of intracranial hemorrhage is a serious consideration before administering tPA that is not adequately addressed in this trial. This paper does not capture the human element of obtaining informed consent for tPA. The risk/benefit analysis of pushing tPA is a personal, individualized decision that depends on many factors including level of disability. Informed consent is a crucial aspect to the decision to push tPA. Lastly, the early termination of this trial does not allow for any definitive conclusions to be drawn. Given the industry sponsorship of this work and what appears to be a trend in harm (ICH) for patients receiving tPA, stopping the trial early makes us wonder if harm from tPA in this population would reach statistical significance if the study was continued.

Bottom line:Management of acute stroke is a complex clinical decision making process, and administration of tPA is multifactorial, taking into account objective findings as well as subjective, ethical factors.

EBM q&a:  This study was originally designed to include 948 patients, but had to be terminated early due to low enrollment and insufficient funding.   How does this decreased enrollment affect the authors’ conclusions? If the expected outcome difference was larger between the two study groups, how would this affect the number of patients needed to be enrolled?

This study was designed to detect a 9% difference in favorable outcome between ASA and tPA groups based on analysis of data from a previous study.  If an insufficient number of patients are enrolled, the study is said to have inadequate power to find the difference.  In this case, and as the authors’ caution, the study lacks power to detect the anticipated difference between treatment groups.  In general, the smaller the anticipated difference between groups, the greater number of subjects that need to be enrolled to find a difference.   Just think how hard it is to find no information on a particular subject.  You need to check many sources to verify nothing is present.

“Postural modification to the standard Valsalva manoeuvre for emergency treatment of supraventricular tachycardias (REVERT): a randomised controlled trial” Appelboam, et al.

Study question: Can a postural modification improve the effectiveness of the Valsalva maneuver for supraventricular tachycardia?

Methods:This was a randomized, controlled, multi-center trial conducted in the UK including 433 patients. Exclusion criteria included age under than 18 years old, systolic blood pressure less than 90, indicated for emergent cardioversion, third trimester pregnancy, or suspected atrial fibrillation or flutter. The primary outcome was return to sinus rhythm 1 minute after intervention.

Results:Each group included 214 patients in an intention to treat analysis. 43% of the patients in the modified Valsalva group achieved normal sinus rhythm, while only 17% of the standard group patients converted to sinus rhythm. No serious adverse events were recorded.

Discussion: Although this trial may not represent the highest class of evidence, the REVERT maneuver is simple to perform and without significant risk to a hemodynamically stable patient. Many clinicians would attempt a vagal maneuver in this population before proceeding to drugs or cardioversion, which are not benign treatments. The data in this trial suggests that the additional postural change may improve the effectiveness of a treatment already in use by many clinicians.

Bottom line:The modified Valsalva is a low-cost, low-risk maneuver in the management of hemodynamically stable SVT.

EBM q&a:  Any study design starts with a research question.  Elements of a research question are: 1. Population (who or what is being studied), 2. Independent variable (the thing the researcher controls), 3. Comparison (fractional benefit or harm usually), and 4. Dependent variable (the outcome of interest).  Identifying each of these elements, write the research question for this study.

For patients presenting to the ED in SVT (1), does modified Valsalva compared to standard Valsalva (2) result in a greater fraction of successful conversions (3) to sinus rhythm (4)? The last sentence in the introduction is typically a statement of the research question, so this is a good place to quickly assess for scientific rigor in any article.