Early this year, two important conferences outside our specialty unveiled a spate of new findings whose impact will be felt in our practice. Here’s a quick rundown of the most interesting trials presented.

Critical Care Reviews 2020

Held this year in Belfast, Northern Ireland, Critical Care Reviews (CCR) brought to first light several important trials relevant to emergency medicine and critical care. One of the most important, the Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock (VITAMINS) trial, was covered in these pages by Jeremy Samuel Faust, MD, MS, MA, FACEP, in February.¹ This trial, one of the first to actually rigorously evaluate a treatment protocol for sepsis featuring thiamine, vitamin C, and corticosteroids, was not able to confirm the hoped-for survival advantage.

A second important trial also has implications for emergency care, the concisely and informatively named “65 trial.”² This trial looks primarily at the enshrined target mean arterial pressure (MAP) of 65 mmHg in patients whose physiology is being supported by vasopressors. Like many things in medicine, this target is based on a combination of observational evidence and opinion, and despite this, it remains a “strong” recommendation in the Surviving Sepsis Campaign (SSC) guidelines.³

The 65 trial was a massive undertaking, with 2,463 patients ultimately included in the primary analysis. In this trial, elderly patients with vasodilatory shock and receiving vasopressors were randomized to either “permissive hypotension” or usual care in line with the SSC guidelines. Permissive hypotension meant patients were targeted to a range between 60 and 65 mmHg rather than titrating care to maintain MAP greater than 65 mmHg.

The topline, unadjusted results demonstrated no significant difference between treatment strategies. Overall mortality at 90 days, the primary outcome, was 41.0 percent in the permissive cohort and 43.8 percent with usual care. This small mortality difference favoring permissive hypotension was insufficient to meet statistical significance, although the prespecified adjusted analysis tipped this finding over the line. It would be erroneous to attribute a reliable mortality advantage to treatment with permissive hypotension, but there is no signal of harm.

These results are not surprising if we realize the MAP is not a measure of blood flow through the capillary bed. We are relying on MAP, the pressure of fluid in those larger muscular arteries and arterioles, as a surrogate for end-organ perfusion. This must be balanced against the potential harmful effects of vasopressors.

Interestingly, the actual treatment received by those in the permissive hypotension arm was not terribly hypotensive. The mean MAP while receiving vasopressors in the permissive arm was still 66.7 mmHg compared to 72.6 mmHg in those receiving usual care. A sizable fraction of those in the trial were treated with metaraminol, a vasopressor with primarily alpha-receptor effects, potentially impacting generalizability to settings where norepinephrine is the preferred first-line agent. However, this study neatly shows you need not exercise vigilance in keeping MAP above 65 mmHg at all times.

Other notable work presented at CCR included a 26,000 patient trial comparing proton pump inhibitors to histamine-2 receptor blockers in ICU patients, cardiac catheterization following out-of-hospital cardiac arrest, and global data on the burden of sepsis.

International Stroke Conference 2020

This year’s International Stroke Conference (ISC) was not in a charming foreign locale but the less-exotic destination of Los Angeles. As of this writing, many of these breaking presentations are available only as slide decks and abstracts pending peer-reviewed full-text publication in scientific journals. These preliminary data represent windows into their likely downstream effects on stroke care.

One of the most notable emerging themes over the last few years is a movement toward use of tenecteplase rather than alteplase in stroke. Tenecteplase is less expensive and is given as a single bolus dose rather than requiring a prolonged infusion. The Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK) Part 2 trial looked specifically at dose response to tenecteplase in achieving recanalization in large vessel strokes.⁴ These authors did not observe a difference in outcomes whether 0.4 mg/kg or 0.25 mg/kg was used, but bleeding was marginally increased by the higher dose. A group from the University of Texas at Austin also presented their initial experience incorporating tenecteplase into practice as their primary thrombolytic. In their limited case series, outcomes and safety appeared consistent with their prior experience with alteplase.

Two studies also looked at outcomes associated with mobile stroke units (MSUs), ambulances equipped with non-contrast CT and the capability of administering thrombolytics and anticoagulant reversal agents in the field. An observational study from Melbourne, Australia, sought to quantify the effect of MSU dispatch on subsequent endovascular intervention.5 As with thrombolytic therapy, stroke unit dispatch expedited downstream stroke care. However, MSU dispatch to 2,348 cases in their first year yielded only 100 cases of prehospital thrombolysis. A similar observational study in Berlin documented increased thrombolysis and improved three-month outcomes associated with MSU care. Similar to the low yield in the Melbourne study, there were more than 14,500 dispatches to yield only 450 cases of thrombolytic administration.

Last, and most interesting, are the first data regarding whether thrombolytics are necessary prior to endovascular therapy in eligible patients. The entire existence of the endovascular industry stems from the utter lack of efficacy for thrombolytics in large vessel occlusion. The Randomized Study of Endovascular Therapy with Versus Without Intravenous Tissue Plasminogen Activator in Acute Stroke with ICA and M1 Occlusion (SKIP) tested the necessity of alteplase administration as a bridge to endovascular therapy and observed neither an advantage nor reliable disadvantage to its use. Intracranial hemorrhage, however, was increased in those who received alteplase prior to endovascular therapy. These data are just the first of multiple trials looking at this question and will add another layer of decision making to the triage of stroke patients in the emergency department.

The opinions expressed herein are solely those of Dr. Radecki and do not necessarily reflect those of his employer or academic affiliates. 

References

1. Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020;323(5):423-431.
2. Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: a randomized clinical trial [published online ahead of print Feb. 12, 2020]. JAMA. doi: 10.1001/jama.2020.0930.
3. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
4. Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of intravenous tenecteplase dose on cerebral reperfusion before thrombectomy in patients with large vessel occlusion ischemic stroke: the EXTEND-IA TNK part 2 randomized clinical trial [published online ahead of print Feb. 20, 2020]. JAMA. doi: 10.1001/jama.2020.1511.
5. Zhao H, Coote S, Easton D, et al. Melbourne mobile stroke unit and reperfusion therapy: greater clinical impact of thrombectomy than thrombolysis. Stroke. 2020;51(3):922-930.